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WO2025172474A1 - Inhibitors of myeloperoxidase - Google Patents

Inhibitors of myeloperoxidase

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Publication number
WO2025172474A1
WO2025172474A1 PCT/EP2025/053911 EP2025053911W WO2025172474A1 WO 2025172474 A1 WO2025172474 A1 WO 2025172474A1 EP 2025053911 W EP2025053911 W EP 2025053911W WO 2025172474 A1 WO2025172474 A1 WO 2025172474A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
crystalline compound
diseases
mpo
crystalline
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.)
Pending
Application number
PCT/EP2025/053911
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French (fr)
Inventor
Okky Dwichandra PUTRA
Tord Bertil Inghardt
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.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2025172474A1 publication Critical patent/WO2025172474A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to crystalline forms of a myeloperoxidase inhibitor, and the use of such forms.
  • MPO catalyses two electron oxidation of halides (primarily chloride) and pseudohalides (like thiocyanate), forming the microbicidal hypohalous acids hypochlorous acid (bleach) and hypothiocyanous acid. These can, in turn, act on a broad number of protein, lipid and nucleic acid targets, causing dysfunction and further inflammation (Davies 2020).
  • MPO catalyses one electron oxidation of numerous electron-rich substrates through the so-called peroxidation cycle, yielding free radicals that are harmful in themselves (e.g. urate radicals (Stamp 2014)) or that may interfere with physiological functions driven by nitric oxide (NO), either by direct oxidation of NO, or by generation of free radicals oxidizing NO (Davies 2020).
  • MPO contributes to the different disease conditions may vary depending on condition, although some mechanisms may be of importance in several of these conditions.
  • MPO-derived reactive oxygen species such as hypochlorous acid (Davies 2020)
  • MPO also appears to play a regulatory role in inflammation that serves to amplify the inflammatory response by activation of neutrophils (Lau 2005) and via activation of proteinases that cleave latent forms into active effector proteins, e.g. cytokines (Ra 2007).
  • the mechanistic association between MPO and fibrosis is possibly also multifactorial, e.g.
  • W02007/142576 disclose thioxantine derivatives and the use thereof as MPO inhibitors in therapy.
  • W02006/062465 and W02007/142577 disclose 2-thioxo-1 ,2,3,4-tetrahydro-pyrrolo[3,2- d]pyrimidin-4-one derivatives claimed to be inhibitors of MPO. It is stated that the compounds may show selectivity against related enzymes such as TPO.
  • WO2016/087338 discloses thioxopyrrolopyrimidone derivatives stated to be MPO inhibitors.
  • novel MPO inhibitors useful in therapy.
  • novel MPO inhibitors having improved selectivity for the MPO enzyme over the TPO enzyme, as well as MPO inhibitors having suitable pharmacological properties.
  • a pharmaceutical composition comprising crystalline 2- thioxo-1 -((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4H-pyrrolo[3,2-c(
  • MPO myeloperoxidase
  • MPO myeloperoxidase
  • a method of treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO) comprising administering to a subject in need thereof crystalline 2- thioxo-1 -((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4A7-pyrrolo[3,2-c(
  • MPO myeloperoxidase
  • a method of treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO) comprising administering to a subject in need thereof crystalline 2- thioxo-1 -((2-((2/ z ?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4H-pyrrolo[3,2-cf
  • MPO myeloperoxidase
  • MPO myeloperoxidase
  • MPO myeloperoxidase
  • Figure 1 illustrates the powder X-ray diffraction diagram of compound 1 in form A.
  • FIG. 1 illustrates the thermogravimetric analysis (TGA) trace of compound 1 in form A.
  • FIG. 3 illustrates the differential scanning calorimetry (DSC) trace of compound 1 in form A.
  • Figure 4 illustrates the powder X-ray diffraction diagram of compound 1 dihydrate in form B.
  • FIG. 5 illustrates the thermogravimetric analysis (TGA) trace of compound 1 dihydrate in form B.
  • FIG. 6 illustrates the differential scanning calorimetry (DSC) trace of compound 1 dihydrate in form B.
  • Form A is most thermodynamically stable anhydrous phase of compound 1 , and has a solubility profile suitable for further development.
  • Dihydrate Form B is the most stable hydrated from of compound 1 , and shows stability in an aqueous environment, such as suspension.
  • compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20 ⁇ O.2° at 18.7°.
  • compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20 ⁇ O.2° at 25.1 °.
  • compound 1 form A has a XRPD pattern comprising at least two peaks expressed as 20 ⁇ O.2° at 18.7° and 25.1°. In some embodiments, compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20° at about 18.7°.
  • compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20° at about 25.1°.
  • compound 1 form A has a XRPD pattern comprising at least two peaks expressed as 20° at about 18.7° and 25.1°. In some embodiments, compound 1 form A has a XRPD pattern comprising the following five peaks expressed as 20 ⁇ O.2°:
  • compound 1 form A has a XRPD pattern comprising five peaks at about the following 20° values:
  • compound 1 form A has a XRPD pattern comprising the following ten peaks expressed as 20 ⁇ O.2°:
  • compound 1 form A has a XRPD pattern comprising ten peaks at about the following 20° values:
  • compound 1 form A has a XRPD pattern substantially similar to Figure 1.
  • the above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu K a radiation. In some embodiments, the measurements take place at room temperature, such as 20°C.
  • compound 1 form A has a TGA thermogram exhibiting a mass loss of less than 0.1% upon heating from about 25°C to 110°C. In some embodiments, compound 1 form A has a TGA thermogram substantially similar to Figure 2.
  • compound 1 form A has a DSC trace comprising a melting endotherm onset of about 260°C. In some embodiments, compound 1 form A has a DSC trace with a heat enthalpy of about 102 J/g for the melting endotherm. In some embodiments, compound 1 form A has a DSC trace substantially similar to Figure 3.
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20 ⁇ O.2° at 19.3°.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20 ⁇ O.2° at 23.9°.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least two peaks expressed as 20 ⁇ O.2° at 19.3° and 23.9°.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20° at about 19.3°.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20° at about 23.9°.
  • compound 1 dihydrate form B has a XRPD pattern comprising at least two peaks expressed as 20° at about 19.3° and 23.9°.
  • compound 1 dihydrate form B has a XRPD pattern comprising the following five peaks expressed as 20 ⁇ O.2°:
  • compound 1 dihydrate form B has a XRPD pattern comprising five peaks at about the following 20° values: 23.9
  • compound 1 dihydrate form B has a XRPD pattern comprising the following ten peaks expressed as 20 ⁇ O.2°: In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising ten peaks at about the following 20° values:
  • compound 1 dihydrate form B has a XRPD pattern substantially similar to Figure 4.
  • compound 1 dihydrate form B has a TGA thermogram exhibiting a mass loss of about 7.95% upon heating from about 25°C to 110°C, corresponding to water loss.
  • compound 1 dihydrate form B has a TGA thermogram substantially similar to Figure 5.
  • compound 1 dihydrate form B has a DSC trace comprising:
  • compound 1 dihydrate form B has a DSC trace with:
  • compound 1 dihydrate form B has a DSC trace substantially similar to Figure 6.
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
  • the crystalline compounds disclosed herein are useful because they possess pharmacological activity as inhibitors of the enzyme MPO.
  • the disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, which are responsive to inhibition of MPO.
  • diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic
  • the disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, in which microvascular dysfunction is prominent.
  • the disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, which are responsive to inhibition of MPO.
  • diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response.
  • diseases and conditions include, but are not limited to Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy.
  • the disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neutrophilic driven diseases and conditions in mammals, including humans.
  • diseases and conditions include, but are not limited to chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
  • the disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, which are responsive to inhibition of MPO.
  • diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic
  • cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halt
  • the disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, which are responsive to inhibition of MPO.
  • diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response.
  • diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage.
  • the disclosed crystalline compounds are indicated for use in the treatment of cancer.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening or identified through specific biomarker pattern to be particularly susceptible to developing the disease or condition.
  • the dosage administered will, of course, vary with the crystalline compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the crystalline compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.
  • crystalline compounds disclosed herein may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition which comprises a crystalline compound disclosed herein, and at least one pharmaceutically acceptable excipient.
  • Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2 nd Ed. 2002.
  • a crystalline compound disclosed herein for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
  • a crystalline compound disclosed herein for use in the prevention or treatment of one or more conditions or diseases with an inflammatory component wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in therapy, especially in the prevention or treatment of one or more cardiovascular diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of one or more neurological diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in therapy, especially in the prevention or treatment of one or more neutrophilic driven diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cyto
  • a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, in a mammal, particularly a human.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic
  • a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, in a mammal, particularly a human.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy,
  • a crystalline compound disclosed herein for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
  • diseases with a neuroinflammatory response such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of one or more neutrophilic driven diseases, such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human.
  • neutrophilic driven diseases such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cyto
  • a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma,
  • cardiovascular diseases or conditions
  • a crystalline compound disclosed herein for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and /or subarachnoid haemorrhage, in a mammal, particularly a human.
  • diseases with a neuroinflammatory response such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and /or subarachnoid haemorrhage, in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the treatment of cancer in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of heart failure in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.
  • CKD chronic kidney disease
  • a crystalline compound disclosed herein for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.
  • NASH non-alcoholic steatohepatitis
  • a crystalline compound disclosed herein for use in the prevention or treatment of arrhythmia in a mammal, particularly a human. In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.
  • COPD chronic obstructive pulmonary disease
  • a crystalline compound disclosed herein for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of acute kidney injury (AKI), in a mammal, particularly a human.
  • AKI acute kidney injury
  • a crystalline compound disclosed herein for use in the prevention or treatment of non-cystic fibrosis bronchiectasis (NCFB), in a mammal, particularly a human.
  • NCFB non-cystic fibrosis bronchiectasis
  • a crystalline compound disclosed herein for use in the prevention or treatment of bronchiectasis), in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, in a mammal, particularly a human.
  • ANCA anti-neutrophilic cytoplasmic autoantibody
  • a crystalline compound disclosed herein for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of nephritis in a mammal, particularly a human.
  • a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.
  • IBD inflammatory bowel disease
  • a crystalline compound disclosed herein for use in the prevention or treatment of irritable bowel syndrome (IBS), in a mammal, particularly a human.
  • a method of treating, preventing, or reducing the risk of, one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more neutrophilic driven diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasm
  • an inflammatory component such
  • a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction
  • a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HF
  • a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions such as but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more neutrophilic driven diseases or conditions such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasm
  • an inflammatory component such
  • a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atherom
  • cardiovascular diseases or conditions such
  • a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions such as but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • diseases with a neuroinflammatory response such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage
  • a method of treating cancer which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of coronary artery disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of acute coronary syndrome which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of heart failure which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of heart failure with reduced ejection fraction which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of heart failure with preserved ejection fraction which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • CKD chronic kidney disease
  • a method of treating, preventing, or reducing the risk of cardiorenal syndrome which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • NASH non-alcoholic steatohepatitis
  • a method of treating, preventing, or reducing the risk of arrhythmia which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • COPD chronic obstructive pulmonary disease
  • a method of treating, preventing, or reducing the risk of sickle cell disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • ANCA anti-neutrophilic cytoplasmic autoantibody
  • a method of treating, preventing, or reducing the risk of acute kidney injury which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • NCFB non-cystic fibrosis bronchiectasis
  • a method of treating, preventing, or reducing the risk of bronchiectasis which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of Alzheimer's disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of Parkinson's disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of nephritis which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of inflammatory bowel disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a method of treating, preventing, or reducing the risk of irritable bowel syndrome which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable or beneficial.
  • MPO myeloperoxidase
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and/or chemotherapy-induced cardiotoxicity.
  • HFrEF heart failure with reduced ejection fraction
  • HFpEF heart failure with preserved ejection fraction
  • arrhythmia cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH),
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and /or epilepsy.
  • MS multiple sclerosis
  • MSA multiple system atrophy
  • ALS amyotrophic lateral sclerosis
  • epilepsy a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and /or epilepsy.
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • IPF idiopathic pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (HFrEF), heart failure
  • a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage.
  • MS multiple sclerosis
  • MSA multiple system atrophy
  • ALS amyotrophic lateral sclerosis
  • epilepsy acute ischemic stroke
  • subarachnoid hemorrhage subarachnoid hemorrhage
  • a crystalline compound disclosed herein for use in the manufacture of a medicament for use in the treatment of cancer.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a crystalline compound disclosed herein and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in in the prevention or treatment of one or more conditions or diseases with an inflammatory component wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more cardiovascular diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of one or more neurological diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more neutrophilic driven diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn’s disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis
  • an inflammatory component
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HfrEF), heart failure with preserved ejection fraction (HfpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity in a mammal, particularly a human.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HfrEF), heart failure
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity in a mammal, particularly a human.
  • cardiovascular diseases or conditions such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
  • diseases with a neuroinflammatory response such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of one or more neutrophilic driven diseases, such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human.
  • neutrophilic driven diseases such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver steatosis,
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, at
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage in a mammal, particularly a human.
  • diseases with a neuroinflammatory response such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment of cancer, in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.
  • CKD chronic kidney disease
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.
  • CRS cardiorenal syndrome
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.
  • NASH non-alcoholic steatohepatitis
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of arrhythmia in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.
  • COPD chronic obstructive pulmonary disease
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, in a mammal, particularly a human.
  • ANCA anti-neutrophilic cytoplasmic autoantibody
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of nephritis in a mammal, particularly a human.
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.
  • IBD inflammatory bowel disease
  • a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of irritable bowel syndrome (IBS), in a mammal, particularly a human.
  • IBS irritable bowel syndrome
  • plasma urate levels may be used as a stratifying tool and a pharmacodynamic biomarker for MPO inhibitor treatment with a crystalline compound disclosed herein.
  • a method of identifying patients suitable for MPO inhibitor treatment with a crystalline compound disclosed herein encompassing the measurement of plasma urate levels.
  • predictive biomarkers i.e. features or variables reflecting an involvement of MPO in disease pathology
  • biomarkers include, but are not limited to, biomarkers of neutrophil activation (MPO, NGAL, sTNFRI , sTNFR2, calprotectin, UPAR, blood neutrophil counts or percentages, blood neutrophil/lymphocyte ratio), other inflammatory prognostic biomarkers (GDF15, FGF23, STRAIL-R2), biomarkers of systemic inflammation (IL6, C-reactive protein or other acute phase proteins), biomarkers of increased purine catabolism (urate) and purine oxidation (allantoin), biomarkers of iron deficiency (transferrin saturation, ferritin, hemoglobin), biomarkers of extracellular matrix remodeling (MMP7, TIMP4, osteopontin), biomarkers of renal dysfunction (e
  • the crystalline compounds disclosed herein also display a promising pharmacological profile by separating desired and undesired effects in vivo.
  • the crystalline compounds disclosed herein are believed to be useful in the prevention or treatment of various conditions wherein the modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable or beneficial, including, but not limited to, diseases with inflammatory, cardiovascular, and/or neurological components, as well as neutrophilic driven diseases.
  • MPO myeloperoxidase
  • treatment includes therapeutic and/or prophylactic treatment.
  • a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse.
  • the crystalline compounds described herein have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art.
  • the crystalline compounds disclosed herein may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • a combination therapy wherein a crystalline compound disclosed herein, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above.
  • a combination may be used in combination with one or more further active ingredients.
  • crystalline compounds described herein may be of use in treating cardiovascular, metabolic and renal disease in combination with agents that are:
  • Examples of the above include, but are not restricted to, digitalis glycosides, anti-arrhythmics, calcium channel antagonists, ACE inhibitors, angiotensin receptor blockers (e.g. Valsartan), endothelin receptor blockers, p-blockers, thiazide diuretics, loop diuretics, cholesterol synthesis inhibitors such as statins (e.g.
  • Rosuvastatin cholesterol absorption inhibitors, cholesterylester transfer protein (CETP) inhibitors, anti-diabetic drugs such as insulin and analogues, GLP-1 analogues, sulphonamides, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, and anti-inflammatory drugs such as NSAID’s and CCR2 antagonists, anti-coagulants such as heparins, thrombin inhibitors and inhibitors of factor Xa, platelet aggregation inhibitors, P2X7 antagonists and neprilysin inhibitors (e.g. Sacubitril).
  • CETP cholesterylester transfer protein
  • the crystalline compounds disclosed herein, and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately.
  • the particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • a method of treatment of a condition where inhibition of MPO is required comprises administration of a therapeutically effective amount of a crystalline compound disclosed herein to a person suffering from, or susceptible to, such a condition.
  • the optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art.
  • reactions refer to being degassed or purged
  • this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g));
  • Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported
  • X-ray powder diffraction data was measured with Corundum as an internal reference.
  • the X-ray powder diffraction (referred to herein as XRPD) pattern was determined by mounting a sample on a zero-background holder single silicon crystal and spreading out the sample into a thin layer.
  • the powder X-ray diffraction was recorded with a theta-two theta scan axis and in one dimensional scan with Rigaku Miniflex 600 (wavelength of X-rays 1.5418 A nickel-filtered Cu K a radiation, 40 kV, 15 mA) equipped with D/Tex Ultra detector. Automatic variable anti scattering slits were used, and the samples were rotated at 30 revolution per minute during measurement. Samples were scanned from 3 - 50° 2-theta using a 0.01° and 1 min step width and scan speed respectively.
  • the relative intensities are derived from diffractograms measured with fixed slits It is known that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore, it should be understood that the crystalline forms disclosed herein are not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns shown in the Figures. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of X-ray powder diffraction patterns.
  • TGA and DSC measurements were performed using a TG Discovery 550 (TA instruments, Germany) and DSC Discovery 2500 (TA instruments, Germany), respectively. Approximately 10 mg for TGA and 2-3 mg of the sample for DSC were weighed into an aluminum pan. The samples were then heated from room temperature to 350°C for TGA and from -50°C to 270°C for DSC, with a heating rate of 10°C/min under a nitrogen purge of 100 mL/min. An empty aluminum pan was used as a reference for DSC. Open and closed pans were used for TGA and DSC measurements, respectively.
  • a 50 L jacketed reactor equipped with mechanical stirrer was charged with 11 under N 2 flow.
  • Toluene was added to the organic phase and the solvent was reduced under vacuum to circa 5 vols. This step was repeated.
  • the jacket temperature was adjusted to 20°C and AcOH (3 equiv.) was charged under N 2 flow, followed by portion-wise addition of NaBH(OAc)3 (3.0 eq.) at 20°C.
  • the reaction mixture was stirred at 20°C for 1 h.
  • K2CO3 aqueous solution (10 w/w%, 7.5 vols) was charged to the reactor and the biphasic mixture was stirred at 20°C for 1 h. The organic phase was separated and concentrated under reduced pressure to circa 3 vols at 45°C.
  • EtOH (1 .5 vols) was charged to the reactor and the mixture was concentrated to circa 3 vols at 45°C under reduced pressure.
  • the jacket temperature was adjusted to 30°C and 0.1% seeds were charged to the reaction mixture under nitrogen flow.
  • the solution was stirred at 30°C for 1 h.
  • the jacket temperature was adjusted to 20°C and n-heptane (15 vols) was charged to the reactor under N 2 flow. The temperature was decreased to 5°C and the reaction mixture was stirred at this temperature for 0.5 h, filtered and the cake was washed with n-heptane (1 .5 vols). The wet cake was dried at 45°C for 16 h under vacuum.
  • the jacket temperature was set to 40°C and n-heptane (circa 3 vols) was charged under N 2 flow at 40°C over 20 min, then the temperature was lowered to 20°C over 2 h and the mixture was stirred at this temperature for 1 h.
  • the suspension was filtered and washed with methyl tert-butyl ether (1 vol) and the wet cake was dried for 38 h at 45°C under vacuum.
  • H 2 SO 4 aqueous solution (2 M, 10 vols) was charged into the reactor equipped with mechanical stirrer. The jacket was set to 70°C and I5 was charged portion-wise under N 2 flow. The mixture was stirred for 1 h at 70°C. NH 3 .H 2 O solution (25 w/w%, 5 vols) was charged into the vessel at 70°C and stirred for 30 min. The temperature was decreased to 20°C and the suspension was filtered. The cake was triturated in 4 vols water at 20°C for 1 h, then filtered and washed with water (1 vol). The wet cake was dried for 44 h at 50°C under vacuum and for additional 24 h at 55°C.
  • the experiments were performed in phosphate-buffered saline (PBS), pH7.4.
  • PBS phosphate-buffered saline
  • a 10 mM luminol (A4695, Sigma Aldrich, St Louis, MO, USA) stock was prepared in distilled water and further diluted in PBS to a final concentration of 100 pM.
  • H 2 O 2 was prepared as 1 mM stock in PBS, yielding a final concentration of 50 pM after addition into the assay.
  • Compound 1 was serially diluted in DMSO in a separate plate as a 100x stock solution, and MPO (purified from HL60 cells) and TPO (produced in insect cells, RSR Ltd, Cambridge, UK), were diluted to yield a final concentration of approximately 14 and 150 ng/mL, generating 5600 and 9300 light counts per seconds (LCPS) upon incubation with luminol.
  • MPO purified from HL60 cells
  • TPO produced in insect cells, RSR Ltd, Cambridge, UK
  • the experiment was run by pipetting 2 pL 100x stock solution of the compound and 200 pL diluted enzyme in PBS into wells in a 96-well Optiplate (6005290, Perkin Elmer /Thermo Fischer, Waltham, MS, USA), followed by addition of 10 pL H2O2 containing PBS.
  • Chemiluminescence measurement (Perkin Elmer Wallac Microbeta Trilux 1450-029 (12- detector), Turkuu, Finland) was started directly and recorded after 2, 10 and 15 minutes. Chemiluminescence recorded after 15 minutes was used to calculate the IC50 values.
  • IC50 values (MPO and TPO) for the compound 1 are:
  • Compound 1 form A has a TGA thermogram as shown in Figure 2. This TGA thermogram exhibits a mass loss of less than 0.1% upon heating from about 25°C to 110°C.
  • Compound 1 form A has a DSC trace as shown in Figure 3.
  • the DSC trace shows a heat enthalpy of about 102 J/g for the melting endotherm.
  • the thermal stability of compound 1 Form A was investigated by incubating solid samples at 115 and 130°C for 1 week in closed vials. Upon completion of the incubation time, the solids were analyzed by HR-XRPD and UPLC. Both solids showed a chemical purity of 100.0%. In both cases, no changes in the solid phase were detected. Compound 1 Form A was recovered unchanged.
  • the thermal stability of the compound 1 Form A was evaluated in EtOH, ACN and acetone. Solutions ( ⁇ 0.4 mg/mL) were prepared in these solvents and split over 3 vials. The solutions were incubated at RT, 50 and 80°C for one hour and then analyzed by UPLC-MS.
  • Compound 1 Form A (500 mg) was slurried in 2mL Acetone: Water (50:50) mixture for 3 days at RT. The solid material then was filtered. The liquid phase was separated and then left for slow evaporation aiming for single crystal growth.
  • Compound 1 dihydrate form B has a TGA thermogram as shown in Figure 5. This TGA thermogram exhibits a mass loss of about 7.95% upon heating from about 25°C to 110°C, corresponding to water loss.
  • Compound 1 dihydrate form B has a DSC trace as shown in Figure 6.
  • the DSC trace shows
  • Compound 1 dihydrate form B has a DSC trace with:
  • Compound 1 dihydrate Form B is physically stable upon storage at 40°C/75% RH for two days.
  • Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20 ⁇ O.2° at 18.7°.
  • Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20 ⁇ O.2° at 25.1 °.
  • Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 20 ⁇ O.2° at 18.7° and 25.1 °.
  • Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20 ⁇ O.2°: 16.1 , 18.7, 20.4, 23.8 and 25.1.
  • Crystalline compound 1 form A according to statement 1 characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20 ⁇ O.2°: 13.2, 13.7, 16.1 , 16.4, 18.7, 19.0, 20.4, 22.9, 23.8 and 25.1.
  • Crystalline compound 1 form A according to statement 1 , wherein the X-ray powder diffraction pattern is substantially similar to Figure 1 .
  • Crystalline compound 1 form A according to any one of statements 1 to 7, having a TGA thermogram exhibiting a mass loss of less than 0.1 % upon heating from about 25°C to 110°C.
  • Crystalline compound 1 form A according to any one of statements 1 to 7, having a TGA thermogram substantially similar to Figure 2.
  • Crystalline compound 1 form A according to any one of statements 1 to 9, having a DSC trace comprising a melting endotherm onset of about 260°C.
  • Crystalline compound 1 form A according to any one of statements 1 to 9, having a DSC trace substantially similar to Figure 3.
  • Crystalline compound 1 dihydrate form B according to statement 12 characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20 ⁇ O.2° at 19.3°.
  • Crystalline compound 1 dihydrate form B according to statement 12 characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20 ⁇ O.2° at 23.9°.
  • Crystalline compound 1 dihydrate form B characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 20 ⁇ O.2° at 19.3° and 23.9°.
  • Crystalline compound 1 dihydrate form B characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20 ⁇ O.2°: 14.7, 16.0, 19.3, 22.2 and 23.9.
  • Crystalline compound 1 dihydrate form B characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20 ⁇ O.2°: 12.0, 14.7, 16.0, 19.3, 19.7, 22.2, 22.6, 23.9, 26.3 and 29.4.
  • Crystalline compound 1 dihydrate form B according to any one of statements 12 to
  • Crystalline compound 1 dihydrate form B according to any one of statements 12 to 18, having a TGA thermogram substantially similar to Figure 5.
  • Crystalline compound 1 dihydrate form B according to any one of statements 12 to
  • a pharmaceutical composition comprising crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vascu
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
  • MPO myeloperoxidase
  • MPO myeloperoxidase
  • a method of treating, preventing, or reducing the risk of, one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound 1 form A according to any one of statements 1 to 11 or a crystalline compound 1 dihydrate form B according to any one of statements 12 to 22.
  • a method according to statement 31 wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases. 33.
  • MPO myeloperoxidase
  • the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic
  • the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing
  • MPO myeloperoxidas
  • a method according to statement 31 wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
  • MPO myeloperoxidase
  • a method according to statement 31 wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
  • MPO myeloperoxidase
  • a method according to statement 31 wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial is cancer.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 for use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 39, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vas
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
  • MPO myeloperoxidase
  • Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
  • MPO myeloperoxidase
  • MPO myeloperoxidase

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Abstract

Crystalline 2-thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)- 1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (compound 1) in form A and crystalline 2- thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro- 4H-pyrrolo[3,2-d]pyrimidin-4-one (compound 1) dihydrate in form B.

Description

INHIBITORS OF MYELOPEROXIDASE
This application claims priority from European Patent Application No. 24157815.2, filed
February 15, 2024, the disclosure of which is incorporated by reference herein in its entirety.
The present disclosure relates to crystalline forms of a myeloperoxidase inhibitor, and the use of such forms.
Background
Myeloperoxidase (MPO) is a heme-containing enzyme primarily expressed in neutrophilic granulocytes (neutrophils). MPO is one member of a diverse protein family of mammalian peroxidases that also includes eosinophil peroxidase (EPX), lactoperoxidase (LPO), thyroid peroxidase (TPO) and others. MPO is activated by hydrogen peroxide, the source of which can be superoxide dismutase (SOD)-catalysed NADPH-derived superoxide anion and xanthine oxidase-derived superoxide anion and hydrogen peroxide formed upon purine oxidation. MPO catalyses two electron oxidation of halides (primarily chloride) and pseudohalides (like thiocyanate), forming the microbicidal hypohalous acids hypochlorous acid (bleach) and hypothiocyanous acid. These can, in turn, act on a broad number of protein, lipid and nucleic acid targets, causing dysfunction and further inflammation (Davies 2020). In addition, MPO catalyses one electron oxidation of numerous electron-rich substrates through the so-called peroxidation cycle, yielding free radicals that are harmful in themselves (e.g. urate radicals (Stamp 2014)) or that may interfere with physiological functions driven by nitric oxide (NO), either by direct oxidation of NO, or by generation of free radicals oxidizing NO (Davies 2020).
By numbers, neutrophils are the dominating leukocyte population (50-70% of blood leukocytes in humans), representing a highly dynamic cellular population that is part of the first line defense towards stressors, be it microbial or sterile triggers. Within neutrophils, preformed MPO is stored at millimolar concentration in granules, which fuse with phagosomes containing the engulfed microbial prey, causing activation of MPO and killing of the microbe (Hampton 1998). In addition, MPO can also be released to the outside of the cells where the oxidative activity may cause damage to adjacent tissue and dysfunction or modulation of biochemical and cellular processes, such as tissue remodeling and fibrosis. The release can either occur as a result of degranulation or NETosis, in which webs of decondensed DNA dressed with intracellular proteins such as MPO, so called neutrophil extracellular traps (NETs), are released (Kolaczkowska 2013). In addition, MPO is also released constitutively (Nauseef 2018). The enzyme is highly cationic and is therefore trapped at negatively charged structures extracellularly, such as proteoglycans in the vascular wall and on extracellular matrix in the interstitium (Hawkins 2021 ).
Given the dominance of neutrophils in inflammatory biology and the abundance of MPO in neutrophils (estimated to 5% of the dry weight of the cells), it is not surprising that a plethora of disease conditions is postulated to be associated with a pathological role of myeloperoxidase. These conditions encompass not only “traditional” inflammatory diseases, such as inflammatory bowel disease and the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus, but also other common diseases in which inflammation is emerging as an important pathophysiological component e.g. cardiovascular disease, neurodegenerative disease, kidney disease, respiratory disease, metabolic disease, obesity, and cancer (Davies 2020).
A pathophysiological role of MPO is further supported by human genetic studies and rodent interventional studies. In humans, a common polymorphism in the MPO-promotor that regulates transcription (Piedrafita 1996) and tissue MPO activity (Van Schooten 2004), have been shown to be associated with coronary microvascular dysfunction (Makela 2004), mortality in heart failure (Rudolph 2009), risk for coronary artery disease (Tang 2013) as well as outcomes thereof (Asselbergs 2004), risk of developing hepatitis C-associated liver fibrosis and cirrhosis (do Carmo 2014, Nahon 2012) and risk of hepatocellular carcinoma and death in alcohol-associated liver-cirrhosis (Nahon 2009). In rodent in vivo and in human in vitro experiments, efficacy using selective MPO-inhibitors have been reported for several diseases and/or conditions: preservation of cardiac function in post-myocardial infarction models (Ali 2016), stabilization of atherosclerotic plaques (Rashid 2018), amelioration of pulmonary artery hypertension (Klinke 2018), glomerulonephritis (Antonelou 2020) and cystic fibrosis (Dickerhof 2020), reduction of liver steatosis and fibrosis (Koop 2020, Piek 2019), attenuation of vascular dysfunction in conditions of inflammatory vascular dysfunction (Cheng 2019), normalization of microvascular function (Chai 2019), improvement of relaxation in human cardiomyocytes (Ramachandra 2022), and inhibition of NETosis in human neutrophils (Bjornsdottir 2015).
How MPO contributes to the different disease conditions may vary depending on condition, although some mechanisms may be of importance in several of these conditions. In addition to damage and dysfunction caused by MPO-derived reactive oxygen species such as hypochlorous acid (Davies 2020), MPO also appears to play a regulatory role in inflammation that serves to amplify the inflammatory response by activation of neutrophils (Lau 2005) and via activation of proteinases that cleave latent forms into active effector proteins, e.g. cytokines (Ra 2007). The mechanistic association between MPO and fibrosis is possibly also multifactorial, e.g. i) secondary to increased inflammation ii) by activation of myofibroblasts (Mollenhauer 2017) and iii) by increasing collagen secretion per se (DeNichilo 2015). Finally, active MPO oxidizes NO directly (as well as indirectly) via the peroxidation cycle and thereby impairs mechanisms driven by nitric oxide, such as smooth muscle cell relaxation (Eiserich 2002). This latter mechanism is likely to be of particular importance for the association between MPO and microvascular dysfunction and the resulting impaired blood supply to the tissues, as MPO is trapped on proteoglycans and transcytosed by endothelial cells and spatially deposited in the subendothelial compartment between the NO-producing endothelium and the NO-receiving smooth muscles (Baldus 2001).
Taken together, there is medical need as well as a good rationale for an orally active inhibitor of MPO for the treatment of chronic inflammatory conditions. In order to increase the therapeutic index of such a medication, it is necessary to obtain an MPO inhibitor being selective for MPO over TPO. The thyroid gland is an important regulator of thermogenic and metabolic functions, and TPO plays a central role by iodination of tyrosine residues, forming the thyroid hormones T4 and T3. TPO activation is under the control of thyroid stimulating hormone, and T4 and T3 are part of a negative feedback mechanism, thus resulting in compensatory increased thyroid stimulating hormone as a result of decreased levels of T3 and T4 upon TPO inhibition (Ekerot 2013).
W02003/089430, W02005/037835, W02007/120097, W02007/120098 and
W02007/142576 disclose thioxantine derivatives and the use thereof as MPO inhibitors in therapy.
W02006/062465 and W02007/142577 disclose 2-thioxo-1 ,2,3,4-tetrahydro-pyrrolo[3,2- d]pyrimidin-4-one derivatives claimed to be inhibitors of MPO. It is stated that the compounds may show selectivity against related enzymes such as TPO.
W02009/025618 discloses thioxantine and 2-thioxo-1 ,2,3,4-tetrahydro-pyrrolo[3,2- d]pyrimidin-4-one derivatives and the use of MPO inhibitors for the treatment of multiple system atrophy (MSA) and Huntington’s disease (HD) and for neuroprotection.
Malmquist 2012 discloses some tritiated, 13C and 14C labeled thioxantine derivatives as well as a 14C labeled pyrrolo[3,2-d]pyrimidin-4-one compound. The compounds are stated to be inactivators of MPO.
Tiden 2011 discloses certain thioxantine derivatives. The compounds are stated to inhibit MPO in plasma and decrease protein chlorination in a mouse model. The compounds are also claimed to be poor inhibitors of TPO.
WO2013/068875 discloses thiopyrimidone derivatives claimed to be MPO inhibitors.
WO2016/087338 discloses thioxopyrrolopyrimidone derivatives stated to be MPO inhibitors.
Therefore, there is a need for novel MPO inhibitors useful in therapy. There is also a need for novel MPO inhibitors having improved selectivity for the MPO enzyme over the TPO enzyme, as well as MPO inhibitors having suitable pharmacological properties.
Summary
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- cf]pyrimidin-4-one (the structure of which is shown below) in Form A:
(also termed “compound 1” herein).
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4-
(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one dihydrate in Form B:
In some embodiments, disclosed is a pharmaceutical composition comprising crystalline 2- thioxo-1 -((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4H-pyrrolo[3,2-c(|pyrimidin-4-one in Form A, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In some embodiments, disclosed is a pharmaceutical composition comprising crystalline 2- thioxo-1 -((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4H-pyrrolo[3,2-c(|pyrimidin-4-one dihydrate in Form B, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one in Form A for use in the treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO).
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- cf]pyrimidin-4-one dihydrate in Form B for use in the treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO).
In some embodiments, disclosed is a method of treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO) comprising administering to a subject in need thereof crystalline 2- thioxo-1 -((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4A7-pyrrolo[3,2-c(|pyrimidin-4-one in Form A. In some embodiments, disclosed is a method of treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO) comprising administering to a subject in need thereof crystalline 2- thioxo-1 -((2-((2/z?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4H-pyrrolo[3,2-cf|pyrimidin-4-one dihydrate in Form B.
In some embodiments, disclosed is the use of crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- cf]pyrimidin-4-one in Form A in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO).
In some embodiments, disclosed is the use of crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one dihydrate in Form B in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions which are responsive to the inhibition of the activity of the enzyme myeloperoxidase (MPO).
In some embodiments, disclosed is a method of obtaining 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one in crystalline form A.
In some embodiments, disclosed is a method of obtaining 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one dihydrate in crystalline form B.
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one.
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2- c(]pyrimidin-4-one having a DSC trace comprising a melting endotherm onset of about 260°C.
In some embodiments, disclosed is crystalline 2-thioxo-1 -((2-((2F?,4S)-4- (trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4H-pyrrolo[3,2- c/]pyrimidin-4-one dihydrate having a DSC trace comprising:
(i) a broad endotherm onset at 127°C, relating to water loss;
(ii) an exotherm onset at 169°C, relating to crystallization; and
(iii) a melting endotherm onset of about 260°C.
Brief Description of the Figures
Figure 1 illustrates the powder X-ray diffraction diagram of compound 1 in form A.
Figure 2 illustrates the thermogravimetric analysis (TGA) trace of compound 1 in form A.
Figure 3 illustrates the differential scanning calorimetry (DSC) trace of compound 1 in form A.
Figure 4 illustrates the powder X-ray diffraction diagram of compound 1 dihydrate in form B.
Figure 5 illustrates the thermogravimetric analysis (TGA) trace of compound 1 dihydrate in form B.
Figure 6 illustrates the differential scanning calorimetry (DSC) trace of compound 1 dihydrate in form B.
Detailed Description
Crystalline Forms 2-Thioxo-1-((2-((2F?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 , 2,3,5- tetrahydro-4H-pyrrolo[3,2-c]pyrimidin-4-one (also termed “compound 1” herein) is example 16b of PCT/EP2023/072655.
Currently over 40 polymorphic forms of compound 1 have been found, some of which would not be suitable for further pharmaceutical development.
Form A is most thermodynamically stable anhydrous phase of compound 1 , and has a solubility profile suitable for further development.
Dihydrate Form B is the most stable hydrated from of compound 1 , and shows stability in an aqueous environment, such as suspension.
In some embodiments, compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20±O.2° at 18.7°.
In some embodiments, compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20±O.2° at 25.1 °.
In some embodiments, compound 1 form A has a XRPD pattern comprising at least two peaks expressed as 20±O.2° at 18.7° and 25.1°. In some embodiments, compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20° at about 18.7°.
In some embodiments, compound 1 form A has a XRPD pattern comprising at least one peak expressed as 20° at about 25.1°.
In some embodiments, compound 1 form A has a XRPD pattern comprising at least two peaks expressed as 20° at about 18.7° and 25.1°. In some embodiments, compound 1 form A has a XRPD pattern comprising the following five peaks expressed as 20±O.2°:
In some embodiments, compound 1 form A has a XRPD pattern comprising five peaks at about the following 20° values:
In some embodiments, compound 1 form A has a XRPD pattern comprising the following ten peaks expressed as 20±O.2°:
In some embodiments, compound 1 form A has a XRPD pattern comprising ten peaks at about the following 20° values:
In some embodiments, compound 1 form A has a XRPD pattern substantially similar to Figure 1.
The above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Ka radiation. In some embodiments, the measurements take place at room temperature, such as 20°C.
In some embodiments, compound 1 form A has a TGA thermogram exhibiting a mass loss of less than 0.1% upon heating from about 25°C to 110°C. In some embodiments, compound 1 form A has a TGA thermogram substantially similar to Figure 2.
In some embodiments, compound 1 form A has a DSC trace comprising a melting endotherm onset of about 260°C. In some embodiments, compound 1 form A has a DSC trace with a heat enthalpy of about 102 J/g for the melting endotherm. In some embodiments, compound 1 form A has a DSC trace substantially similar to Figure 3.
When it is stated that the present disclosure relates to a compound 1 form A, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20±O.2° at 19.3°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20±O.2° at 23.9°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least two peaks expressed as 20±O.2° at 19.3° and 23.9°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20° at about 19.3°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least one peak expressed as 20° at about 23.9°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising at least two peaks expressed as 20° at about 19.3° and 23.9°.
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising the following five peaks expressed as 20±O.2°:
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising five peaks at about the following 20° values: 23.9
In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising the following ten peaks expressed as 20±O.2°: In some embodiments, compound 1 dihydrate form B has a XRPD pattern comprising ten peaks at about the following 20° values:
In some embodiments, compound 1 dihydrate form B has a XRPD pattern substantially similar to Figure 4.
The above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Ka radiation. In some embodiments, the measurements take place at room temperature, such as 20°C. In some embodiments, compound 1 dihydrate form B has a TGA thermogram exhibiting a mass loss of about 7.95% upon heating from about 25°C to 110°C, corresponding to water loss. In some embodiments, compound 1 dihydrate form B has a TGA thermogram substantially similar to Figure 5.
In some embodiments, compound 1 dihydrate form B has a DSC trace comprising:
(i) a broad endotherm onset at 127°C, relating to water loss;
(ii) an exotherm onset at 169°C, relating to crystallization; and
(iii) a melting endotherm onset of about 260°C.
In some embodiments, compound 1 dihydrate form B has a DSC trace with:
(i) a heat enthalpy of about 241 J/g for the water loss endotherm;
(ii) a heat enthalpy of about 15 J/g for the crystallization exotherm; and
(iii) a heat enthalpy of about 91 J/g for the melting endotherm.
In some embodiments, compound 1 dihydrate form B has a DSC trace substantially similar to Figure 6.
When it is stated that the present disclosure relates to a compound 1 dihydrate form B, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
Medical and Pharmaceutical Use
The crystalline compounds disclosed herein are useful because they possess pharmacological activity as inhibitors of the enzyme MPO.
The crystalline compounds disclosed herein are indicated for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable or beneficial. In particular, linkage of MPO activity to disease has been implicated in numerous diseases, including diseases with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, as well as neutrophilic driven diseases. The terms prophylaxis and prevention are used interchangeably herein.
The disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, which are responsive to inhibition of MPO. Such diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, and type 2 diabetes.
The disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of cardiovascular diseases or conditions in mammals, including humans, which are responsive to inhibition of MPO. Such cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.
The disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, in which microvascular dysfunction is prominent.
The disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, which are responsive to inhibition of MPO. Such diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response. These diseases and conditions include, but are not limited to Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy.
The disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neutrophilic driven diseases and conditions in mammals, including humans. Such diseases and conditions include, but are not limited to chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
The disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, which are responsive to inhibition of MPO. Such diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD. In some embodiments, such disease or condition is bronchiectasis.
The disclosed crystalline compounds are indicated for use in the treatment or prophylaxis of cardiovascular diseases or conditions in mammals, including humans, which are responsive to inhibition of MPO. Such cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction.
The disclosed crystalline compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, which are responsive to inhibition of MPO. Such diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response. These diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage.
The disclosed crystalline compounds are indicated for use in the treatment of cancer.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening or identified through specific biomarker pattern to be particularly susceptible to developing the disease or condition.
For the above-mentioned therapeutic indications, the dosage administered will, of course, vary with the crystalline compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the crystalline compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.
The crystalline compounds disclosed herein may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Thus, another aspect concerns a pharmaceutical composition comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Thus, another aspect concerns a pharmaceutical composition which comprises a crystalline compound disclosed herein, and at least one pharmaceutically acceptable excipient. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.
In some embodiments there is provided a crystalline compound disclosed herein, for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of one or more conditions or diseases with an inflammatory component wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in therapy, especially in the prevention or treatment of one or more cardiovascular diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of one or more neurological diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in therapy, especially in the prevention or treatment of one or more neutrophilic driven diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes in a mammal, particularly a human. In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of one or more neutrophilic driven diseases, such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and /or subarachnoid haemorrhage, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the treatment of cancer in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of heart failure in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of arrhythmia in a mammal, particularly a human. In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of acute kidney injury (AKI), in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of non-cystic fibrosis bronchiectasis (NCFB), in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of bronchiectasis), in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of nephritis in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.
In some embodiments there is provided a crystalline compound disclosed herein for use in the prevention or treatment of irritable bowel syndrome (IBS), in a mammal, particularly a human. In some embodiments there is provided a method of treating, preventing, or reducing the risk of, one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more neutrophilic driven diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more neutrophilic driven diseases or conditions, such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch- Schonlein Purpura), Immunoglobulin A nephropathy ( Ig AN) , lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating cancer which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of coronary artery disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of acute coronary syndrome which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of heart failure which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of heart failure with reduced ejection fraction which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of heart failure with preserved ejection fraction which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of chronic kidney disease (CKD) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of cardiorenal syndrome (CRS) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of non-alcoholic steatohepatitis (NASH) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of arrhythmia which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of chronic obstructive pulmonary disease (COPD) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of sickle cell disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein. In some embodiments there is provided a method of treating, preventing, or reducing the risk of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of acute kidney injury (AKI) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of non-cystic fibrosis bronchiectasis (NCFB), which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of bronchiectasis, which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of Alzheimer's disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of Parkinson's disease which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of nephritis which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of inflammatory bowel disease (I BD) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a method of treating, preventing, or reducing the risk of irritable bowel syndrome (IBS) which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound disclosed herein.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable or beneficial.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, and/or type 2 diabetes.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and/or chemotherapy-induced cardiotoxicity.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and /or epilepsy.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction.
In some embodiments there is provided a crystalline compound disclosed herein use in the manufacture of a medicament for use in the treatment or prophylaxis of Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage.
In some embodiments there is provided a crystalline compound disclosed herein for use in the manufacture of a medicament for use in the treatment of cancer.
In some embodiments there is provided a pharmaceutical formulation comprising a therapeutically effective amount of a crystalline compound disclosed herein and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more conditions or diseases where inhibition of MPO would be beneficial.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in in the prevention or treatment of one or more conditions or diseases with an inflammatory component wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more cardiovascular diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of one or more neurological diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of one or more neutrophilic driven diseases wherein inhibition of MPO would be beneficial in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn’s disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HfrEF), heart failure with preserved ejection fraction (HfpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of one or more neutrophilic driven diseases, such as, but not limited to, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), in a mammal, particularly a human. In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch- Schonlein Purpura), Immunoglobulin A nephropathy ( Ig AN) , lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD, in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction, in a mammal, particularly a human. In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions including, but not limited to diseases with a neuroinflammatory response, such as but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and /or subarachnoid hemorrhage in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment of cancer, in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of arrhythmia in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, in a mammal, particularly a human. In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of nephritis in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of irritable bowel syndrome (IBS), in a mammal, particularly a human.
In some embodiments, plasma urate levels may be used as a stratifying tool and a pharmacodynamic biomarker for MPO inhibitor treatment with a crystalline compound disclosed herein.
In still a further embodiment, there is provided a method of identifying patients suitable for MPO inhibitor treatment with a crystalline compound disclosed herein encompassing the measurement of plasma urate levels.
In some embodiments, predictive biomarkers, i.e. features or variables reflecting an involvement of MPO in disease pathology, may be used as a stratifying tool and a pharmacodynamic biomarker for MPO inhibitor treatment with a crystalline compound disclosed herein. Such biomarkers include, but are not limited to, biomarkers of neutrophil activation (MPO, NGAL, sTNFRI , sTNFR2, calprotectin, UPAR, blood neutrophil counts or percentages, blood neutrophil/lymphocyte ratio), other inflammatory prognostic biomarkers (GDF15, FGF23, STRAIL-R2), biomarkers of systemic inflammation (IL6, C-reactive protein or other acute phase proteins), biomarkers of increased purine catabolism (urate) and purine oxidation (allantoin), biomarkers of iron deficiency (transferrin saturation, ferritin, hemoglobin), biomarkers of extracellular matrix remodeling (MMP7, TIMP4, osteopontin), biomarkers of renal dysfunction (eGFR, UACR, cystatin C), biomarkers of nitric oxide production (SDMA, ADMA, Arg, cGMP). Several of these biomarkers may be quantified from blood, plasma, sera, urine, feces or saliva.
In still a further embodiment, there is provided a method of identifying patients suitable for MPO inhibitor treatment with a crystalline compound disclosed herein encompassing the measurement of such predictive biomarkers as disclosed herein.
The crystalline compounds disclosed herein also display a promising pharmacological profile by separating desired and undesired effects in vivo.
These and other embodiments are described in greater detail herein below, where further aspects will be apparent to one skilled in the art from reading this specification.
Pharmacological Properties
The crystalline compounds disclosed herein are believed to be useful in the prevention or treatment of various conditions wherein the modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable or beneficial, including, but not limited to, diseases with inflammatory, cardiovascular, and/or neurological components, as well as neutrophilic driven diseases.
For the avoidance of doubt, as used herein, the term “treatment” includes therapeutic and/or prophylactic treatment.
When a crystalline compound described herein is administered as therapy for treating a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse.
The crystalline compounds described herein are thus indicated both in the therapeutic and/or prophylactic treatment of these conditions.
The crystalline compounds described herein have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art.
Combination Therapy
The crystalline compounds disclosed herein may also be administered in conjunction with other compounds used for the treatment of the above conditions.
In some embodiments, there is a combination therapy wherein a crystalline compound disclosed herein, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above. Such a combination may be used in combination with one or more further active ingredients.
The crystalline compounds described herein may be of use in treating cardiovascular, metabolic and renal disease in combination with agents that are:
• cardiac therapies,
• anti-hypertensives,
• diuretics,
• peripheral vasodilators,
• lipid modifying agents,
• anti-diabetic,
• anti-inflammatory, or
• anti-coagulant.
Examples of the above include, but are not restricted to, digitalis glycosides, anti-arrhythmics, calcium channel antagonists, ACE inhibitors, angiotensin receptor blockers (e.g. Valsartan), endothelin receptor blockers, p-blockers, thiazide diuretics, loop diuretics, cholesterol synthesis inhibitors such as statins (e.g. Rosuvastatin), cholesterol absorption inhibitors, cholesterylester transfer protein (CETP) inhibitors, anti-diabetic drugs such as insulin and analogues, GLP-1 analogues, sulphonamides, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, and anti-inflammatory drugs such as NSAID’s and CCR2 antagonists, anti-coagulants such as heparins, thrombin inhibitors and inhibitors of factor Xa, platelet aggregation inhibitors, P2X7 antagonists and neprilysin inhibitors (e.g. Sacubitril). When used in a combination therapy, it is contemplated that the crystalline compounds disclosed herein, and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately. The particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
Pharmaceutical Compositions
There is provided a method of treatment of a condition where inhibition of MPO is required, which method comprises administration of a therapeutically effective amount of a crystalline compound disclosed herein to a person suffering from, or susceptible to, such a condition.
The crystalline compounds disclosed herein will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Aulton 2002.
The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art.
In some embodiments there is provided a pharmaceutical formulation comprising a crystalline compound disclosed herein or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. The crystalline compounds disclosed herein may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation. Examples
The following abbreviations are used herein:
AcOH Acetic acid
Aq Aqueous
Boc terf-Butoxycarbonyl
Bu Butyl
DCM Dichloromethane
DMSO Dimethyl sulfoxide
Et Ethyl
EtOAc Ethyl acetate
EtOH Ethanol g Gram h Hour(s)
HPLC High performance liquid chromatography
IPA 2-propyl alcohol iPr Isopropyl
L Litre
LC Liquid chromatography
M Molar
Me Methyl
MeCN Acetonitrile mL Millilitre pL Microlitre
MeOH Methanol
Min Minutes
Mmol Millimole
MS Mass spectrometry
NMR Nuclear magnetic resonance
Ph Phenyl
Rt Room temperature
SFC Supercritical fluid chromatography
THF Tetrahydrofuran
TLC Thin layer chromatography Ts Tosyl or 4-methylbenzenesulfonyl
General conditions
(i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28°C and where needed under an atmosphere of an inert gas such as N2;
(ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g));
(iii) where reactions refer to the use of a microwave reactor, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer;
(iv) in general, the course of reactions was followed by thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS).
(v) when necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4, or by using ISOLUTE® Phase Separator, and work-up procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4 or Na2SO4 is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer.
(vi), evaporations were carried out either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10;
(vii) unless otherwise stated, flash column chromatography was performed on straight phase silica, using either Merck Silica Gel (Art. 9385) or prep-packed cartridges such as Biotage® SNAP cartridges (40-63 pm silica, 4-330 g), Biotage® Star Silica HC D cartridges (20 pm, 10-100 g), Interchim puriFlash™ cartridges (25 pm, 4-120 g), Interchim puriFlash™ cartridges (50 pm, 25-330 g), Grace™ GraceResolv™ Silica Flash Cartridges (4-120 g) or Agela Flash Colum Silica-CS cartridges (80-330g), or on reversed phase silica using Agela Technologies C-18, spherical cartridges (20-35pm, 100A, 80-330g), manually or automated using a Grace Reveleris® X2 Flash system or similar system;
(viii) preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and/or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section.
Relevant fractions were collected, combined and freeze-dried or evaporated to give the purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried either over Na2SC>4 or by using a phase-separator, and then concentrated at reduced pressure to give the purified compound.
(ix) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instruments, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section;
(x) yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required;
(xi) where certain compounds were obtained as an acid-addition salt, for example a mono-hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data;
(xii) in general, the structures of the end-products of the compounds described herein were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at 1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet.
In some cases, the structures of the end-products of the compounds disclosed herein might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported
(xiii) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry;
(xiv) unless stated otherwise compounds containing an asymmetric carbon and/or sulfur atom were not resolved. In general, chemical structures of compounds containing the label '&' at a stereocenter, means the configuration of such compound at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such compound at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure.
In general, for structures of compounds where all of the stereocenters are designated as '&', the structure is named with a “rac-” prefix. For structures of compounds where all of the stereocenters are designated as 'or', the structure is named with a “rel-” prefix.
In general, for compounds containing more than one stereocenter the relative stereochemistry is described using configurational descriptors ‘S’ and ‘R’ for the stereogenic centers and using the “rac-“ or “rel-“ prefix cited at the front of the name.
Powder X-ray diffraction
X-ray powder diffraction data was measured with Corundum as an internal reference. The X- ray powder diffraction (referred to herein as XRPD) pattern was determined by mounting a sample on a zero-background holder single silicon crystal and spreading out the sample into a thin layer.
The powder X-ray diffraction was recorded with a theta-two theta scan axis and in one dimensional scan with Rigaku Miniflex 600 (wavelength of X-rays 1.5418 A nickel-filtered Cu Ka radiation, 40 kV, 15 mA) equipped with D/Tex Ultra detector. Automatic variable anti scattering slits were used, and the samples were rotated at 30 revolution per minute during measurement. Samples were scanned from 3 - 50° 2-theta using a 0.01° and 1 min step width and scan speed respectively.
The X-ray powder diffraction analysis was performed according to standard methods, which can be found in e.g. Kitaigorodsky 1973, Bunn 1961 , Klug & Alexander 1974.
Definition of intensity
The relative intensities are derived from diffractograms measured with fixed slits It is known that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore, it should be understood that the crystalline forms disclosed herein are not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns shown in the Figures. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of X-ray powder diffraction patterns.
Persons skilled in the art of X-ray powder diffraction will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios, which may affect analysis of samples. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. (Jenkins & Snyder 1996, Bunn 1961 , Klug & Alexander 1974).
TGA and DSC
TGA and DSC measurements were performed using a TG Discovery 550 (TA instruments, Germany) and DSC Discovery 2500 (TA instruments, Germany), respectively. Approximately 10 mg for TGA and 2-3 mg of the sample for DSC were weighed into an aluminum pan. The samples were then heated from room temperature to 350°C for TGA and from -50°C to 270°C for DSC, with a heating rate of 10°C/min under a nitrogen purge of 100 mL/min. An empty aluminum pan was used as a reference for DSC. Open and closed pans were used for TGA and DSC measurements, respectively.
Example 1
Chiral separation of 11-rac
11 -rac was purified by supercritical fluid chromatography (SFC) separation in IPA.
Acetal deprotection of 11
A 50 L jacketed reactor equipped with mechanical stirrer was charged with 11 under N2 flow.
MeCN (10 vols) and H2O (5 vols) were then charged to the reactor, followed by formic acid (2.0 equiv.) at 20°C. The reactor temperature was set to 60°C and the reaction mixture was stirred for 45 h.
Condensation with A 1
Toluene (7.5 vols) and K3PO4 aqueous solution (1 M, 7.5 vols) were charged to the reactor, followed by A1 (1 .0 eq.). The reaction mixture was stirred at 60°C for 1 h. The organic phase was separated and concentrated under reduced pressure to circa 3 vols (jacket temperature was set to 45°C).
Toluene was added to the organic phase and the solvent was reduced under vacuum to circa 5 vols. This step was repeated.
The jacket temperature was adjusted to 20°C and AcOH (3 equiv.) was charged under N2 flow, followed by portion-wise addition of NaBH(OAc)3 (3.0 eq.) at 20°C. The reaction mixture was stirred at 20°C for 1 h.
K2CO3 aqueous solution (10 w/w%, 7.5 vols) was charged to the reactor and the biphasic mixture was stirred at 20°C for 1 h. The organic phase was separated and concentrated under reduced pressure to circa 3 vols at 45°C.
EtOH (1 .5 vols) was charged to the reactor and the mixture was concentrated to circa 3 vols at 45°C under reduced pressure. The jacket temperature was adjusted to 30°C and 0.1% seeds were charged to the reaction mixture under nitrogen flow. The solution was stirred at 30°C for 1 h.
The jacket temperature was adjusted to 20°C and n-heptane (15 vols) was charged to the reactor under N2 flow. The temperature was decreased to 5°C and the reaction mixture was stirred at this temperature for 0.5 h, filtered and the cake was washed with n-heptane (1 .5 vols). The wet cake was dried at 45°C for 16 h under vacuum.
(d) Reaction with A2 to form 14 and ring closure to form 15
13 and 2-MeTHF (6 vols) were charged to the reactor equipped with mechanical stirrer, followed by A2 (1 .3 equiv.) under nitrogen flow. The reaction mixture was stirred for 1 h at 30°C. MeOH (5 vols) and K2COs (2.2 equiv.) were charged to the reactor. The mixture was stirred at 45°C for 18 h. The jacket temperature was set to 20°C. Acetic acid (0.4 M, 12 vols) was charged followed by 2-MeTHF (12 vols) and the biphasic mixture was stirred for 1 h at 20°C. The organic phase was separated and concentrated to circa 3 vols at 45 °C under reduced pressure.
The jacket temperature was set to 40°C and n-heptane (circa 3 vols) was charged under N2 flow at 40°C over 20 min, then the temperature was lowered to 20°C over 2 h and the mixture was stirred at this temperature for 1 h. The suspension was filtered and washed with methyl tert-butyl ether (1 vol) and the wet cake was dried for 38 h at 45°C under vacuum.
Boc deprotection of 15 to give compound 1
H2SO4 aqueous solution (2 M, 10 vols) was charged into the reactor equipped with mechanical stirrer. The jacket was set to 70°C and I5 was charged portion-wise under N2 flow. The mixture was stirred for 1 h at 70°C. NH3.H2O solution (25 w/w%, 5 vols) was charged into the vessel at 70°C and stirred for 30 min. The temperature was decreased to 20°C and the suspension was filtered. The cake was triturated in 4 vols water at 20°C for 1 h, then filtered and washed with water (1 vol). The wet cake was dried for 44 h at 50°C under vacuum and for additional 24 h at 55°C.
Crystallisation process to obtain compound 1 Form A
Compound 1 was charged to a reactor equipped with mechanical stirrer. H2O (3 vols) was charged to the reactor at 20°C and the mixture was stirred for 3 h at 50°C under N2 flow. The jacket was set to 20°C and the suspension was filtered. The filtered cake was re-charged to the vessel. MeOH (9.7 vols) and H2O (1 vol) were charged and the mixture was stirred for 2 h at 50°C, then filtered and dried for 45 h at 55°C under vacuum.
Example 2 - Assessment of MPO and TPO activity
The experiments were performed in phosphate-buffered saline (PBS), pH7.4. A 10 mM luminol (A4695, Sigma Aldrich, St Louis, MO, USA) stock was prepared in distilled water and further diluted in PBS to a final concentration of 100 pM. H2O2 was prepared as 1 mM stock in PBS, yielding a final concentration of 50 pM after addition into the assay. Compound 1 was serially diluted in DMSO in a separate plate as a 100x stock solution, and MPO (purified from HL60 cells) and TPO (produced in insect cells, RSR Ltd, Cardiff, UK), were diluted to yield a final concentration of approximately 14 and 150 ng/mL, generating 5600 and 9300 light counts per seconds (LCPS) upon incubation with luminol.
The experiment was run by pipetting 2 pL 100x stock solution of the compound and 200 pL diluted enzyme in PBS into wells in a 96-well Optiplate (6005290, Perkin Elmer /Thermo Fischer, Waltham, MS, USA), followed by addition of 10 pL H2O2 containing PBS.
Chemiluminescence measurement (Perkin Elmer Wallac Microbeta Trilux 1450-029 (12- detector), Turkuu, Finland) was started directly and recorded after 2, 10 and 15 minutes. Chemiluminescence recorded after 15 minutes was used to calculate the IC50 values.
The IC50 values (MPO and TPO) for the compound 1 are:
Example 3 - Analysis of compound 1 Form A
The X-ray powder diffraction pattern of compound 1 Form A is shown in Figure 1 . The ten most prominent peaks are shown below:
Compound 1 form A has a TGA thermogram as shown in Figure 2. This TGA thermogram exhibits a mass loss of less than 0.1% upon heating from about 25°C to 110°C.
Compound 1 form A has a DSC trace as shown in Figure 3. The DSC trace shows a heat enthalpy of about 102 J/g for the melting endotherm.
Example 4 - Stability of compound 1 Form A
The thermal stability of compound 1 Form A was investigated by incubating solid samples at 115 and 130°C for 1 week in closed vials. Upon completion of the incubation time, the solids were analyzed by HR-XRPD and UPLC. Both solids showed a chemical purity of 100.0%. In both cases, no changes in the solid phase were detected. Compound 1 Form A was recovered unchanged. The thermal stability of the compound 1 Form A was evaluated in EtOH, ACN and acetone. Solutions (~ 0.4 mg/mL) were prepared in these solvents and split over 3 vials. The solutions were incubated at RT, 50 and 80°C for one hour and then analyzed by UPLC-MS. The chemical purity of compound 1 Form A in EtOH, acetone and ACN solutions incubated at 50°C and 80°C for 1 h was comparable to that at the start of the experiment. Starting solutions tO were remeasured after 24h. In all samples, a chemical purity of 100% was determined. No signs of degradation were detected.
Example 5 - Synthesis of compound 1 dihydrate Form B
Compound 1 Form A (500 mg) was slurried in 2mL Acetone: Water (50:50) mixture for 3 days at RT. The solid material then was filtered. The liquid phase was separated and then left for slow evaporation aiming for single crystal growth.
Example 6 - Analysis of compound 1 dihydrate Form B
The X-ray powder diffraction pattern of compound 1 dihydrate Form B is shown in Figure 4. The ten most prominent peaks are shown below:
Compound 1 dihydrate form B has a TGA thermogram as shown in Figure 5. This TGA thermogram exhibits a mass loss of about 7.95% upon heating from about 25°C to 110°C, corresponding to water loss.
Compound 1 dihydrate form B has a DSC trace as shown in Figure 6. The DSC trace shows
(i) a broad endotherm onset at 127°C, relating to water loss;
(ii) an exotherm onset at 169°C, relating to crystallization; and (iii) a melting endotherm onset of about 260°C.
Compound 1 dihydrate form B has a DSC trace with:
(i) a heat enthalpy of about 241 J/g for the water loss endotherm; (ii) a heat enthalpy of about 15 J/g for the crystallization exotherm; and
(iii) a heat enthalpy of about 91 J/g for the melting endotherm.
Example 7 - Stability of compound 1 dihydrate Form B
Compound 1 dihydrate Form B is physically stable upon storage at 40°C/75% RH for two days.
References
All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety for all purposes. Statements
1 . Crystalline 2-thioxo-1 -((2-((2/z?,4S)-4-(trifl uoromethyl)piperidin-2-yl)pyridin-3- yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one (compound 1 ) in form A:
2. Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20±O.2° at 18.7°.
3. Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20±O.2° at 25.1 °.
4. Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 20±O.2° at 18.7° and 25.1 °.
5. Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 16.1 , 18.7, 20.4, 23.8 and 25.1.
6. Crystalline compound 1 form A according to statement 1 , characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 13.2, 13.7, 16.1 , 16.4, 18.7, 19.0, 20.4, 22.9, 23.8 and 25.1.
7. Crystalline compound 1 form A according to statement 1 , wherein the X-ray powder diffraction pattern is substantially similar to Figure 1 . 8. Crystalline compound 1 form A according to any one of statements 1 to 7, having a TGA thermogram exhibiting a mass loss of less than 0.1 % upon heating from about 25°C to 110°C.
9. Crystalline compound 1 form A according to any one of statements 1 to 7, having a TGA thermogram substantially similar to Figure 2.
10. Crystalline compound 1 form A according to any one of statements 1 to 9, having a DSC trace comprising a melting endotherm onset of about 260°C.
11 . Crystalline compound 1 form A according to any one of statements 1 to 9, having a DSC trace substantially similar to Figure 3.
12. Crystalline 2-thioxo-1 -((2-((2/z?,4S)-4-(trifl uoromethyl)piperidin-2-yl)pyridin-3- yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one (compound 1 ) dihydrate in form B:
13. Crystalline compound 1 dihydrate form B according to statement 12, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20±O.2° at 19.3°.
14. Crystalline compound 1 dihydrate form B according to statement 12, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 20±O.2° at 23.9°.
15. Crystalline compound 1 dihydrate form B according to statement 12, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 20±O.2° at 19.3° and 23.9°.
16. Crystalline compound 1 dihydrate form B according to statement 12, characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 14.7, 16.0, 19.3, 22.2 and 23.9.
17. Crystalline compound 1 dihydrate form B according to statement 12, characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 12.0, 14.7, 16.0, 19.3, 19.7, 22.2, 22.6, 23.9, 26.3 and 29.4.
18. Crystalline compound 1 dihydrate form B according to statement 12, wherein the X- ray powder diffraction pattern is substantially similar to Figure 4.
19. Crystalline compound 1 dihydrate form B according to any one of statements 12 to
18, having a TGA thermogram exhibiting a mass loss of about 7.95% upon heating from about 25°C to 110°C.
20. Crystalline compound 1 dihydrate form B according to any one of statements 12 to 18, having a TGA thermogram substantially similar to Figure 5.
21 . Crystalline compound 1 dihydrate form B according to any one of statements 12 to
20, having a DSC trace comprising:
(i) a broad endotherm onset at 127°C, relating to water loss;
(ii) an exotherm onset at 169°C, relating to crystalization; and
(iii) a melting endotherm onset of about 260°C.
22. Crystalline compound 1 dihydrate form B according to any one of statements 12 to
20, having a DSC trace substantially similar to Figure 6.
23. A pharmaceutical composition comprising crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
24. Crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial.
25. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
26. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and obesity with CKD.
27. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and non-ST segment elevation myocardial infarction.
28. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
29. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
30. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 24, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial is cancer.
31 . A method of treating, preventing, or reducing the risk of, one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a crystalline compound 1 form A according to any one of statements 1 to 11 or a crystalline compound 1 dihydrate form B according to any one of statements 12 to 22.
32. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases. 33. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD) , Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch- Schonlein Purpura), Immunoglobulin A nephropathy ( Ig AN) , lupus nephritis, diabetic CKD, hypertensive CKD, and obesity with CKD.
34. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial f ibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and non-ST segment elevation myocardial infarction.
35. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
36. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
37. A method according to statement 31 , wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial is cancer.
38. Crystalline compound 1 form A according to any one of statements 1 to 11 or crystalline compound 1 dihydrate form B according to any one of statements 12 to 22 for use in the manufacture of a medicament for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial.
39. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 39, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are diseases or conditions with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, and/or neutrophilic driven diseases.
40. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (I BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and obesity with CKD.
41 . Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and non-ST segment elevation myocardial infarction.
42. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
43. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
44. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to statement 38, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial is cancer.
45. A method of obtaining 2-thioxo-1 -((2-((2/z?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin- 3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one in crystalline form A.
46. A method of obtaining 2-thioxo-1 -((2-((2/z?,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin- 3-yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one dihydrate in crystalline form B.

Claims

Claims
1 . Crystalline 2-thioxo-1 -((2-((2/z?,4S)-4-(trifl uoromethyl)piperidin-2-yl)pyridin-3- yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one (compound 1 ) in form A:
2. Crystalline compound 1 form A according to claim 1 , characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 16.1 , 18.7, 20.4, 23.8 and 25.1.
3. Crystalline compound 1 form A according to claim 1 , characterised by an X-ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 13.2, 13.7, 16.1 , 16.4, 18.7, 19.0, 20.4, 22.9, 23.8 and 25.1.
4. Crystalline compound 1 form A according to any one of claims 1 to 3, having a TGA thermogram exhibiting a mass loss of less than 0.1 % upon heating from about 25°C to 110°C.
5. Crystalline compound 1 form A according to any one of claims 1 to 4, having a DSC trace comprising a melting endotherm onset of about 260°C.
6. Crystalline 2-thioxo-1 -((2-((2/z?,4S)-4-(trifl uoromethyl)piperidin-2-yl)pyridin-3- yl)methyl)-1 ,2,3,5-tetrahydro-4/-/-pyrrolo[3,2-c(|pyrimidin-4-one (compound 1 ) dihydrate in form B:
7. Crystalline compound 1 dihydrate form B according to claim 6, characterised by an X- ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 14.7, 16.0, 19.3, 22.2 and 23.9.
8. Crystalline compound 1 dihydrate form B according to claim 6, characterised by an X- ray powder diffraction pattern comprising the following peaks expressed as 20±O.2°: 12.0, 14.7, 16.0, 19.3, 19.7, 22.2, 22.6, 23.9, 26.3 and 29.4.
9. Crystalline compound 1 dihydrate form B according to any one of claims 6 to 8, having a TGA thermogram exhibiting a mass loss of about 7.95% upon heating from about 25°C to 110°C.
10. Crystalline compound 1 dihydrate form B according to any one of claims 6 to 9, having a DSC trace comprising:
(i) a broad endotherm onset at 127°C, relating to water loss;
(ii) an exotherm onset at 169°C, relating to crystalization; and
(iii) a melting endotherm onset of about 260°C.
11. A pharmaceutical composition comprising crystalline compound 1 form A according to any one of claims 1 to 5 or crystalline compound 1 dihydrate form B according to any one of claims 6 to 10 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
12. Crystalline compound 1 form A according to any one of claims 1 to 5 or crystalline compound 1 dihydrate form B according to any one of claims 6 to 10 for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial.
13. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to claim 12, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and obesity with CKD.
14. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to claim 12, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/f lutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and non-ST segment elevation myocardial infarction.
15. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to claim 12, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and subarachnoid haemorrhage.
16. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to claim 12, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial are selected from chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).
17. Crystalline compound 1 form A or crystalline compound 1 dihydrate form B for use according to claim 12, wherein the diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is beneficial is cancer.
PCT/EP2025/053911 2024-02-15 2025-02-13 Inhibitors of myeloperoxidase Pending WO2025172474A1 (en)

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