WO2016012917A1 - Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 - Google Patents

Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 Download PDF

Info

Publication number
WO2016012917A1
WO2016012917A1 PCT/IB2015/055404 IB2015055404W WO2016012917A1 WO 2016012917 A1 WO2016012917 A1 WO 2016012917A1 IB 2015055404 W IB2015055404 W IB 2015055404W WO 2016012917 A1 WO2016012917 A1 WO 2016012917A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
oxy
disease
pharmaceutically acceptable
compounds
Prior art date
Application number
PCT/IB2015/055404
Other languages
English (en)
Inventor
Vipulkumar Kantibhai Patel
Original Assignee
Glaxosmithkline Intellectual Property Development Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Intellectual Property Development Limited filed Critical Glaxosmithkline Intellectual Property Development Limited
Publication of WO2016012917A1 publication Critical patent/WO2016012917A1/fr

Links

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
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to novel compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy for the treatment of diseases or disorders mediated by Lp-PLA 2 .
  • Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) previously known as platelet-activating factor acetylhydrolase (PAF-AH), is a phospholipase A2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids.
  • Lp-PLA 2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from the oxidation of LDL. (See e.g., Zalewski A, et al., Arterioscler. Thromb. Vase. Biol., 25, 5, 923-31 (2005)).
  • Lp-PLA 2 hydrolyzes the sn-2 ester of the oxidized phosphatidylcholines to give lipid mediators, lyso-phosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has been observed that lysoPC and NEFAs elicit inflammatory responses. (See e.g., Zalewski A, et al. (2005)).
  • Lp-PLA 2 inhibitors and/or uses thereof have been previously described. See e.g., published patent application nos. W096/13484, W096/19451, WO97/02242, W097/12963, W097/21675, W097/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911,
  • Disclosed uses include treating disease that involves or is associated with endothelial dysfunction, disease that involves lipid oxidation in conjunction with Lp-PLA 2 activity (e.g., associated with the formation of lysophosphatidylcholine and oxidized free fatty acids), and disease that involves activated monocytes, macrophages or lymphocytes or which is associated with increased involvement of monocytes, macrophages or lymphocytes.
  • diseases include atherosclerosis (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, after ischaemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as
  • Alzheimer's Disease various neuropsychiatric disease such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute and chronic inflammation, and psoriasis.
  • Lp-PLA 2 inhibitors and/or uses thereof are also reported, for example, in PCT Publication Nos. WO05/003118 (and its Canadian family member CA 2530816A1); WO06/063811;
  • Lp-PLA2 activity products of Lp-PLA2 activity (lysophosphatidylcholine and oxidized fatty acids) promote atherosclerosis.
  • Macphee CH et al. "Lipoprotein-associated phospholipase A2, platelet- activating factor acetylhydrolase, generates the oxidation of low-density lipoprotein: use of a novel inhibitor" Biochem J 1999; 338: 479-87; Macphee CH et al. "Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target" Current Opinion in Pharmacology 2006, 6: 154-161; Zalewski A, et al.
  • Lp-PLA2 activity are implicated in plaque vulnerability and pathology. See e.g. Kolodgie FD, et al. "Lipoproteinassociated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis” Arteriosclerosis Thrombosis and Vascular Biology, 2006;26:2523-9; Wilensky RL, et al. "Inhibition of
  • lipoproteinassociated phospholipase A2 reduces complex coronary atherosclerotic plaque development" Nature Medicine (21 Sep 2008), doi: 10.1038/nm.l870; Ferguson, J. F., et al. (2012) "Translational studies of lipoprotein-associated phospholipase A2 in inflammation and atherosclerosis” Journal of the American College of Cardiology, 59: 764-772; Chinetti-Gbaguidi, G. et al. (2011) "Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARy and LXRct pathways" Circulation Research, 108: 985-995; Mannheim D., et al.
  • Lp-PLA 2 inhibitors may be useful to treat atherosclerosis and diseases associated with atherosclerosis.
  • AD Alzheimer's disease
  • oxidized LDL have also been observed in AD patients (See e.g., Kassner et al. Current Alzheimer Research, 5, 358-366 (2008); Dildar, et a ⁇ ., Alzheimer Dis Assoc Disord, 24, April-June ( 2010); Sinem, et al. Current Alzheimer Research, 7, 463-469
  • Lp-PLA 2 inhibitors for treating neurodegenerative diseases, e.g., associated with blood-brain-barrier leakage, including, e.g., Alzheimer's disease and vascular dementia.
  • neuroinflammation including multiple cytotoxic cytokine release
  • neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.
  • Lp-PLA 2 inhibitors can reduce inflammation, for example, reducing multiple cytokine release by suppressing lysoPC production.
  • Lp-PLA 2 inhibiting Lp-PLA 2 is a potential therapeutic treatment approach for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.
  • Subjects (with a diagnosis of possible AD with radiological evidence of cerebrovascular disease) took 250mg of rilapladib or placebo once daily for a period of 24 weeks in addition to their stable background therapy consisting of an acetylcholinesterase inhibitor (AChEI) and/or memantine.
  • Rilapladib exhibited approximately 80% inhibition of Lp-PLA2 throughout the treatment phase, and maintained cognitive performance around baseline levels after 24 weeks compared to a decline in the placebo group.
  • Lp-PLA 2 inhibitors can be used to treat tissue damage associated with diabetes by reducing the production of lysoPC, which can cause a continuous cycle of vascular inflammation and increased reactive oxygen species ( OS) production.
  • OS reactive oxygen species
  • Glaucoma and age-related macular degeneration are retina neurodegenerative diseases.
  • inflammation including TNF-alpha signaling, may play an important role in the pathogenesis of glaucoma and AMD (See e.g., Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28).
  • Lp-PLA 2 inhibitors their function of blocking inflammatory cytokine release (See e.g., Shi, et al. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA 2 inhibitors can provide a potential therapeutic application for neurodegenerative eye diseases and disorders such as retina neurodegenerative diseases, e.g. glaucoma and AMD.
  • WO2012/080497 describes the use of Lp-PLA2 inhibitors for treating or preventing eye conditions, including e.g. eye diseases or disorders associated with the breakdown of the inner blood-retinal barrier (iBRB), macular edema of any cause (e.g., macular edema associated with diabetic eye diseases (e.g. diabetic retinopathy), uveitis, or other causes such as retinal vein occlusion (RVO), inflammation, post-surgical, traction, and the like), age-related macular degeneration (AMD), uveitis, diabetic eye diseases and disorders (e.g.
  • iBRB inner blood-retinal barrier
  • macular edema of any cause e.g., macular edema associated with diabetic eye diseases (e.g. diabetic retinopathy), uveitis, or other causes such as retinal vein occlusion (RVO), inflammation, post-surgical, traction, and the like
  • AMD age-related macular de
  • diabetic macular edema diabetic retinopathy
  • central retinal vein occlusion branched retinal vein occlusion
  • Irvine-Gass syndrome post cataract and post-surgical
  • retinitis pigmentosa pars planitis
  • birdshot retinochoroidopathy epiretinal membrane
  • choroidal tumors cystic macular edema
  • parafoveal telengiectasis tractional maculopathies
  • vitreomacular traction syndromes retinal detachment
  • neuroretinitis idiopathic macular edema, and the like.
  • Subjects were stratified based on baseline visual acuity for balance between groups: >50 letters and ⁇ 50 letters. Eligibility for each subject was based only on one eye, which was designated as the study eye. The study eye was examined for changes over the life of the study. Administration of darapladib 160 mg for 3 months resulted in statistically significant improvements from baseline at Day 90 in vision as measured by by best-corrected visual acuity (BCVA) and macular edema as measured by spectral domain optical coherence tomography(SD- OCT) center subfield and center point.
  • BCVA best-corrected visual acuity
  • SD- OCT spectral domain optical coherence tomography
  • Lp-PLA 2 inhibitors on diseases associated with macrophage polarization, e.g., M1/M2 macrophage polarization, has been described. See e.g. WO2012/076435 and WO2013/014185.
  • Lp-PLA2 inhibitors in treating diseases or disorders associated with macrophage polarization (e.g., M1/M2 macrophage polarization), such as liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • WO2008/141176 and US2010/0239565 describe the use of Lp-PLA 2 inhibitors for treating or preventing skin ulcers.
  • WO2008/140450 and US20080280829 describe the use of Lp-PLA 2 inhibitors for treating or preventing metabolic bone disorders, including e.g., bone marrow abnormalities, osteoporosis, and osteopenia.
  • Lp-PLA 2 In view of the number of pathological responses that are mediated by Lp-PLA 2 , attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp- PLA 2 which can be used in the treatment of a variety of conditions.
  • this invention relates to compounds of Formula (I):
  • the compound represented by the structure Formula (I) may be named 4-(((7-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid.
  • the compounds of Formula (I) include but are not limited to stereoisomers thereof.
  • the present invention provides a compound of
  • salts e.g., pharmaceutically acceptable salts thereof.
  • the present invention provides a compound of Formula (I) which isS,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo- l,2,3,5-tetrahydroimidazo[l,2 ut-2-enoic acid:
  • compositions comprising a compound of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients.
  • the invention also relates to methods of treating a disease or disorder associated with the activity of Lp-PLA 2 , which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention described herein (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the invention described herein e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also provides methods of treating a disease or disorder by inhibiting Lp- PLA 2 activity, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention described herein (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the invention described herein e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the methods of the invention may be used, e.g., for diseases or disorders such as:
  • ocular diseases or disorders including ocular diseases or disorders associated with the breakdown of the inner blood-retinal barrier (iB B), and neurodegenerative eye diseases or disorders, such as: diabetic eye diseases or disorders (e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like), retinal vein occlusion (e.g.
  • diabetic eye diseases or disorders e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like
  • retinal vein occlusion e.g.
  • central retinal vein occlusion branched retinal vein occlusion
  • Irvine-Gass syndrome post cataract and post-surgical
  • retinitis pigmentosa pars planitis
  • birdshot retinochoroidopathy epiretinal membrane
  • choroidal tumors cystic macular edema
  • parafoveal telengiectasis tractional maculopathies
  • vitreomacular traction syndromes retinal detachment, neuroretinitis, macular edema (e.g., in addition to diabetic macular edema, macular edema associated with uveitis (particularly posterior uveitis), retinal vein occlusion, inflammation, post-surgical traction and the like, and idiopathic macular edema), glaucoma, macular degeneration (e.g. age-related macular degeneration) and the like, systemic inflammatory disease which may be the underlying cause of posterior uveitis affecting the
  • diseases or disorders which involve and/or are associated with: (1) endothelial dysfunction (2) lipid oxidation in conjunction with enzyme activity, and/or (3) activated or increased involvement of monocytes, macrophages or lymphocytes, such as: atherosclerosis, (e.g.
  • peripheral vascular atherosclerosis and cerebrovascular atherosclerosis diabetes, hypertension, angina pectoris, after ischaemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute inflammation and chronic inflammation, psoriasis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, multiple sclerosis, autoimmune diseases such as lupus, cardiovascular events (e.g. a heart attack, myocardial infarction or stroke), acute coronary events, restenosis, or diabetic or hypertensive renal insufficiency;
  • cardiovascular events e.g. a heart attack, myocardial infarction
  • BBB blood brain barrier
  • ⁇ abnormal beta amyloid
  • vascular dementia including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease
  • Alzheimer's disease Parkinson's disease
  • Huntington's disease amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • brain hemorrhage and cerebral amyloid angiopathy
  • cerebral amyloid angiopathy vascular dementia (including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), brain hemorrhage, and cerebral amyloid angiopathy;
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • metabolic bone diseases or disorders such as: diseases/disorders associated with loss of bone mass and density including osteoporosis and osteopenic related diseases (e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases);
  • osteoporosis and osteopenic related diseases e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases
  • diseases or disorders associated with macrophage polarization such as: liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • the present invention is not limited to any particular stage of the disease or disorder (e.g. early or advanced).
  • This invention also provides methods of decreasing beta amyloid (also referred to as beta amyloid
  • ⁇ accumulation in the brain of a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the present invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also provides for use of the compounds of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating any disease or disorder described herein.
  • compounds of the invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • the invention also provides compounds of the invention (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment of any disease or disorder described herein.
  • This invention also provides compounds of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy, in particular in the treatment of any disease or disorder described herein.
  • This invention is directed, in a first aspect, to compounds of Formula (I):
  • the structure represented by Formula (I) may be named 4-(((7-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid.
  • the structure represented as Formula (I) contains an asymmetric carbon center (also referred to as a chiral carbon).
  • the stereochemistry of the chiral carbon center present in compounds of this invention is generally represented in the compound names and/or in the chemical structures illustrated herein.
  • stereochemistry of the chiral carbon center is not indicated in the compound structure or name (e.g. as in Formula (I) or the corresponding name referenced above), it is intended that the structure or name encompasses any enantiomer or mixture of enantiomers, including racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.
  • the present invention provides a compound of Formula (I) which is ?,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)- 2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2 enoic acid:
  • salts e.g., pharmaceutically acceptable salts thereof.
  • the present invention provides a compound of Formula (I) which iS,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo- l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid:
  • salts e.g., pharmaceutically acceptable salts thereof.
  • the compound(s) of the invention is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in any physical form.
  • the present invention encompasses compounds of Formula (I) as the free acid and as salts thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention relates to compounds of Formula (I) in the form of a free acid.
  • the invention relates to compounds of Formula (I) in the form of a salt, particularly, a pharmaceutically acceptable salt.
  • the invention relates to compounds of the Examples in the form of a free acid.
  • the invention relates to compounds of the Examples in the form of a salt, particularly, a pharmaceutically acceptable salt.
  • this invention is directed to ?,f)-4-(((7-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid, or a salt, particularly a
  • one particular compound of the invention is ?,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo- l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid (free acid).
  • the compound of the invention is a salt of (R,E )-4-(((7-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid (in particular embodiments, a pharmaceutically acceptable salt thereof).
  • the compound of the invention is an ammonium, calcium, magnesium, sodium, potassium, or zinc salt of ?,f)-4- (((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid.
  • solvates of a compound of Formula (I), or solvates of salts (e.g. pharmaceutically acceptable salts) of a compound of Formula (I), may be formed when solvent molecules are incorporated into the crystalline lattice during crystallization.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric solvate forms.
  • One or more solvents may form a solvate.
  • the solvent(s) which forms a solvate may be aqueous, e.g. water, and/or nonaqueous, e.g. ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and/or ethyl acetate.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates".
  • the salts and/or solvates of the compounds of Formula (I) are preferably pharmaceutically acceptable.
  • pharmaceutically acceptable means a compound or other material (e.g. composition, dosage form) which is suitable for pharmaceutical (medicinal) use.
  • pharmaceutically acceptable compounds or other materials may include those which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their salts and solvates.
  • Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I). If a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK a than the free acid form of the compound. This invention also provides for the conversion of one salt of a compound of this invention into another salt of a compound of this invention.
  • Suitable pharmaceutically acceptable salts can include base salts.
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts, zinc salts, and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ /, ⁇ /'-dibenzylethylenediamine, 2- hydroxyethylamine, b/s-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,
  • dibenzylpiperidine dehydroabietylamine, ⁇ /, ⁇ /'-bisdehydroabietylamine, glucamine, N- methylglucamine, collidine, choline, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • compounds of Formula (I) contain a chiral carbon center.
  • Compounds of this invention containing a chiral center may be present as racemic mixtures, enantiomerically enriched mixtures, , or as enantiomerically pure individual stereoisomers (e.g., >99% enantiomeric purity).
  • the compound of Formula (I) is ?,f)-4-(((7-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid having an enantiomeric purity of >99%, or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • Individual stereoisomers of a compound of this invention may be resolved (or mixtures of stereoisomers may be enriched) using methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compound or salt including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as
  • polymorphs it is to be understood that when named or depicted by structure, the disclosed compound or salt, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, I spectra, and X-ray powder diffraction (XRPD) patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • XRPD X-ray powder diffraction
  • the invention also includes various deuterated forms of the compounds of the invention.
  • One or more available hydrogen atoms attached to a carbon atom may be independently replaced with a deuterium atom.
  • a person of ordinary skill in the art will know how to synthesize deuterated forms of compounds of the invention.
  • commercially available deuterated starting materials may be employed in the preparation of deuterated forms of compounds of the invention. Employing such compounds may allow for the preparation of compounds in which the hydrogen atom at a chiral center is replaced with a deuterium atom.
  • Deuterated starting materials may alternatively be synthesized using conventional techniques employing deuterated reagents (e.g. by reduction using lithium aluminum deuteride or sodium borodeuteride or by metal-halogen exchange followed by quenching with D 2 0 or methanol-d 3 ).
  • compounds of the invention are not in a deuterated form.
  • the invention also includes isotopically-labeled forms of the compounds of the invention, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into isotopically-labeled forms of the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, and fluorine, such as 3 H, n C, 14 C and 18 F.
  • Such isotopically-labeled forms of the compounds of the invention are useful in drug and/or substrate tissue distribution assays.
  • n C and 18 F isotopes are useful in PET (positron emission tomography), which is useful in brain imaging.
  • Isotopically-labeled forms of the compounds of the invention can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the invention are not in and isotopically-labeled form.
  • the compounds of this invention are intended for use in pharmaceutical compositions it will be readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of the invention may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the syntheses provided in these Schemes are applicable for producing compounds of the invention having a different groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See for example, "Protective groups in organic synthesis” by T.W. Green and P.G.M Wuts (Wiley & Sons, 1991) or “Protecting Groups” by P.J.Kocienski (Georg Thieme Verlag, 1994). Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds of Formula (I), they are illustrative of processes that may be used to make the compounds of the invention.
  • R 2 , R 3 , R 4 and A are as defined in Formula (I), i.e. R 1 and R 3 are H, R 2 is CH 3 , A is 3,5-difluoro-4- benzyl, R 4 is 2-(trifluoromethyl)pyridin-4-yl)oxy.
  • PG is a protecting group.
  • Step (i) may be carried out by reacting H 2 NC(R 1 )(R 2 ) C(R 5 ) 2 OH with trichloropyrimidine using appropriate reagents such as potassium carbonate or triethylamine in an appropriate solvent such as acetonitrile under a suitable temperature such as room temperature to provide compound 2.
  • appropriate reagents such as potassium carbonate or triethylamine
  • an appropriate solvent such as acetonitrile
  • Step (ii) may use appropriate reagents such as methanesulfonyl chloride (MsCI) and triethylamine (NEt 3 ) in a suitable solvent such as THF at a suitable temperature such as RT.
  • MsCI methanesulfonyl chloride
  • NEt 3 triethylamine
  • Step (iii) may be taken place by reacting compound 3 with a suitable reagent such as potassium carbonate (K 2 C0 3 ) at an appropriate temperature such as 80 °C.
  • Steps (ii) and (iii) can be accomplished in a one pot procedure may use appropriate reagent such as methanesulfonyl chloride (MsCI) and triethylamine (NEt 3 ) in a suitable solvent such as THF at a suitable temperature such as 25 °C.
  • MsCI methanesulfonyl chloride
  • NEt 3 triethylamine
  • the pyrimidinone may be protected by using a reagent such as di- f-butyldicarbonate and a base such as triethylamine and a catalyst such as N,N- dimethylaminopyrimidine in a suitable solvent such as tetrahydrofuran (THF) at suitable temperature such as room temperature to provide protected compound 5.
  • a reagent such as di- f-butyldicarbonate and a base such as triethylamine and a catalyst such as N,N- dimethylaminopyrimidine in a suitable solvent such as tetrahydrofuran (THF) at suitable temperature such as room temperature to provide protected compound 5.
  • THF tetrahydrofuran
  • Step (v) may be carried out by reacting compound 5 with R 4 -A-OH in the presence of suitable base such as sodium hydride (NaH) in a suitable solvent such as A/,/ ⁇ /-dimethyformamide (DMF) at suitable temperature such as room temperature to provide the compounds 6 or 7 or 8.
  • suitable base such as sodium hydride (NaH)
  • suitable solvent such as A/,/ ⁇ /-dimethyformamide (DMF)
  • suitable temperature such as room temperature
  • Step (vi) A protecting group such as t-butoxycarbonyl may be removed from compound 8 by a reagent such as 4M hydrogen chloride in 1,4-dioxane ot a strong acid such as trifluoroacetic acid at a temperature such as room temperature to provide de-protected compound 7.
  • a reagent such as 4M hydrogen chloride in 1,4-dioxane ot a strong acid such as trifluoroacetic acid at a temperature such as room temperature to provide de-protected compound 7.
  • the intermediate R -A-OH can be prepared by using nucleophilic aromatic substitution chemistry to prepare the R 4 -A species with a base such as potassium carbonate (K 2 C0 3 ) and a solvent such as acetonitrile at a temperature such as 80 °C.
  • A can be modified by standard function group manipulation, for example the reduction of an aldehyde or an ester by reagents such as sodium borohydride or lithium aluminium hydride to furnish a primary alcohol.
  • R5 and R6 are H.
  • Step (i) may be carried out by reacting compound 7 with an acylating XC(0)OC(R 5 R 6 )Y using appropriate bases such as potassium carbonate or triethylamine and a catalyst such as N,N- dimethylaminopyridine in an appropriate solvent such as dichloromethane under a suitable temperature such as room temperature to provide compound 8.
  • X and Y could be leaving groups such as chloride.
  • X could be Y(R 5 R 6 )CO(0)- i.e an anhydride.
  • Step (ii) may use appropriate reagents such as the sodium salt of the acid R 7 C0 2 H in as solvent such as DMF at a temperature such as 115 Q C.
  • the reaction mixture was partitioned between ethyl acetate (1000 mL) and water (1000 mL) and the layers separated. The organic layer was washed with brine and dried over Na 2 S0 4 . The solvent was evaporated under reduced pressure to give a gum which was then dissolved in ethyl acetate (500 mL) and stirred for lh. The precipitated solid was filtered to afford 40 g of the title compound. The filtrate was resubjected to the above procedure to give a further 60 g of the title compound. The two batches were then combined.
  • reaction mixture was stirred for 1 h at RT under nitrogen.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL), the organic layers were combined and then washed with brine solution (50 mL).
  • the organic layer was separated, dried over anhydrous Na 2 S04 and concentrated under reduced pressure to give the title compounds (1 g) as an off white solid which was used without further purification.
  • Example 1 /?,£)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2- enoic acid
  • reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL), the organic layers were combined and washed with brine solution (4 x 25 mL). The organic layer was separated, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford crude product which was purified using preparative HPLC method A. The product containing fractions were combined and lyophilized to give the title compound (135 mg) as a white solid.
  • Example 2 S,£)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2- enoic acid
  • the compounds of present invention are Lp-PLA 2 inhibitors, and therefore may be useful in the treatment of diseases or disorders associated with Lp-PLA 2 activity.
  • the biological activities of the compounds of present invention can be determined by using any suitable assay for determining the activity of a compound as an Lp-PLA 2 inhibitor, as well as tissue and in vivo models, including the assays described herein.
  • l-0-hexadecyl-2-deoxy-2-thio-S-acetyl-sn-glyceryl-3-phosphorylcholine (2-thio-PAF) is a substrate for PAF-hydrolases (PAF-AH) commercially available from Cayman Chemical.
  • the biological activity data for the Example 1 title compound was either reported in at least one experiment or the average of multiple experiments.
  • the data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments.
  • the Thio-PAF assay was run as an unquenched 20 ⁇ assay.
  • the source plate containing the compounds to be tested was prepared by making 1:3 (by volume) serial dilution of the compounds within DMSO on 384-well microplate. Then, 5 ⁇ of the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ⁇ of recombinant human Lp-PLA2 enzyme (20 pM rhLp-PLA2 in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to each well of the plate.
  • substrate comprising 40 ⁇ 2-thio-PAF [from ethanol stock], 40 ⁇ CPM [from a DMSO stock] and 400 ⁇ NEM (N- ethylmaleimide) [made fresh daily in DMSO] in assay buffer (50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to 384 well Greiner 784076 black plates. Plates were vortexed for 10 sec. The plate was covered to protect it from light and incubated for 20 min at 25 °C. The plates were read for fluorescence intensity at ex: 380nm / em: 485nm using Envision plate reader (Perkin Elmer). Raw data are transferred to Excel software and plC50 data, curve and QC analysis was conducted by using XL fit module in Excel.
  • the Thio-PAF assay was run as an unquenched 20 ⁇ assay.
  • the source plate containing the compounds to be tested was prepared by making 1:3 (by volume) serial dilution of the compounds within DMSO on 384-well microplate. Then, 5 ⁇ ⁇ the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ⁇ of recombinant human PLA2 -VIIB enzyme (200 pM rhPLA2 -VIIB in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to each well of the plate.
  • substrate comprising 40 ⁇ 2-thio-PAF [from ethanol stock], 40 ⁇ CPM [from a DMSO stock] and 400 ⁇ NEM (N- ethylmaleimide) [made fresh daily in DMSO] in assay buffer (50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to 384 well Greiner 784076 black plates. Plates were vortexed for 10 sec. The plate was covered to protect it from light and incubated for 20 min at 25 °C. The plates were read for fluorescence intensity at ex: 380nm / em: 485nm using Envision plate reader (Perkin Elmer). Raw data are transferred to Excel software and plC50 data, curve and QC analysis was conducted by using XL fit module in Excel.
  • Lipoprotein-associated phospholipase A2 (Lp-PI_A2) Human Plasma assay
  • the human plasma assay utilizes the same thioester analog of PAF as described in the above Recombinant human Lp-PLA2 assay. This assay may detect the activity of Lp-PI_A2 in human plasma, as determined by specific inhibition by Lp-PLA2 inhibitors.
  • the thio-PAF assay was run as a quenched 20 ⁇ assay.
  • Compounds source plate was prepared by making 1:3 (by volume) serial dilution of the compounds into pure DMSO on 96-well microplate. 5 ⁇ of compounds on compound source plate were transferred to 96-well Corning 3686 (black) low-volume plates by STAR+ (Hamilton) liquid dispenser. 10 ⁇ pooled human plasma, which was previously aliquoted and frozen, was added. Plates were centrifuged for 30 sec at 1000 rpm.
  • Example 1 The compound of Example 1 has been found to have significantly improved solubility in FaSSIF compared to the parent compound (Intermediate 7) whilst having good solution stability.
  • the solution stability of Example 1 was assessed in Fed and Fasted State Simulated Intestinal Fluid (FeSSIF pH 6.5 and FaSSIF pH 6.5 respectively) and in Simulated Gastric Fluid (SGF pH 1.6) stored for up to 24 hours at 37°C.
  • Example 1 FaSSIF and FeSSIF pH 6.5 samples were prepared at a concentration of 50 g/mL in each media.
  • the SGF pH 1.6 sample was also prepared at 50 g/mL with the addition of 12%v/v of acetonitrile which was added to ensure the solubility of the compound.
  • Example 1 drug-related impurity profile was determined by reverse phase gradient HPLC. The method used a 3.5 ⁇ (4.6 x 150mm) Waters Xbridge C18. The mobile phase was a mixture of acetonitrile, water and trifluoroacetic acid, with UV detection at 280 nm.
  • Example 1 The solubility of Example 1 and Intermediate 7 were measured in Fasted State Simulated Intestinal Fluid pH 6.5 (FaSSIF) media at room temperature over 24 hours in separate
  • Example 2 As shown in Table 2, the compound of Example 1 was highly soluble in Fassif at T. In comparison, the parent compound has very low solubility.
  • PK pharmacokinetic
  • PK pharmacokinetic
  • Example 1 compound in solution was administered orally [solution of DMSO/hydroxypropyl-beta-cyclodextrin 6% in phosphate buffer 60mM pH 7 (3:97)] to fed animals at a target dose of 3mg/kg.
  • Non-compartmental methods were used for pharmacokinetic analysis of blood concentration versus time data. Summary results are shown in Table 5 (Except for Tmax and F, results are given as mean +/- standard deviation).
  • PK pharmacokinetic
  • Example 1 title compound is efficiently converted to the parent compound (Intermediate 7 title compound).
  • the solution and bioavailability studies indicate that the compound of Example 1 is a pro-drug of the Intermediate 7 compound, and is efficiently converted to the parent compound (Intermediate 7).
  • the studies also indicate that the pro-drug has a greatly improved solubility in Fassif at RT, compared to the parent which has very low solubility, and good solution stability. These properties are typically desirable in a compound to be used as a pharmaceutical.
  • the compounds of the invention are inhibitors of Lp-PLA 2 . Therefore, these compounds may be used in therapy, for example, in the treatment of diseases or disorders associated with the activity of Lp-PLA 2 , including for example treatment of diseases or disorders where inhibition of Lp-PLA 2 is of therapeutic benefit.
  • inhibition of Lp- PLA 2 may involve one or more mechanisms, and a particular disease or disorder or its treatment may involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including those described herein.
  • the invention provides a method of inhibiting Lp-PLA 2 comprising contacting a biological material comprising the protein with a compound of the invention.
  • the contact is made in-vitro
  • the biological material is, e.g., cell culture or cellular tissue.
  • the contact is made in-vivo.
  • the invention also provides a method of treating a disease or disorder associated with Lp-PLA 2 activity, comprising administering a therapeutically effective amount of a compound of the invention, to a subject in need of such treatment.
  • This invention also provides a compound of the invention, for use in therapy.
  • This invention particularly provides for the use of a compound of the invention as an active therapeutic substance in the treatment of a disease or disorder associated with Lp-PLA 2 activity.
  • the invention also provides for the use of a compound of the invention in the
  • Treatment according to each of the methods of the invention comprises administering a therapeutically effective amount of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt, to a subject in need thereof.
  • treatment according to the methods of the invention comprises administering a therapeutically effective amount of ( ?,f)-4-(((7-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid to a subject in need thereof.
  • treatment according to the methods of the invention comprises administering a therapeutically effective amount of a
  • the subject in need of treatment has a disease or disorder disclosed herein. In some embodiments, the subject in need of treatment is at risk of having a disease or disorder disclosed herein.
  • the subject is a mammal, particularly a human.
  • Treatment according to any one or more of the methods of the invention applies to any of the diseases or disorders associated with Lp-PLA 2 activity disclosed herein, including any particular disease or disorder.
  • neurodegenerative disease or disorders refers to a varied assortment of central nervous system disorders characterized by gradual and progressive loss of neural tissue and/or neural tissue function.
  • Neurodegenerative diseases or disorders are a class of neurological diseases/disorders where the neurological disease/disorder is characterized by a gradual and progressive loss of neural tissue, and/or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue.
  • the neurodegenerative diseases or disorders described herein include neurodegenerative diseases and disorders where there is a defective blood brain barrier, for example a permeable blood brain barrier.
  • vascular dementia refers to a group of syndromes caused by different mechanisms, which all result in vascular lesions in the brain.
  • the main subtypes of vascular dementia are, for example, vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulated gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, e.g. vascular dementia due to lacunar lesions and Binswanger disease), and mixed dementia.
  • blood-brain barrier or "BBB” are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the brain tissue that severely restricts and closely regulates what is exchanged between the blood and the brain tissue.
  • the blood brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel.
  • the BBB prevents most substances in the blood from entering brain tissue, including most large molecules such as Ig, antibodies, complement, albumin and drugs and small molecules.
  • inner blood-retinal barrier or “iB B” are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the retinal tissue that severely restricts and closely regulates what is exchanged between the blood and the retinal tissue.
  • the blood retinal barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the iBRB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytic cells and pericytes, including glial cells, which cover nearly all of the exposed outer surface of the blood vessel.
  • abnormal BBB is used to refer to a dysfunctional BBB, for example, where the BBB does not allow transit of molecules that normally transit a functional BBB, for example nutrients and sugars such as glucose.
  • An abnormal BBB can also refer to when the BBB is permeable to molecules that a normally functioning BBB would typically exclude, which is typically referred to "BBB permeability" herein.
  • abnormal inner BRB is used to refer to a dysfunctional iBRB, for example, where the iBRB does not allow transit of molecules that normally transit a functional iBRB, for example nutrients and sugars such as glucose.
  • An abnormal iBRB can also refer to when the iBRB is permeable to molecules that a normally functioning iBRB would typically exclude, which is typically referred to "iBRB permeability" herein.
  • BBB permeability or “permeable BBB” are commonly referred to by persons in the art as “leaky BBB”. The terms are used interchangeably herein to refer to impaired BBB integrity and increased vascular permeability.
  • a permeable BBB allows transit of molecules through the BBB that an intact BBB would normally exclude from the brain tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins.
  • An assay to determine the presence of a permeable BBB can be, for example, to assess the presence of extravascular Ig in the brain tissue which is normally restricted to the lumen of blood vessels when the BBB is functioning normally (i.e., when the BBB is not permeable), such as known in the art.
  • iBRB permeability or "permeable iBRB” are commonly referred to by persons in the art as “leaky iBRB”. The terms are used interchangeably herein to refer to impaired iBRB integrity and increased vascular permeability.
  • a permeable iBRB allows transit of molecules through the iBRB that an intact iBRB would normally exclude from the retinal tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins.
  • An assay to determine the presence of a permeable iBRB can be, for example, to assess the presence of extravascular Ig in the retinal tissue which is normally restricted to the lumen of blood vessels when the iBRB is functioning normally (i.e., when the BRB is not permeable), such as known in the art.
  • the disease or disorder is an ocular disease or disorder.
  • the ocular disease or disorder is associated with the breakdown of the inner blood-retinal barrier (iBRB).
  • the ocular disease or disorder is a neurodegenerative eye disease or disorder, e.g. a neurodegenerative retina eye disease or disorder.
  • Exemplary ocular diseases/disorders include diabetic eye diseases or disorders (e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like), retinal vein occlusion (e.g.
  • central retinal vein occlusion central retinal vein occlusion, branched retinal vein occlusion), Irvine-Gass syndrome (post cataract and post-surgical), retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy, epiretinal membrane, choroidal tumors, cystic macular edema, parafoveal telengiectasis, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, macular edema (e.g., in addition to diabetic macular edema, macular edema associated with uveitis (particularly posterior uveitis), retinal vein occlusion, inflammation, post-surgical traction and the like, and idiopathic macular edema), glaucoma, macular degeneration (e.g. age-related macular degeneration) and the like.
  • macular degeneration e.g. age-
  • the disease is a systemic inflammatory disease which may be the underlying cause of posterior uveitis affecting the retina, which can result in macular edema, such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt- Koyanagi-Harada syndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis, chronic granulomatous disease, or enthesitis.
  • ocular diseases and disorders which may be treated by the methods of the invention herein are include those disclosed in WO2012/080497, which is incorporated by reference herein.
  • the disease or disorder is selected from the diseases or disorders disclosed in the following published patent applications:
  • the disease or disorder involves and/or is associated with: (1) endothelial dysfunction, for example, atherosclerosis, (e.g.
  • peripheral vascular atherosclerosis and cerebrovascular atherosclerosis diabetes, hypertension, angina pectoris and after ischaemia and reperfusion
  • lipid oxidation in conjunction with enzyme activity for example, atherosclerosis, diabetes, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute inflammation and chronic inflammation
  • activated or increased involvement of monocytes, macrophages or lymphocytes as all of these cell types express Lp-PLA 2 including diseases involving activated macrophages such as Ml, dendritic and/or other macrophages which generate oxidative stress (e.g., psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysem
  • COPD chronic
  • the disease or disorder is a cardiovascular event (e.g. a heart attack, myocardial infarction or stroke).
  • a cardiovascular event e.g. a heart attack, myocardial infarction or stroke.
  • compounds of the present invention may be used to lower the chances of having a cardiovascular event, e.g. in a patient with coronary heart disease.
  • the disease or disorder is an acute coronary event, restenosis, or diabetic or hypertensive renal insufficiency.
  • compounds of the invention may be used for the primary or secondary prevention of acute coronary events, e.g. caused by atherosclerosis; adjunctive therapy in the prevention of restenosis; or delaying the progression of diabetic or hypertensive renal insufficiency.
  • the disease or disorder is a neurological disease or disorder associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation.
  • BBB blood brain barrier
  • the abnormal BBB is a permeable BBB.
  • the disease is a neurodegenerative disease, e.g., vascular dementia (including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).
  • vascular dementia including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease
  • Alzheimer's disease Parkinson's disease
  • Huntington's disease Huntington's disease
  • MS amyotrophic lateral sclerosis
  • the disease or disorder is associated with blood brain barrier (BBB) leakage.
  • BBB blood brain barrier
  • diseases/disorders include, but are not limited to, brain hemorrhage and cerebral amyloid angiopathy.
  • the disease or disorder is associated with abnormal beta amyloid (" ⁇ ") accumulation in the brain.
  • treatment may be used to decrease ⁇ levels of a subject or to decrease accumulation of ⁇ in the brain of subject.
  • the beta amyloid is Abeta-42.
  • Examples of neurodegenerative diseases and disorders, and diseases and disorders associated with an abnormal BBB (e.g., permeable BBB) which may be treated by the methods of the invention include those disclosed in U.S. Patent Application Publication No. 2008/0279846 and WO2008/140449 , which are incorporated by reference herein.
  • the disease or disorder is a metabolic bone disease or disorder.
  • exemplary metabolic bone diseases/disorders include diseases/disorders associated with loss of bone mass and density including, but not limited to, osteoporosis and osteopenic related diseases (e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases).
  • osteoporosis and osteopenic related diseases e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases.
  • Examples of metabolic bone diseases and disorders which may be treated by the methods of the invention include those disclosed in WO2008/140450 and US20080280829 , which are incorporated by reference herein.
  • the disease or disorder is a skin ulcer.
  • skin ulcers which may be treated by the methods of the invention include those disclosed in WO2008/141176 and US2010/0239565 , which are incorporated herein by reference.
  • the disease or disorder is associated with macrophage polarization, for example, M1/M2 macrophage polarization.
  • Exemplary diseases associated with macrophage polarization include, but are not limited to, liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • Treatment is intended to mean at least the mitigation of a disease or disorder in a subject.
  • the methods of treatment for mitigation of a disease or disorder include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy, improvement or cure of a disease or disorder.
  • treatment may involve at least the mitigation of one or more symptoms of a disease or disorder.
  • Treatment may involve: (1) to amelioration of the disease/disorder or one or more of the biological manifestations of the disease/disorder, (2) interference with (a) one or more points in the biological cascade that leads to or is responsible for the or (b) one or more of the biological manifestations of the disease/disorder, (3) alleviation one or more of the symptoms or effects associated with the disease/disorder, (4) slowing the progression of the disease/disorder or one or more of the biological manifestations of the disease/disorder, and/or (5) diminishing the likelihood of severity of a disease/disorder or biological manifestations of the disease/disorder.
  • treat includes “prevent”, “preventing” or “prevention”.
  • prevent means the prophylactic administration of a drug to diminish the likelihood of the onset of or to delay the onset of a disease disorder or biological manifestation thereof, including administration to a subject at risk of having a disease or disorder.
  • a “therapeutically effective amount” is intended to mean that amount of a compound that, when administered to a subject in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the invention is a quantity of such agent that, when administered to a subject (e.g., human) in need thereof, is sufficient to modulate or inhibit the activity of Lp-PLA 2 such that a disease/disorder condition which is mediated or inhibited by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (plC 50 ) and the biological half-life of the particular compound), disease/disorder condition and its severity, and the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (plC 50 ) and the biological half-life of the particular compound
  • disease/disorder condition and its severity e.g., age, size and weight
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the patient in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease/disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • a therapeutically effective amount of a compound of the invention for the treatment of a disease or disorder described herein will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or in a number of sub-daily doses per day as such as two, three, four, five or six doses per day.
  • the dosing can be done intermittently, such as once every other day, once a week, once a month, or frequencies therebetween.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal
  • Oral administration includes enteral (digestive tract) and buccal or sublingual administration. Parenteral
  • administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion into tissue or blood.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • Compounds of the invention may also be administered intradermal ⁇ or through transdermal implants.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, four or more times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. In some embodiments, total daily dosages range from 1 mg to 2000 mg, e.g., total daily dosages may range from 1 mg to 250 mg.
  • the methods of the invention including methods of treating herein described may be achieved using a compound of this invention as a monotherapy, or in dual or multiple
  • Combination therapy includes administration of the therapeutic agents in separate dosage forms or together in a single dosage form. Combination therapy may involve
  • combination therapy will involve administration of each agent such that therapeutically effective amounts of each agent are present in the subject's body in at least an overlapping period.
  • the other therapeutic agent(s) used in combination therapy with a compound of the invention may be administered in therapeutically effective amounts, e.g., as is known in the art, or lesser or greater amounts than known in the art provided that the amount administered is therapeutically effective.
  • treatment can involve combination with other existing modes of treatment, e.g. existing agents and procedures for treatment of ocular diseases or disorders, such as anti VEGF therapeutics (e.g. Lucentis ® , Avastin ® and Aflibercept ® ),steroids, e.g., triamcinolone, and steroid implants containing fluocinolone acetonide, retinal focal laser photocoagulation, and pan-retinal photocoagulation,.
  • VEGF therapeutics e.g. Lucentis ® , Avastin ® and Aflibercept ®
  • steroids e.g., triamcinolone
  • steroid implants containing fluocinolone acetonide
  • retinal focal laser photocoagulation e.g., and pan-retinal photocoagulation
  • combination therapy may include treatment with one or more therapeutic actives for treating atherosclerosis, cardiovascular disease or coronary heart disease.
  • the compounds of the present invention may be used to treat the disease or disorder described herein in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lipoprotein (a) (Lp(a)).
  • agents include, but are not limited to, cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitizers, calcium channel antagonists, and anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs).
  • agents for lowering Lp(a) include aminophosphonates, e.g. those described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312.
  • the compounds of the present invention may be used with one or more statins, e.g., atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin.
  • the compounds of the present invention may be used with an anti-diabetic agent or an insulin sensitizer.
  • a compound of the present invention may be used with a PPA gamma activator, for instance GI262570 (GlaxoSmithKline) and a compound from the glitazone class such as rosiglitazone, troglitazone and pioglitazone.
  • a PPA gamma activator for instance GI262570 (GlaxoSmithKline) and a compound from the glitazone class such as rosiglitazone, troglitazone and pioglitazone.
  • the other therapeutic agent is useful in treating a
  • the present invention provides methods of slowing or delaying the progression of cognitive and/or function decline in patients with Alzheimer's disease, e.g. mild or moderate Alzheimer's disease, cerebrovascular (CVD) disease, and/or similar disease.
  • the compounds of the present invention may be used as an adjunct to an agent that is used to provide symptomatic treatment to patients with such diseases.
  • the subject may be treated with other agents targeting Alzheimer's disease such as memantine, ARICEPT' or donepezil, COGNEX * or tacrine, EXELON * or rivastigmine, REMINYL * or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • agents targeting Alzheimer's disease such as memantine, ARICEPT' or donepezil, COGNEX * or tacrine, EXELON * or rivastigmine, REMINYL * or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • the additional therapeutic agent(s) is used in the treatment of skin ulcers, for example, anti-microbial therapy, anti-parasitic therapy, anti-obesity therapy, diabetes therapy, cardiovascular disease therapy, renal failure therapy, vasculitis therapy, venous insufficiency therapy, arterial insufficiency therapy, cancer therapy, immunosuppressant therapy, immunodeficiency therapy, steroid therapy, burn therapy, standard wound-care management, and/or bioengineered skin substitutes.
  • skin ulcers for example, anti-microbial therapy, anti-parasitic therapy, anti-obesity therapy, diabetes therapy, cardiovascular disease therapy, renal failure therapy, vasculitis therapy, venous insufficiency therapy, arterial insufficiency therapy, cancer therapy, immunosuppressant therapy, immunodeficiency therapy, steroid therapy, burn therapy, standard wound-care management, and/or bioengineered skin substitutes.
  • the additional therapeutic agent(s) is used in the treatment of metabolic bone diseases or disorders.
  • the metabolic bone disease is osteoporosis additional therapeutic agent(s) such as bisphosphates (e.g., alendronate,
  • ibandromate risedronate, calcitonin, raloxifene
  • SE M selective estrogen modulator
  • E/HRT hormone replacement therapy
  • teriparatide a selective estrogen modulator
  • the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a subject. Accordingly, the invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising ( ⁇ fJ- ⁇ iiiy-iiS ⁇ -difluoro- ⁇ iiZ-itrifluoromethylJpyridin ⁇ -ylJoxyJbenzylJoxyJ-Z-methyl- 5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises ( ?,f)-4-(((7-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid.
  • the pharmaceutical composition comprises a salt, e.g., a pharmaceutically acceptable salt, of ( ?,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2- enoic acid.
  • a salt e.g., a pharmaceutically acceptable salt
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the subject such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (particularly, a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • the pharmaceutical compositions may contain from 0.1 mg to 1000 mg (e.g., 0.1 - 500 mg, 0.1 - 250 mg, or 0.1 - 100 mg) of a compound of this invention.
  • the pharmaceutical compositions contain from 1 mg to 1000 mg (e.g., 1 - 500 mg, 1 - 250, or 1 - 100 mg) of a compound of the invention.
  • Unit dosage form pharmaceutical compositions containing from 0.1 to 1000 mg of a compound of the invention may be administered one, two, three, four or more times per day, preferably one, two or three times per day, and more preferably one or two times a day, to effect treatment of an Lp-PLA 2 -mediated disease or disorder, e.g., as described herein.
  • the pharmaceutical composition may include one or more compounds of the invention and/or one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention.
  • the pharmaceutical composition of the invention contains both ⁇ fJ ⁇ -iiiy-iiS ⁇ -difluoro ⁇ -iiZ-itrifluoromethy pyridin ⁇ -ylJoxyJbenzylJoxyJ-Z- methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2- enoic acid and S,f)-4-(((7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidine-l-carbonyl)oxy)methoxy)-4-oxobut-2- enoic acid, and/or a pharmaceutically acceptable salt of one or both compounds (e.g.,
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle other than the active pharmaceutical ingredient(s) intended for treating a disease or disorder (e.g., a compound of the invention).
  • Pharmaceutically acceptable excipients are involved in providing a property or function useful to a pharmaceutical composition, for example an excipient may be involved in modifying physical, sensory, stability, or pharmaco-kinetic properties of the composition, for example in giving form or consistency to the composition, in bulking up the active ingredient (e.g. for convenient and accurate
  • each excipient will be involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention (or any other active ingredient, if present) when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compounds of the invention and the pharmaceutically acceptable excipient(s) will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, lozenges, troches, powders, granules, syrups, elixirs, suspensions, solutions, edible foams or whips, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, lyophiles, microparticles, nanocarriers, implants, preformed implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions and solutions; and (6) topical administration such as creams, ointments, lotions
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to: facilitate the production of uniform dosage forms, to facilitate the production of stable dosage forms, to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the subject from one organ, or portion of the body, to another organ, or portion of the body, and/or to enhance subject compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, carriers, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press), including current and past editions.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising the step of admixing a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients.
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a diluent or filler, and optionally a binder, disintegrant, and/or lubricant.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • Suitable binders include starch (e.g.
  • Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

Abstract

La présente invention concerne de nouveaux composés qui inhibent l'activité de la Lp-PLA2, des procédés pour les préparer, des compositions les contenant, et leur utilisation pour le traitement de maladies ou de troubles associés à l'activité de la Lp-PLA2.
PCT/IB2015/055404 2014-07-22 2015-07-16 Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 WO2016012917A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462027417P 2014-07-22 2014-07-22
US62/027,417 2014-07-22

Publications (1)

Publication Number Publication Date
WO2016012917A1 true WO2016012917A1 (fr) 2016-01-28

Family

ID=53718074

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/055404 WO2016012917A1 (fr) 2014-07-22 2015-07-16 Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2

Country Status (1)

Country Link
WO (1) WO2016012917A1 (fr)

Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013484A1 (fr) 1994-10-29 1996-05-09 Smithkline Beecham Plc Derives d'azetidinone destines au traitement de l'atherosclerose
WO1996019451A1 (fr) 1994-12-22 1996-06-27 Smithkline Beecham Plc Azetidin-2-ones substituees, destinees au traitement de l'atherosclerose
WO1997002242A1 (fr) 1995-07-01 1997-01-23 Smithkline Beecham Plc Derives de l'azetidinone pour le traitement de l'atherosclerose
WO1997002037A1 (fr) 1995-06-30 1997-01-23 Symphar S.A. Composes et compositions pharmaceutiques les contenant
WO1997012963A2 (fr) 1995-09-29 1997-04-10 Smithkline Beecham Plc Paf-acetylhydrolase paf et son utilisation en therapie
WO1997021676A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
WO1997021675A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041099A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives d'azetidinone pour le traitement de l'atherosclerose
WO1997041098A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
WO1998028310A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1998028312A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques de l'acide aminophosphonique
WO1998028311A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1999024420A1 (fr) 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
JP2001088847A (ja) 1999-09-22 2001-04-03 Toppan Printing Co Ltd 再封可能な開口維持部材付パウチ
WO2001060805A1 (fr) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030904A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2002030911A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2003015786A1 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
WO2003016287A2 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes
WO2003041712A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2003042206A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Composes pyridinone et pyrimidinone
WO2003042179A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives heterocycliques de glycinamide et leur utilisation medicale
WO2003042218A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives condenses de pyrimidone en tant qu'inhibiteurs de lp-pla2 pour le traitement de l'atherosclerose
WO2003087088A2 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Nouveaux composes
WO2003086400A1 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Derives de pyridinone et de pyrimidinone substitues en n a utiliser en tant qu'inhibiteurs de lp-pla2 dans le traitement de l'atherosclerose
CA2530816A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
WO2006063813A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazone-5(2h)-ones substituees par 3-arylalkyle et 3-heteroarylalkyle
WO2006063811A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazin-5(2h)-ones substituees
US20080090852A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
US20080090851A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
WO2008048866A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétéroaromatiques bicycliques
WO2008048867A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétoroaromatiques bicycliques
US20080280829A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of metabolic bone diseases and disorders
US20080279846A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
WO2008140450A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles osseux métaboliques
WO2008141176A1 (fr) 2007-05-11 2008-11-20 The Trustees Of The University Of Pennsylvania Procédés de traitement des ulcères de la peau
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2013013503A1 (fr) * 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2014114694A1 (fr) * 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one

Patent Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013484A1 (fr) 1994-10-29 1996-05-09 Smithkline Beecham Plc Derives d'azetidinone destines au traitement de l'atherosclerose
WO1996019451A1 (fr) 1994-12-22 1996-06-27 Smithkline Beecham Plc Azetidin-2-ones substituees, destinees au traitement de l'atherosclerose
WO1997002037A1 (fr) 1995-06-30 1997-01-23 Symphar S.A. Composes et compositions pharmaceutiques les contenant
WO1997002242A1 (fr) 1995-07-01 1997-01-23 Smithkline Beecham Plc Derives de l'azetidinone pour le traitement de l'atherosclerose
WO1997012963A2 (fr) 1995-09-29 1997-04-10 Smithkline Beecham Plc Paf-acetylhydrolase paf et son utilisation en therapie
WO1997021676A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
WO1997021675A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041099A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives d'azetidinone pour le traitement de l'atherosclerose
WO1997041098A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
WO1998028312A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques de l'acide aminophosphonique
WO1998028310A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1998028311A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1999024420A1 (fr) 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
JP2001088847A (ja) 1999-09-22 2001-04-03 Toppan Printing Co Ltd 再封可能な開口維持部材付パウチ
WO2001060805A1 (fr) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030904A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2002030911A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2003015786A1 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
WO2003016287A2 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes
WO2003042206A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Composes pyridinone et pyrimidinone
WO2003041712A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2003042179A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives heterocycliques de glycinamide et leur utilisation medicale
WO2003042218A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives condenses de pyrimidone en tant qu'inhibiteurs de lp-pla2 pour le traitement de l'atherosclerose
WO2003087088A2 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Nouveaux composes
WO2003086400A1 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Derives de pyridinone et de pyrimidinone substitues en n a utiliser en tant qu'inhibiteurs de lp-pla2 dans le traitement de l'atherosclerose
CA2530816A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
WO2005003118A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
WO2006063813A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazone-5(2h)-ones substituees par 3-arylalkyle et 3-heteroarylalkyle
WO2006063811A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazin-5(2h)-ones substituees
WO2008048867A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétoroaromatiques bicycliques
US20080090851A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
WO2008048866A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétéroaromatiques bicycliques
US20080090852A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
US20080103156A1 (en) 2006-10-13 2008-05-01 Leach Colin A Bicyclic Heteroaromatic Compounds
WO2008140450A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles osseux métaboliques
US20080279846A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
US20080280829A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of metabolic bone diseases and disorders
WO2008141176A1 (fr) 2007-05-11 2008-11-20 The Trustees Of The University Of Pennsylvania Procédés de traitement des ulcères de la peau
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
US20100239565A1 (en) 2007-05-11 2010-09-23 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2013013503A1 (fr) * 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2014114694A1 (fr) * 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one

Non-Patent Citations (35)

* Cited by examiner, † Cited by third party
Title
"Effect of Darapladib on Prevention of Ischemic Events in Stable Coronary Heart Disease", N ENGL J MED., vol. 370, no. 18, 2014, pages 1702 - 1711
"Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque", CIRCULATION, vol. 118, 2008, pages 1172 - 1182
"Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies", LANCET, vol. 375, 2010, pages 1536 - 1544
"The Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent: The Results of a Multicenter, Randomized Double-Blind, Placebo-Controlled Study", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 51, 2008, pages 1632 - 1641
"The Handbook of Pharmaceutical Excipients", AMERICAN PHARMACEUTICAL ASSOCIATION AND THE PHARMACEUTICAL PRESS
.: "The Handbook of Pharmaceutical Additives", GOWER PUBLISHING LIMITED
ACHARYA NK ET AL.: "Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib", J ALZHEIMERS DIS., vol. 35, no. 1, 2013, pages 179 - 98
BUSCHINI ET AL., PROGRESS IN NEUROBIOLOGY, vol. 95, 2011, pages 14 - 25
CHINETTI-GBAGUIDI, G. ET AL.: "Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARy and LXRa pathways", CIRCULATION RESEARCH, vol. 108, 2011, pages 985 - 995
COLANGELO ET AL., JOURNAL OF NEUROSCIENCE RESEARCH, vol. 70, 2002, pages 462 - 473
DILDAR ET AL., ALZHEIMER DIS ASSOC DISORD, 24 April 2010 (2010-04-24)
FERGUSON, J. F. ET AL.: "Translational studies of lipoprotein-associated phospholipase A2 in inflammation and atherosclerosis", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 59, 2012, pages 764 - 772
GARZA CA ET AL.: "Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review", MAYO CLIN PROC, vol. 82, 2007, pages 159 - 165
GONÇALVES, I. ET AL.: "Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 32, 2012, pages 1505 - 1512
HERRMANN, J. ET AL.: "Expression of lipoprotein-associated phospholipase A2 in carotid artery plaques predicts long-term cardiac outcome", EUROPEAN HEARTJOURNAL, vol. 30, 2009, pages 2930 - 2938
JOHNSON JL ET AL.: "Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial", PLOS ONE, vol. 9, no. 2, 20 February 2014 (2014-02-20), pages E89034
KASSNER ET AL., CURRENT ALZHEIMER RESEARCH, vol. 5, 2008, pages 358 - 366
KOLODGIE FD ET AL.: "Lipoproteinassociated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis", ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, vol. 26, 2006, pages 2523 - 9
LIU CHUNJIAN ET AL: "Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38[alpha] inhib", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 23, no. 10, 15 March 2013 (2013-03-15), pages 3028 - 3033, XP028582237, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2013.03.022 *
MACPHEE CH ET AL.: "Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates the oxidation of low-density lipoprotein: use of a novel inhibitor", BIOCHEM J, vol. 338, 1999, pages 479 - 87
MACPHEE CH ET AL.: "Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target", CURRENT OPINION IN PHARMACOLOGY, vol. 6, 2006, pages 154 - 161
MANNHEIM D. ET AL.: "Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques", STROKE, vol. 39, 2008, pages 1448 - 55
P.J.KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG
PERRY, ACTA NEUROPATHOL, vol. 120, 2010, pages 277 - 286
SHI ET AL., ATHEROSCLEROSIS, vol. 191, 2007, pages 54 - 62
SINEM ET AL., CURRENT ALZHEIMER RESEARCH, vol. 7, 2010, pages 463 - 469
T.W. GREEN; P.G.M WUTS: "Protective groups in organic synthesis", 1991, WILEY & SONS
TEZEL: "Progress in Brain Research", vol. 173, ISBN: 0079-6123, article "Chapter 28"
VAN OIJEN ET AL.: "Annals of Neurology", vol. 59, 2006, pages: 139
WILENSKY ET AL., CURRENT OPINION IN LIPIDOLOGY, vol. 20, 2009, pages 415 - 420
WILENSKY ET AL., NATURE MEDICINE, vol. 10, 2008, pages 1015 - 1016
WILENSKY RL ET AL.: "Inhibition of lipoproteinassociated phospholipase A2 reduces complex coronary atherosclerotic plaque development", NATURE MEDICINE, 21 September 2008 (2008-09-21)
WYSS-CORAY, NATURE MEDICINE, vol. 12, September 2006 (2006-09-01)
ZALEWSKI A ET AL., ARTERIOSCLER. THROMB. VASC. BIOL., vol. 25, no. 5, 2005, pages 923 - 31
ZALEWSKI A ET AL.: "Role of lipoprotein-associated phospholipase A2 in atherosclerosis", ARTERIOSCLER THROMB VASC BIOL, vol. 25, 2005, pages 923 - 31

Similar Documents

Publication Publication Date Title
AU2015292049B2 (en) Compounds
EP2948452B1 (fr) Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one
AU2012288865B2 (en) Bicyclic pyrimidone compounds
CN114805389B (zh) 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
WO2016012916A1 (fr) Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
CA2899143A1 (fr) Composes de pyrimidone bicycliques utilises en tant qu'inhibiteurs de lp-pla2
CA2790707A1 (fr) Derives de fluorouracile
AU2014210259B2 (en) Compounds
WO2016012917A1 (fr) Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
BR112016028591B1 (pt) Composto inibidor da atividade de lp-pla2, composição farmacêutica que compreende o referido composto e uso do mesmo para tratar doença neurodegenerativa
US9051325B2 (en) Bicyclic [5,6] imidazo pyrimodone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2

Legal Events

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

Ref document number: 15741365

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15741365

Country of ref document: EP

Kind code of ref document: A1