WO2016011931A1 - Compounds - Google Patents

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Publication number
WO2016011931A1
WO2016011931A1 PCT/CN2015/084607 CN2015084607W WO2016011931A1 WO 2016011931 A1 WO2016011931 A1 WO 2016011931A1 CN 2015084607 W CN2015084607 W CN 2015084607W WO 2016011931 A1 WO2016011931 A1 WO 2016011931A1
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WIPO (PCT)
Prior art keywords
disease
present
compound
diseases
treating
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PCT/CN2015/084607
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English (en)
French (fr)
Inventor
Zehong Wan
Xiaomin Zhang
Jian Wang
Original Assignee
Glaxosmithkline Intellectual Property Development Limited
Glaxosmithkline (China) R&D Company Limited
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Publication date
Application filed by Glaxosmithkline Intellectual Property Development Limited, Glaxosmithkline (China) R&D Company Limited filed Critical Glaxosmithkline Intellectual Property Development Limited
Priority to US15/327,685 priority Critical patent/US9783546B2/en
Priority to RU2017105353A priority patent/RU2690190C2/ru
Priority to BR112016028591-3A priority patent/BR112016028591B1/pt
Priority to KR1020177001423A priority patent/KR20170034889A/ko
Priority to CA2955910A priority patent/CA2955910C/en
Priority to ES15824385T priority patent/ES2744339T3/es
Priority to EP15824385.7A priority patent/EP3172208B1/en
Priority to JP2017503504A priority patent/JP6625603B2/ja
Priority to CN201580039345.0A priority patent/CN106536521B/zh
Priority to AU2015292049A priority patent/AU2015292049B2/en
Publication of WO2016011931A1 publication Critical patent/WO2016011931A1/en

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    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel tricyclic imidazo-pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy for the treatment of diseases 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. Vasc. 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.
  • WO96/13484 WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, and WO08/048866.
  • 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 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′sdisease
  • 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; WO06/063813 and WO 2008/141176; JP 200188847; and US Published Patent Application Nos. US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1.
  • Lp-PLA 2 Lp-PLA 2
  • inhibitors may be used to treat 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 al., Alzheimer Dis Assoc Disord, 24, April-June (2010) ; Sinem, et al. Current Alzheimer Research, 7, 463-469 (2010) ) .
  • neuroinflammation is present in AD patients and multiple cytotoxic inflammatory cytokines are up-regulated in AD patients.
  • LysoPC function is a pro-inflammatory factor inducing multiple cytotoxic inflammatory cytokine release (See Shi, et al. Atherosclerosis, 191, 54-62 (2007) ) . Therefore, these studies provide additional evidence that that the inhibitors of Lp-PLA 2 can be used to treat AD by inhibiting activity of Lp-PLA 2 and reducing lysoPC production.
  • Lp-PLA 2 inhibitors for treating diseases associated with blood-brain-barrier leakage, including, e.g., Alzheimer’s disease and vascular dementia.
  • Lp-PLA 2 inhibitors can reduce inflammation, for example, reducing multiple cytokine release by suppressing lysoPC production. (See e.g., Shi, et al. Atherosc/erosis 191, 54-62 (2007) ) .
  • inhibiting Lp-PLA 2 is a potential therapeutic treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, etc.
  • 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 (ROS) production.
  • ROS 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 function of blocking inflammatory cytokine release (See e.g., Shi, et al. Atherosclerosis, 191, 54-62 (2007) )
  • Lp-PLA 2 inhibitors can provide a potential therapeutic application for both glaucoma and AMD.
  • this invention relates to compounds having a structure of
  • salts thereof e.g., pharmaceutically acceptable salts thereof.
  • the invention relates to compounds having a structure of
  • salts thereof e.g., pharmaceutically acceptable salts thereof.
  • the invention relates to compounds having a structure of
  • salts thereof e.g. pharmaceutically acceptable salt thereof.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising compounds described in this invention and a pharmaceutically acceptable excipient.
  • the invention also relates to methods of treating or preventing a disease associated with the activity of Lp-PLA 2 , which comprises administering to a subject in need thereof with a therapeutically effective amount of a compound of the invention described herein.
  • the disease may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidized free fatty acids; with lipid oxidation in conjunction with Lp-PLA 2 activity; or with endothelial dysfunction.
  • This invention also provides methods of treating or preventing a disease by inhibiting Lp-PLA 2 activity.
  • diseases include, but are not limited to, neurodegeneration disease (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, vascular dementia) , atherosclerosis, stroke, metabolic bone disorder (e.g., bone marrow abnormalities) , dyslipidemia, Paget’s diseases, type II diabetes, metabolic syndrome, insulin resistance, and hyperparathyroidism, diabetic ocular disorder (e.g., macular edema, diabetic retinopathy, and posterior uveitis) , macular edema, wound healing, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) , psoriasis, and multiple sclerosis.
  • the methods comprise administering a therapeutically effective amount of a compound of this invention to a subject in need thereof. It is not intended that the present invention is limited to any particular stage of the disease (e.g
  • This invention also provides methods of treating or preventing Alzheimer’s disease.
  • the methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound of this invention.
  • This invention also provides methods of treating or preventing atherosclerosis.
  • the methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound of this invention.
  • This invention also provides methods of decreasing beta amyloid (also referred to as “A ⁇ ” ) accumulation in the brain of a subject.
  • the methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.
  • the beta amyloid is Abeta-42.
  • This invention also provides methods for treating or preventing ocular diseases by administering a compound of this invention.
  • this invention provides methods of treating macular edema, which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • the macular edema is associated with diabetic ocular disease, for example, diabetic macular edema or diabetic retinopathy.
  • the macular edema is associated with posterior uveitis.
  • This invention also provides a use of compounds of this invention in the manufacture of a medicament for treating or preventing diseases described herein.
  • This invention also provides compounds of this invention for use in the treatment or prevention described herein.
  • disease refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person.
  • a disease can also include a distemper, ailing, ailment, malady, disorder, sickness, illness, complain, interdisposition and/or affectation.
  • neurodegeneration disease refers to a varied assortment of central nervous system disorder characterized by gradual and progressive loss of neural tissue and/or neural tissue function.
  • a neurodegeneration disease is a class of neurological disease where the neurological disease 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 neurodegeneration diseases described herein include neurodegeneration diseases where there is a defective blood brain barrier, for example a permeable blood brain barrier. Examples of neurodegeneration diseases where there is a defective blood brain barrier include, but are not limited to, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, vascular dementia and the like.
  • vascular dementia is also referred to as “multi-infarct dementia” , which 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 permeable 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 structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot process of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel.
  • metabolic bone disease refers to a varied assortment of bone diseases characterized by gradual and progressive loss of bone tissue. Metabolic bone diseases described herein are metabolic bone diseases where there is a condition of diffusely decreased bone density and/or diminished bone strength. Such diseases are characterized by histological appearance. Exemplary metabolic bone diseases include, but are not limited to, osteoporosis which is characterized by decreased mineral and bone matrix, and osteomalacia which is characterized by decreased mineral but intact bone matrix.
  • osteoopenic diseases or “osteopenia” are used interchangeably herein, and refer to conditions with decreased calcification and/or bone density, and is a descriptive term used to refer to all skeletal systems in which decreased calcification and/or bone density is observed. Osteopenia also refers to a reduced bone mass due to inadequate osteiod synthesis.
  • osteoporosis refers to conditions in which mineral and/or bone matrix are decreased and/or bone mass is reduced.
  • “treat” , “treating” or “treatment” in reference to a disease means: (1) to ameliorate the disease or one or more of the biological manifestations of the disease, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disease or (b) one or more of the biological manifestations of the disease, (3) to alleviate one or more of the symptoms or effects associated with the disease, (4) to slow the progression of the disease or one or more of the biological manifestations of the disease, and/or (5) to diminish the likelihood of severity of a disease or biological manifestations of the disease.
  • “treat” “treating” or “treatment” in reference to Alzheimer’s disease means: to slow the progression of congnitive function decline.
  • prevent means the prophylactic administration of a drug to diminish the likelihood of the onset of or to delay the onset of a disease or biological manifestation thereof.
  • subject means a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc. ) , and particularly human subjects including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects, and further including various races and ethnicities including, but not limited to, white, black, Asian, American Indian and Hispanic.
  • mammalian subject e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.
  • human subjects including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects, and further including various races and ethnicities including, but not limited to, white, black, Asian, American Indian and Hispanic.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in treating or preventing a disease, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a therapeutically effective amount of a compound will vary with the particular compound chosen (e.g.
  • One aspect of the present invention provides compounds having the structure of 3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetrahydropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6 H) -one
  • Another aspect of the present invention provides compounds having the structure of 3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetrahyd ropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • this invention relates to compounds having the structure of (R) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hydropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • this invention relates to compounds having the structure of (R) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hydropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention relates to a compound having the structure of (R) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hyd ropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention relates to a compound having the structure of a pharmaceutically acceptable salt of (R) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hydropyrrolo [1′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention relates to a compound having the structure of (S) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hydropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention relates to a compound having the structure of (S) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hyd ropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention is related to a compound having the structure of (S) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hyd ropyrrolo [1 ′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the invention is related to a compound having the structure of a pharmaceutically acceptable salt of (S) -3- ( (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetra hydropyrrolo [1′, 2′: 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one
  • the compounds described above, salts (e.g., pharmaceutically acceptable salts) thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms) .
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the scope of the present invention includes purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods (e.g. chiral HPLC) , or any given isomer may be obtained by conventional synthetic methods e.g. stereospecific or asymmetric syntheses.
  • the invention also includes various deuterated forms of compounds described above, and salts (e.g., pharmaceutically acceptable salts) thereof.
  • Each available hydrogen atom 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 described above, and salts (e.g., pharmaceutically acceptable salts) thereof.
  • Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of compounds described above, and salts (e.g., pharmaceutically acceptable salts) thereof, or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride) .
  • the salt form of the compounds is also within the scope of the present invention.
  • the salts or pharmaceutically acceptable salts of the compounds described herein may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable base or acid, respectively.
  • suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986) , 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.
  • compounds of the present invention may contain a basic group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. These salts may be crystalline or amophorus.
  • Exemplary pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate,
  • the pharmaceutically acceptable salts include the L-tartrate, ethanedisulfonate (edisylate) , sulfate, phosphate, p-toluenesulfonate (tosylate) , hydrochloride salt, methanesulfonate, citrate, fumarate, benzenesulfonate, maleate, hydrobromate, L-lactate, malonate, and S-camphor-10-sulfonate.
  • Some of these salts form solvates, some are crystalline.
  • the compounds described herein, their salts (e.g., pharmaceutically acceptable salts) , deuterated forms, solvates or hydrates thereof, may exist in one or more polymorphic form. Therefore, in a further aspect, the invention provides a polymorph of a compound defined herein, their salts (e.g., pharmaceutically acceptable salts) , or a polymorph of a solvate or hydrate of a compound described herein or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • the compounds described above and salts (including pharmaceutically acceptable salts) thereof may be in the form of a solvate.
  • solvates of the compounds described above including solvates of salts of the compounds described above, that are in crystalline form
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as “hydrates. ” Solvates include stoichiometric solvates as well as compositions containing variable amounts of the incorporated solvent (s) , e.g. a hydrate includes stoichiometic hydrates and compositions containing variable amounts of water.
  • the invention also includes isotopically labeled compounds and salts, which are identical to compounds described above or salts thereof, but for the fact that 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 compounds described above or salts thereof isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C and 18 F.
  • isotopically labeled compound described above or salts thereof are useful in drug and/or substrate tissue distribution assays.
  • 11 C and 18 F isotopes are useful in PET (positron emission tomography) . PET is useful in brain imaging.
  • Isotopically-labeled compounds described above and salts thereof 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 one embodiment, compounds described above or salts thereof are not isotopically labeled.
  • the terms “compound(s) of the invention” or “compound(s) of the present invention” mean a compound described above, as defined herein, in any form, i.e., any salt or non-salt form (e.g., as a free base form, or as a salt, for example, a pharmaceutically acceptable salt thereof) , deuterated form and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms) , and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates) ) , and mixtures of various forms.
  • any salt or non-salt form e.g., as a free base form, or as a salt, for example, a pharmaceutically acceptable salt thereof
  • deuterated form and any physical form thereof e.g., including non-solid forms (e.g., liquid or
  • the terms of “compounds of the invention” mean a compound described above, in the form of any pharmaceutically acceptable salt thereof or non-salt form (e.g., as a free base form) , deuterated form and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms) , and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi-hydrates) ) , and mixtures of various forms.
  • any pharmaceutically acceptable salt thereof or non-salt form e.g., as a free base form
  • deuterated form and any physical form thereof e.g., including non-solid forms (e.g., liquid or semi-solid forms) , and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di-
  • a compound of the invention includes a compound described above, or a salt thereof, for example a pharmaceutically acceptable salt thereof.
  • Representative compounds of this invention include the specific compounds described.
  • the compounds of the present invention may be prepared by standard techniques known in the art and by known processes analogous thereto. General methods for preparing compounds of the present invention are set forth below. All starting material and reagents described in the below general experimental schemes are commercially available.
  • the title compound was prepared by a procedure similar to that described for (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol starting from D-prolinol and 2, 4, 6-trichloropyrimidine.
  • the title compound was prepared by a procedure similar to that described for (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol starting from L-prolinol and 2, 4, 6-trichloropyrimidine.
  • reaction mixture was quenched with ice water (200 mL) and evaporated under reduced pressure to remove methanol and crude was diluted with ethyl acetate (200 mL) and water (200 mL) , organic layer was separated and washed with brine solution (100 mL) , dried over Na 2 SO 4 evaporated completely and afforded crude product 50 g, washed with PE and dried to afford the title compound (45 g, 144 mmol, 88 % yield) as a white solid.
  • the title compound was prepared by a procedure similar to that described for 3- ( (3, 5-difluoro-4- ( (1-methyl-1H-pyrazol-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetrahydro pyrrolo [1′ , 2′ : 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one starting from (S) -3-chloro-7, 8, 8a, 9-tetrahydropyrrolo [1 ′, 2′ : 3, 4] imidazo [1, 2-c] pyrimidin-1 (6H) -one and (3, 5-difluoro-4- ( (2- (trifluoromethyl) pyridin-4-yl) oxy) phenyl)methanol.
  • the compounds of present invention are Lp-PLA 2 inhibitors, and may be useful in the treatment and prevention of diseases mediated by Lp-PLA 2 .
  • 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 a Lp-PLA 2 inhibitor, as well as tissue and in vivo models.
  • Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) biochemical assay (1) Recombinant human Lp-PLA 2 assays (rhLp-PLA 2 ) -PED6 assay
  • the PED6 assay was run as an unquenched 10 ⁇ L 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, 0.01 ⁇ L of the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using ECHO liquid dispenser. 5 ⁇ L of recombinant human Lp-PLA 2 enzyme (4 nM (or 110 pM) rhLp-PLA 2 in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well of the plate. Plates were centrifuged for 10 sec at 500 rpm.
  • Examples 1 and 2 were tested in the PED6 assay.
  • the pIC 50 value for compounds tested was either reported in at least one experiment or the average of multiple experiments.
  • pIC50 values of recombinant human Lp-PLA 2 assay are:
  • PLA2 VIIB (also known as Novel Serine Dependent Lipase, NSDL) is a serine hydrolase with 40% amino acid identity with human Lp-PLA 2 . Sequence comparisons indicate that the PLA VIIB active site catalytic triad positions are similar to those of Lp-PLA 2 . Similar to Lp-PLA 2 , it is capable of hydrolyzing oxidatively modified phospholipids and may be assayed using known Lp-PLA 2 substrates.
  • PLA2 VIIB Upon cleavage by a phopholipase, PLA2 VIIB liberates a fluorescent Bodipy group. Recombinant human PLA2 VIIB is used as the phospholipase source in this assay, and compounds are screened to test their degree of inhibition in this assay. The assay is used to determine the degree of selectivity of the testing compounds between PLA2 VIIB and Lp-PLA 2 .
  • the PLA2 VIIB assay was applied as an unquenched 10 ⁇ L assay.
  • the source plate containing the compounds is prepared by making 1 ⁇ 3 (by volume) serial dilution of the compounds with pure DMSO on 384-well microplate. 0.01 ⁇ L of compounds on the compound source plate were transferred into 384 well Greiner 784076 (black) plates by ECHO liquid dispenser. 5 ⁇ L of Novel Serine Dependent Lipase (NSDL) enzyme (5 nM NSDL in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well.
  • NSDL Novel Serine Dependent Lipase
  • this step was carried out by adding 10 ⁇ L of recombinant human PLA2 VIIB (200 pM rhPLA 2 VIIB in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) to each well. Plates were centrifuged for 10 sec at 500 rpm. After 30 minutes preincubation, 5 ⁇ L of substrate (5 ⁇ M PED6 [from 5 mM DMSO stock] in assay buffer of 50mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to 384 well Greiner 784076 (black) low-volume plates.
  • substrate 5 ⁇ M PED6 [from 5 mM DMSO stock] in assay buffer of 50mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS
  • Plates were kinetic read by starting read immediately after PED6 addition at ex: 480 /em: 540 using ViewLux microplate reader or Envision spectrofluorimeters.
  • IC 50 data (which may be converted to plC50 data)
  • curve and QC analysis was conducted using XLfit module in Excel.
  • Examples 1 and 2 were tested in the PLA2 VIIB assay described above. Both examples had at least 100 fold selectivity between human recombinant Lp-PLA 2 and PLA2 VIIB.
  • Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) Human Plasma assay-Thio-PAF assay
  • the human plasma assay utilizes a thioester analog of PAF (phosphatidylcholine) , where hydrolysis yields to the formation of a phospholipid containing a free thiol group.
  • PAF phosphatidylcholine
  • the amount of thiol is quantitated continuously by reacting with CPM (7-diethylamino-3- (4’-maleimidylphenyl) -4-methylcoumarin) , a maleimide which increases in fluoresence after Michael addition of thiols.
  • This assay may detect the activity of Lp-PLA 2 in human plasma, as determined by specific inhibition by Lp-PLA 2 inhibitors.
  • the thio-PAF assay was run as a quenched 15 ⁇ L assay.
  • Compounds source plate was prepared by making 1 ⁇ 3 (by volume) serial dilution of the compounds into pure DMSO on 384-well microplate. 0.01 ⁇ L of compounds on compound source plate were transferred to 384 well Greiner 784076 (black) low-volume plates by ECHO liquid dispenser. 8 ⁇ L pooled human plasma, which was previously aliquoted and frozen, was added. Plates were centrifuged for 10 sec at 500 rpm.
  • Examples 1 and 2 were tested in the Thio-PAF assay described above.
  • the pIC 50 values for tested compounds were either reported in at least one experiment or the average of multiple experiments.
  • the pIC 50 value in the Lp-PLA 2 human plasma assays for Example 1 was 8.1.
  • the pIC 50 value in the Lp-PLA 2 human plasma assays for Example 2 was 7.7.
  • the compounds of the invention are inhibitors of Lp-PLA 2 . Therefore, these compounds may be used in therapy, for example, in the treatment or prevention of diseases associated with the activity of Lp-PLA 2 , which comprises treating a subject in need thereof with a therapeutically effective amount of an inhibitor of Lp-PLA 2 . Accordingly, one aspect of the invention is directed to methods of treating or preventing diseases associated with the activity of Lp-PLA 2 . As will be appreciated by those skilled in the art, a particular disease or its treatment may involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including one or more of the mechanisms described herein.
  • an inhibitor of Lp-PLA 2 may be used in treating or preventing any of diseases disclosed in the following published patent applications: WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866,WO05/003118 CA 2530816A
  • the compounds of the present invention may be used to treat or prevent any diseases that involve endothelial dysfunction, for example, atherosclerosis, (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis) , diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
  • atherosclerosis e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis
  • diabetes e.g. hypertension, angina pectoris and after ischaemia and reperfusion.
  • the compounds of the present invention may be used to treat or prevent any disease that involves lipid oxidation in conjunction with enzyme activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as 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, and acute and chronic inflammation.
  • the compounds of the present invention may be used to lower the chances of having a cardiovascular event (such as a head attack, myocardial infarction or stroke) in a patient with coronary heart disease.
  • a cardiovascular event such as a head attack, myocardial infarction or stroke
  • the compounds of the present invention may be used to treat or prevent diseases that involve activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages which generate oxidative stress.
  • Exemplary diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD) , liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer’s disease, and autoimmune diseases such as lupus.
  • COPD chronic obstructive pulmonary disease
  • the 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. Prevention includes treating a subject at risk of having such conditions.
  • the present invention provides methods of treating or preventing a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation in a subject in need thereof.
  • BBB blood brain barrier
  • the present invention provides methods of treating a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation in a subject in need thereof.
  • the methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the abnormal BBB is a permeable BBB.
  • the disease is a neurodegeneration disease.
  • Such neurodegeneration diseases are, for example, but are not limited to, vascular dementia, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
  • the present invention provides methods of treating or preventing disease associated with a subject with blood brain barrier (BBB) leakage. In some embodiments, the present invention provides methods of treating disease associated with a subject with blood brain barrier (BBB) leakage.
  • Exemplary diseases include, but are not limited to, brain hemorrhage, cerebral amyloid angiopathy.
  • the neurodegeneration disease is Alzheimer’s disease. In a certain embodiment, the neurodegeneration disease is vascular dementia. In one embodiment, the neurodegeneration disease is multiple sclerosis (MS) .
  • the compounds of the present invention may be used to treat or prevent a neurodegeneration disease in a subject.
  • the methods comprise administering to a subject in need thereof a compound of the invention, e.g., as a pharmaceutical composition comprising a compound of the invention.
  • the compounds of the present invention may be used to treat a neurodegeneration disease in a subject.
  • Exemplary neurodegeneration diseases include, but are not limited to, Alzheimer’s disease, vascular dementia, Parkinson’s disease and Huntington’s disease.
  • the neurodegeneration disease described herein is associated with an abnormal blood brain barrier.
  • the subject which is administered an agent that inhibits the activity of Lp-PLA 2 is a human.
  • the present invention provides methods of treating or preventing a subject with or at risk of vascular dementia.
  • the methods comprise administering to the subject a compound of the invention, e.g., as a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention.
  • the present invention provides methods of treating a subject with or at risk of vascular dementia.
  • the vascular dementia is associated with Alzheimer’s disease.
  • the present invention provides methods of decreasing beta amyloid, referred to as “A ⁇ ” accumulation in the brain of a subject.
  • the methods comprise administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention.
  • the beta amyloid is Abeta-42.
  • the methods may further comprise administering to the subject another therapeutic agent that may be useful in treating the neurodegenerative disease for which the subject is being treated, or that may be a co-morbidity.
  • the present invention provides methods of slowing or delaying the progression of cognitive and function decline in patients with mild Alzheimer’s disease.
  • the compounds of the present invention described herein may be used as an adjunct to an agent that used to provide symptomatic treatment to patients with Alzheimer’s disease.
  • the present invention provides methods of slowing or delaying the progression of cognitive or function decline in a patient with mild or moderate Alzheimer’s disease and/or cerebrovascular disease (CVD) comprise administering a therapeutically effective amount of a compound of the present invention to the patient who has been administered an agent used to provide symptomatic treatment to Alzheimer’s disease (e.g., or memantine) for 6 months or longer.
  • an agent used to provide symptomatic treatment to Alzheimer’s disease e.g., or memantine
  • the present invention relates to methods of treating or preventing metabolic bone diseases by administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention.
  • the present invention relates to methods of treating metabolic bone diseases by administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention.
  • Exemplary metabolic bone diseases include, diseases associated with loss of bone mass and density including, but are not limited to, osteoporosis and osteopenic related diseases.
  • Exemplary osteoporosis and osteopenic related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget’s diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases.
  • the subject in need thereof is a human.
  • methods of preventing osteoporosis and/or osteopenic diseases described herein may be affected by inhibiting the expression of Lp-PLA 2 and/or inhibiting the protein activity of Lp-PLA 2 . Accordingly, some embodiments of the present invention provide methods for inhibiting Lp-PLA 2 by blocking enzyme activity. In a further embodiment, methods for inhibiting Lp-PLA 2 by reducing and/or down-regulating the expression of Lp-PLA 2 RNA are provided. In a further embodiment, preventing and/or reducing loss of bone mass and/or loss of bone density leads to preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/orosteopenic diseases.
  • the methods further comprise administering to a subject in need thereof additional therapeutic agents used in the treatment of metabolic bone diseases.
  • additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene) , a selective estrogen modulator (SERM) , estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide may be used.
  • bisphosphates e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene
  • SERM selective estrogen modulator
  • E/HRT hormone replacement therapy
  • teriparatide teriparatide
  • One aspect of the present invention provides methods for treating and/or preventing ocular diseases by administering a therapeutically effective amount of a compound of the present invention.
  • the present invention provides methods for treating ocular diseases by administering a therapeutically effective amount of a compound of the present invention.
  • Ocular diseases applicable in the present invention may be associated with the breakdown of the inner blood-retinal barrier (iBRB) .
  • Exemplary ocular diseases relate to diabetic ocular, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like.
  • the present invention relates to methods for treating ocular diseases by administering a compound of the present invention to inhibit Lp-PLA 2 .
  • Exemplary ocular diseases include, but are not limited to, 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. More details of using Lp-PLA 2 inhibitor to treat eye diseases are provided in WO2012/080497, which is incorporated by reference herein.
  • some embodiments of the present invention provide methods for treating or preventing diabetic macular edema in a subject.
  • the present invention provides methods for treating diabetic macular edema in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.
  • the present invention provides methods of treating or preventing a subject with or at risk of macular edema
  • the present invention provides methods of treating a subject with or at risk of macular edema.
  • the methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the macular edema is associated with diabetic ocular disease, for example, diabetic macular edema or diabetic retinopathy.
  • the macular edema is associated with posterior uveitis.
  • the present invention provides methods of treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides methods of treating glaucoma or macular degeneration. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the present invention provides methods of treating or preventing a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof. In one embodiment, the present invention provides methods of treating a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.
  • systemic inflammatory diseases 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, enthesitis, may be the underlying cause of posterior uveitis affecting the retina, and which can result in macula edema.
  • systemic inflammatory diseases 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
  • the present invention relates to methods for treating or preventing posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention.
  • the present invention provides methods for treating posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention.
  • Lp-PLA 2 inhibitors may have beneficial effects on diseases associated with M1/M2 macrophage polarization.
  • a study was carried out by GSK to investigate the relationship between M1/M2 macrophage polarization and different diseases.
  • 94 human markers described in Martinez FO et al., which distinguished M1 and M2 phenotypes was used against a GSK subscribed GeneLogic database. (See Martinez FO et al. (2006) J Immunol 177, 7303-7311. )
  • the Connectivity Map methodology described in Lamb J et al. was used to identify the fraction of samples in each disease state having expression characteristics consistent with a M1-favoring or M2-favoring macrophage population. (See Lamb J et al.
  • liver cirrhosis showed that liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, and aortic aneurysm have M1/M2 imbalance.
  • M1 and M2 markers Ex vivo analysis of proinflammatory (M1) and anti-inflammatory (M2) markers in control and compound treated EAE rats.
  • Splenic macrophages were harvested at day 13 post MBP-immunization and assayed for expression of a variety of markers by realtime PCR.
  • CNS infiltrating cells were harvested and macrophages were analyzed for expression of M1 and M2 markers by realtime PCR.
  • Treatment with compound resulted in the decrease in M1 markers and increase in M2 markers, which potentially indicated the possibility of anti-inflammation and tissue repair.
  • the present invention provides methods of treating or preventing disease associated with macrophage polarization, for example, M1/M2 macrophage polarization. In some embodiments, the present invention provides methods of treating disease 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 and or prevention of a disease associated with Lp-PLA 2 activity may be achieved using a compound of this invention as a monotherapy, or in dual or multiple combination therapy.
  • the compounds of the present invention may be used to treat or prevent the disease 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 for lowering Lp (a) include the aminophosphonates 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.
  • the statins are a well-known class of cholesterol lowering agents and include atorvastatin, simvarstatin, 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 PPAR gamma activators, for instance GI262570 (GlaxoSmithKline) and the glitazone class of compounds such as rosiglitazone, troglitazone and pioglitazone.
  • Such agents 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.
  • Combination therapy includes administration of the therapeutic agents in separate dosage forms or together in a single dosage form.
  • Combination therapy may involve simultaneous administration or separate administration of the therapeutic agents, which may be substantially simultaneous or substantially separate administration.
  • 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.
  • One aspect of the present invention provides the use of a compound of the present invention for the preparation of a medicament for carrying out a method described herein.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing diseases associated with the activity of Lp-PLA 2 .
  • WO96/13484 WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO05/003118 CA 25
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing any diseases that involve endothelial dysfunction, for example, atherosclerosis, (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis) , diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
  • atherosclerosis e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing any disease that involves lipid oxidation in conjunction with enzyme activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as 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, and acute and chronic inflammation.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for lowering the chances of having a cardiovascular event (such as a heart attack, myocardial infarction or stroke) in a patient with coronary heart disease.
  • a cardiovascular event such as a heart attack, myocardial infarction or stroke
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing diseases that involve activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages which generate oxidative stress.
  • Exemplary diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD) , liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer’s disease, and autoimmune diseases such as lupus.
  • COPD chronic obstructive pulmonary disease
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament 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. Prevention includes treating a subject at risk of having such conditions.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation in a subject in need thereof.
  • BBB blood brain barrier
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation in a subject in need thereof.
  • BBB blood brain barrier
  • the abnormal BBB is a permeable BBB.
  • the disease is a neurodegeneration disease.
  • Such neurodegeneration diseases are, for example, but are not limited to, vascular dementia, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
  • the present invention provides use of a compound of the present invention for the preparation of a medicament for treating or preventing disease associated with a subject with blood brain barrier (BBB) leakage.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating disease associated with a subject with blood brain barrier (BBB) leakage.
  • BBB blood brain barrier
  • exemplary diseases include, but are not limited to, brain hemorrhage, cerebral amyloid angiopathy.
  • the neurodegeneration disease is Alzheimer’s disease.
  • the neurodegeneration disease is vascular dementia.
  • the neurodegeneration disease is multiple sclerosis (MS) .
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a neurodegeneration disease in a subject. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating a neurodegeneration disease in a subject.
  • exemplary neurodegeneration diseases include, but are not limited to, Alzheimer’s disease, vascular dementia, Parkinson’s disease and Huntington’s disease.
  • the neurodegeneration disease described herein is associated with an abnormal blood brain barrier.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a subject with or at risk of vascular dementia. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating a subject with or at risk of vascular dementia. In a certain embodiment, the vascular dementia is associated with Alzheimer’s disease.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for decreasing beta amyloid, referred to as “A ⁇ ” accumulation in the brain of a subject.
  • the beta amyloid is Abeta-42.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of cognitive function decline in patients with mild Alzheimer’s disease.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament as an adjunct to an agent that used to provide symptomatic treatment to patients with Alzheimer’s disease.
  • the neurodegenerative disease is or is similar to Alzheimer’s disease
  • the subject may be treated with other agents targeting Alzheimer’s disease such as or donepezil, or tacrine, or rivastigmine, or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of cognitive function decline in a patient with mild or moderate Alzheimer’s disease and/or cerebrovascular disease (CVD) , wherein the patient who has been administered an agent used to provide symptomatic treatment to Alzheimer’s disease (e.g., or memantine) for 6 months or longer.
  • CVD cerebrovascular disease
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of cognitive function decline in a patient with mild or moderate Alzheimer’s disease and cerebral small vessel disease (SVD) , wherein the patient who has been administered an agent used to provide symptomatic treatment to Alzheimer’s disease (e.g., or memantine) for 6 months or longer.
  • an agent used to provide symptomatic treatment to Alzheimer’s disease e.g., or memantine
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing metabolic bone diseases.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating metabolic bone diseases.
  • Exemplary metabolic bone diseases include, diseases associated with loss of bone mass and density including, but are not limited to, osteoporosis and osteopenic diseases.
  • Exemplary osteoporosis and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget’s diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for preventing and/or reducing loss of bone mass and/or loss of bone density leads to preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating metabolic bone diseases, wherein the medicament is used with additional therapeutic agents used in the treatment of metabolic bone diseases.
  • additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene) , a selective estrogen modulator (SERM) , estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide may be used.
  • bisphosphates e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene
  • SERM selective estrogen modulator
  • E/HRT hormone replacement therapy
  • teriparatide teriparatide
  • One aspect of the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating and/or preventing ocular diseases.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating ocular diseases.
  • Ocular diseases applicable in the present invention may be associated with the breakdown of the inner blood-retinal barrier (iBRB) .
  • Exemplary ocular diseases relate to diabetic ocular, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like.
  • More ocular diseases include, but are not limited to, 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. More details of using Lp-PLA 2 inhibitor to treat eye diseases are provided in WO2012/080497, which is incorporated by reference herein.
  • some embodiments of the present invention provide the use of a compound of the present invention for the preparation of a medicament for treating or preventing diabetic macular edema in a subject.
  • the present invention provides the use of a compound of the present invention for treating diabetic macular edema in a subject.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a subject with or at risk of macular edema. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating a subject with or at risk of macular edema. In a further embodiment, the macular edema is associated with diabetic ocular disease, for example, diabetic macular edema or diabetic retinopathy. In yet a further embodiment, the macular edema is associated with posterior uveitis.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating glaucoma or macular degeneration.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof.
  • systemic inflammatory diseases 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, enthesitis, may be the underlying cause of. posterior uveitis affecting the retina, and which can result in macula edema.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating posterior uveitis or any of these systemic inflammatory diseases.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing disease associated with macrophage polarization, for example, M1/M2 macrophage polarization. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating disease 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) , ischemic cardiomyopathy, chronic heart failure post myocardial infarction (MI) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • MI myocardial infarction
  • Another aspect of the present invention provides a compound of the present invention for use in carrying out methods of treatment or prevention described herein.
  • a further aspect of the present invention provides a compound described herein or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention provides a compound of the present invention for use in treating or preventing diseases associated with the activity of Lp-PLA 2 .
  • the present invention provides a compound of the present invention for use in treating or preventing any of diseases disclosed in the following published patent applications: WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO05/003118 CA 2530816A1)
  • the present invention provides a compound of the present invention for use in treating or preventing any diseases that involve endothelial dysfunction, for example, atherosclerosis, (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis) , diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
  • atherosclerosis e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis
  • diabetes e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis
  • hypertension e.g. angina pectoris and after ischaemia and reperfusion.
  • the present invention provides a compound of the present invention for use in treating or preventing any disease that involves lipid oxidation in conjunction with enzyme activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as 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, and acute and chronic inflammation.
  • the present invention provides a compound of the present invention for use in lowering the chances of having a cardiovascular event (such as a heart attack, myocardial infarction or stroke) in a patient with coronary heart disease.
  • a cardiovascular event such as a heart attack, myocardial infarction or stroke
  • the present invention provides a compound of the present invention for use in treating or preventing diseases that involve activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages which generate oxidative stress.
  • Exemplary diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD) , liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer’s disease, and autoimmune diseases such as lupus.
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a compound of the present invention for use in 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. Prevention includes treating a subject at risk of having such conditions.
  • the present invention provides a compound of the present invention for use in treating or preventing a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation in a subject in need thereof.
  • BBB blood brain barrier
  • the present invention provides a compound of the present invention for use in treating a neurological disease associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation.
  • the abnormal BBB is a permeable BBB.
  • the disease is a neurodegeneration disease.
  • Such neurodegeneration diseases are, for example, but are not limited to, vascular dementia, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
  • the present invention provides a compound of the present invention for use in treating or preventing disease associated with a subject with blood brain barrier (BBB) leakage.
  • BBB blood brain barrier
  • the present invention provides a compound of the present invention for use in treating disease associated with a subject with blood brain barrier (BBB) leakage.
  • Exemplary diseases include, but are not limited to, brain hemorrhage, cerebral amyloid angiopathy.
  • the neurodegeneration disease is Alzheimer’s disease.
  • the neurodegeneration disease is vascular dementia.
  • the neurodegeneration disease is multiple sclerosis (MS) .
  • the present invention provides a compound of the present invention for use in treating or preventing a neurodegeneration disease in a subject. In one embodiment, the present invention provides a compound of the present invention for use in treating a neurodegeneration disease in a subject.
  • exemplary neurodegeneration diseases include, but are not limited to, Alzheimer’s disease, vascular dementia, Parkinson’s disease and Huntington’s disease.
  • the neurodegeneration disease described herein is associated with an abnormal blood brain barrier.
  • the present invention provides a compound of the present invention for use in treating or preventing a subject with or at risk of vascular dementia. In one embodiment, the present invention provides a compound of the present invention for use in treating a subject with or at risk of vascular dementia. In a certain embodiment, the vascular dementia is associated with Alzheimer’s disease.
  • the present invention provides a compound of the present invention for use in decreasing beta amyloid, referred to as “A ⁇ ” accumulation in the brain of a subject.
  • the beta amyloid is Abeta-42.
  • the present invention provides a compound of the present invention for use in slowing or delaying the progression of cognitive function decline in patients with mild Alzheimer’s disease.
  • the present invention provides a compound of the present invention for use as an adjunct to an agent that used to provide symptomatic treatment to patients with Alzheimer’s disease.
  • the neurodegenerative disease is or is similar to Alzheimer’s disease
  • the subject may be treated with other agents targeting Alzheimer’s disease such as or donepezil, or tacrine, or rivastigmine, or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • the present invention provides a compound of the present invention for use in slowing or delaying the progression of cognitive function decline in a patient with mild or moderate Alzheimer’s disease and/or cerebrovascular disease (CVD) , wherein the patient who has been administered an agent used to provide symptomatic treatment to Alzheimer’s disease (e.g., or memantine) for 6 months or longer.
  • CVD cerebrovascular disease
  • the present invention provides a compound of the present invention for use in slowing or delaying the progression of cognitive function decline in a patient with mild or moderate Alzheimer’s disease and cerebral small vessel disease (SVD) , wherein the patient who has been administered an agent used to provide symptomatic treatment to Alzheimer’s disease (e.g., or memantine) for 6 months or longer.
  • SGD small vessel disease
  • the present invention provides a compound of the present invention for use in treating or preventing metabolic bone diseases.
  • the present invention provides a compound of the present invention for use in treating metabolic bone diseases.
  • Exemplary metabolic bone diseases include, diseases associated with loss of bone mass and density including, but are not limited to, osteoporosis and osteopenic diseases.
  • Exemplary osteoporosis and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget’s diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases.
  • the present invention provides a compound of the present invention for use in preventing and/or reducing loss of bone mass and/or loss of bone density leads to preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.
  • the present invention provides a compound of the present invention for use in treating metabolic bone diseases, wherein the medicament is used with additional therapeutic agents used in the treatment of metabolic bone diseases.
  • additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene) , a selective estrogen modulator (SERM) , estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide may be used.
  • bisphosphates e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene
  • SERM selective estrogen modulator
  • E/HRT hormone replacement therapy
  • teriparatide teriparatide
  • One aspect of the present invention provides a compound of the present invention for use the use in treating and/or preventing ocular diseases.
  • the present invention provides a compound of the present invention for use in treating ocular diseases.
  • Ocular diseases applicable in the present invention may be associated with the breakdown of the inner blood-retinal barrier (iBRB) .
  • Exemplary ocular diseases relate to diabetic ocular, which include macular edema, diabetic retinopathy, posterior uveitis,retinal vein occlusion and the like.
  • More ocular diseases include, but are not limited to, 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. More details of using Lp-PLA 2 inhibitor to treat eye diseases are provided in WO2012/080497, which is incorporated by reference herein.
  • some embodiments of the present invention provide a compound of the present invention for use in treating or preventing diabetic macular edema in a subject.
  • the present invention provides a compound of the present invention for use in treating diabetic macular edema in a subject.
  • the present invention provides a compound of the present invention for use in treating or preventing a subject with or at risk of macular edema. In some embodiments, the present invention provides a compound of the present invention for use in treating a subject with or at risk of macular edema. In a further embodiment, the macular edema is associated with diabetic ocular disease, for example, diabetic macular edema or diabetic retinopathy. In yet a further embodiment, the macular edema is associated with posterior uveitis.
  • the present invention provides a compound of the present invention for use in treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides a compound of the present invention for use in treating glaucoma or macular degeneration.
  • the present invention provides a compound of the present invention for use in treating or preventing a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof. In one embodiment, the present invention provides a compound of the present invention for use in treating a disease associated with the breakdown of the inner blood-retinal barrier in a subject in need thereof.
  • systemic inflammatory diseases 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, enthesitis, may be the underlying cause of posterior uveitis affecting the retina, and which can result in macula edema.
  • the present invention provides a compound of the present invention for use in treating posterior uveitis or any of these systemic inflammatory diseases.
  • the present invention provides a compound of the present invention for use in treating or preventing disease associated with macrophage polarization, for example, M1/M2 macrophage polarization.
  • the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating disease 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) ,ischemic cardiomyopathy, chronic heart failure post myocardial infarction (MI) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • MI myocardial infarction
  • the compounds of the present invention may be formulated into pharmaceutical compositions prior to administration to a subject. Accordingly, one aspect of the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. In accordance with another aspect of the invention, a process is provided for the preparation of a pharmaceutical composition including admixing a compound described above or salts thereof, solvates etc thereof, with one or more pharmaceutically acceptable excipient.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.1 mg, 0.5 mg, or 1 mg to 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1g of a compound of the present invention, depending on the condition being treated, the route of administration and the age, weight and condition of the subject, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • the unit dosage compositions are those containing a daily dose or sub-dose as described herein, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known to one skilled in the art.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication.
  • a therapeutically effective amount of a compound of present invention for the treatment of the disease 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-doses per day as such as two, three, four, five or six doses per day. Or the dosing can be done intermittently, such as once every other day, once a week or once a month. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the pharmaceutical compositions of the invention may contain one or more compounds of the invention. In some embodiments, the pharmaceutical compositions may contain more than one compound of the invention. For example, in some embodiments, the pharmaceutical compositions may contain two or more compounds of the invention. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient may 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 when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) nasal inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration (including buccal, sublingual or transdermal) such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration including buccal or sublingual
  • parenteral administration including subcutaneous, intramuscular, intravenous or intradermal
  • transdermal administration such as transdermal patches
  • rectal administration such as supposi
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Suitable pharmaceutically acceptable excipients may 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.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate carrying or transporting the compound or compounds of the invention once administered to the subject from an organ, or a portion of the body, to another organ, or a portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient 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, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much 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) .
  • 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 is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler.
  • 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.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising 0.01 to 1000 mg of one or more compounds described above described herein or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising 0.01 to 1000 mg (calculated as free base) of a compound having the structure of
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising 0.01 to 1000 mg of a compound having the structure of
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising 0.01 to 1000 mg (calculated as free base) of a compound having the structure of
  • the present invention is directed a pharmaceutical composition for the treatment of neurodegeneration disease comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceitucally acceptable excipient.
  • the present invention is directed a pharmaceutical composition for the treatment of Alzheimer’s disease comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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BR112016028591-3A BR112016028591B1 (pt) 2014-07-22 2015-07-21 Composto inibidor da atividade de lp-pla2, composição farmacêutica que compreende o referido composto e uso do mesmo para tratar doença neurodegenerativa
KR1020177001423A KR20170034889A (ko) 2014-07-22 2015-07-21 화합물
CA2955910A CA2955910C (en) 2014-07-22 2015-07-21 Tricyclic imidazo-pyrimidinone compounds as lp-pla2 inhibitors
ES15824385T ES2744339T3 (es) 2014-07-22 2015-07-21 Compuestos
EP15824385.7A EP3172208B1 (en) 2014-07-22 2015-07-21 Compounds
JP2017503504A JP6625603B2 (ja) 2014-07-22 2015-07-21 化合物
CN201580039345.0A CN106536521B (zh) 2014-07-22 2015-07-21 化合物
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