Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D235/08—Radicals containing only hydrogen and carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
  • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D263/57—Aryl or substituted aryl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
  • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • C07D471/02—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 two hetero rings
  • C07D471/04—Ortho-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
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6503—Five-membered rings
  • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
  • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the invention relates to the use of 2-arylbenzimidazole, 2-arylbenzoxazole, 2- arylbenzothiazole, 2-arylimidazo[l,2-a]pyridine, and prodrug derivatives thereof as chemical activators of Ppargcla to treat neurodegenerative diseases.
• ALS Amyotrophic lateral sclerosis
• Activation of immune cells in the central as well as peripheral nervous system has been suggested to be a critical determinant of disease progression in ALS (Phani et al, Front Pharmacol. 3: 150, 2012). Specifically, microglia and macrophages have been shown to play distinct roles in the orchestration of neuroinflammation in this disease (Dibaj et al, PLoS One 6(3):el79l0, 2011; Boillee et al, Science, 312: 1389-92, 2006).
• BMT bone marrow transplantation
• AD Alzheimer's Disease
• oxidative stress has been proposed to be an underlying cause of neurodegeneration in AD (Friedland-Leuner et al Mol Biol Transl Sci, 127: 183-201, 2014).
• AD Alzheimer's disease
• symptoms are often mistakenly thought to be age-related concerns, or manifestations of stress.
• the most common symptoms are motor decline and difficulty in remembering recent events, known as short-term memory loss (Buchman et al, Exp Rev Neurother, 11 :665-76, 2011).
• the diagnosis is usually based on tests that evaluate behavior and thinking abilities, often followed by a brain scan if available.
• examination of brain tissue is required for a definitive diagnosis.
• symptoms can include confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss.
• bodily functions are lost, ultimately leading to death.
• Parkinson's disease also known as idiopathic or primary parkinsonism
• PD is a degenerative neurological disorder of the central nervous system.
• the motor symptoms of PD result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown.
• movement-related include shaking, rigidity, slowness of movement and difficulty with fine motor skills, walking, and gait.
• thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom.
• Other symptoms include sensory, sleep and emotional problems.
• PD is characterized by progressive motor impairment and neuroinflammation induced by microglia, the resident immune cells of the central nervous system (Aguzzi et al, Science, 339: 156-61, 2013). Inflammatory mediators produced by dysfunctional microglia have been shown to induce neuronal cell death, which underlies the progressive impairment in cognitive and behavioral performance in neurodegenerative diseases (Czirr et al J Clin Invest,
• HD Huntington's disease
• Frontotemporal degeneration is a disease that is closely related to AD in which progressive degeneration occurs in the frontal and temporal lobes of the brain. Gliosis and inflammatory activation of microglia have been documented in humans and animal models of FTD (Cagnin et al Annals of Neurol. 2004 6: 894-897; Yi et al. J. Exp. Med. 2010. 1 : 117- 128). Patients with FTD experience a gradual decline in behavior and language with memory usually relatively preserved. As the disease progresses, it becomes increasingly difficult for afflicted subjects to organize activities, behave appropriately, and care for oneself. There are currently no treatments to slow or stop the progression of the disease. Dementia with Lewy Bodies
• Dementia with Lewy bodies is a type of dementia that is related to PD.
• the hallmark of this disease is the presence of alpha synuclein aggregates in brains of afflicted subjects. These patients experience PD-like symptoms including hunched posture, rigid muscles, a shuffling walk and trouble initiating movement as well as changes in reasoning and thinking, memory loss (but less significantly than AD). Since Lewy bodies are also present in PD, these two diseases may be linked to the same underlying abnormalities in how the brain processes the protein alpha-synuclein.
• microglia-related neuroinflammation is present in brains of subjects with DLB, although this pathological feature occurs more extensively (Iannaccone et al, Parkinsonism Reiat. Disord. 2013 19: 47- 52).
• MND Motor neuron diseases
• ALS motor neuron diseases
• progranuiin a specific pathway called progranuiin can trigger inflammatory activation of microglia in an animal model of MND and genetic ablation of this pathway can delay disease progression (Philips et al J Neuropathol Exp Neurol. 2010 69: 1191-200).
• Demyelinating diseases such as Guillain-Barre syndrome and multiple sclerosis (MS) are degenerative di sorders in which in which the myelin sheath of neurons is compromised. This damage impairs signal conductivity in the affected nerves, causing deficiency in sensation, movement, cognition, or other functions. There is no cure for these diseases. Its most well-known form is MS, a disease in which the cellular subsets of the immune system have been implicated. For instance, on-going demyelination is often associated with infiltration of T cells and macrophages from the circulation as well as inflammatory activation of microglia (Kutzelnigg et al. Handb. Clin. Neurol. 2014, 122:15-58).
• W 2 is N or C-R 2 ;
• W 3 is N or C-R 3 ;
• W 4 is N or C-R 4 ;
• W 5 is N or C-R 5 ;
• W 6 is N or C-R 6 ;
• W 7 is N or C-R 7 ;
• W 8 is N or C-R 8 ;
• R 30 is chosen from (Ci-Cio)hydrocarbyl, (Ci-Cio)hydrocarbyl substituted with amino, (Ci-Cio)hydrocarbyl substituted with (Ci-C 4 )alkoxycarbonyl, (Ci- Cio)hydrocarbyl substituted with carboxyl, carboxy, (Ci-C 6 )alkoxycarbonyl, (Ci- C 6 )alkoxycarbonylamino, methylthio, heterocyclyl, (Ci-Cio)oxaalkyl, CHR 44 NHR 45 , and guanidino;
• R 44 is chosen from any naturally occurring amino acid sidechain; and R 45 is chosen from H, methyl, and (Ci-C 4 )alkoxycarbonyl; and R 40 and R 41 are chosen independently from hydrogen and (Ci-C 6 )hydrocarbyl; R 42 is (Ci-C 5 )alkyl; and
• R 43 is (Ci-C 3 )alkyl
• R 6 and R 10 are chosen independently from hydrogen, deuterium, halo, (Ci-C 3 )alkyl, perfluoro(Ci-C 3 )alkyl, hydroxy, (Ci-C 3 )alkoxy, perfluoro(Ci-C 3 )alkoxy, and amino;
• R 7 and R 9 are chosen independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, and halo(Ci- C 4 )alkoxy; and
• R 8 is chosen from hydrogen, deuterium, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci- C 4 )alkoxy, halo(Ci-C 4 )alkoxy, cyano, phenyl, phenoxy, benzyl oxy, and amino;
• W 1 is chosen from O, S, and N-R 1 , or, when W 9 is N, W 1 may additionally be C-R 50
• W 2 is N or C-R 2 ;
• W 3 is N or C-R 3 ;
• W 4 is N or C-R 4 ;
• W 5 is N or C-R 5 ;
• W 9 is C, or, when W 1 is C-R 50 ; W 9 may be N;
• R 30 is chosen from (Ci-Cio)hydrocarbyl, (Ci-Cio)hydrocarbyl substituted with amino, (Ci-Cio)hydrocarbyl substituted with (Ci-C 4 )alkoxycarbonyl, (Ci- Cio)hydrocarbyl substituted with carboxyl, carboxy, (Ci-C 6 )alkoxycarbonyl, (Ci- C 6 )alkoxycarbonylamino, methylthio, heterocyclyl, (Ci-Cio)oxaalkyl, CHR 44 NHR 45 , and guanidino;
• R 44 is chosen from any naturally occurring amino acid sidechain; and R 45 is chosen from H, methyl, and (Ci-C 4 )alkoxycarbonyl; and R 40 and R 41 are chosen independently from hydrogen and (Ci-C 6 )hydrocarbyl; R 42 is (Ci-C 5 )alkyl; and
• R 43 is (Ci-C 3 )alkyl
• R 50 is H or (Ci-C 3 )alkyl
• W 1 is N-R 1 ;
• R 1 is not H or (Ci-C 3 )alkyl.
• the invention relates to a method of treating a neurodegenerative disease, comprising administering a compound of formula (III):
• W 1 is chosen from O, S, and N-R 1 , or, when W 9 is N, W 1 may additionally be C-R 50 ;
• W 2 is N or C-R 2 ;
• W 3 is N or C-R 3 ;
• W 4 is N or C-R 4 ;
• W 5 is N or C-R 5 ;
• W 6 is N or C-R 6 ;
• W 7 is N or C-R 7 ;
• W 8 is N or C-R 8 ;
• W 9 is C, or, when W 1 is C-R 50 ; W 9 may be N;
• R 30 is chosen from (Ci-Cio)hydrocarbyl, (Ci-Cio)hydrocarbyl substituted with amino, (Ci-Cio)hydrocarbyl substituted with (Ci-C 4 )alkoxycarbonyl, (Ci- Cio)hydrocarbyl substituted with carboxyl, carboxy, (Ci-C 6 )alkoxycarbonyl, (Ci-C 6 )alkoxycarbonylamino, methylthio, heterocyclyl, (Ci-Cio)oxaalkyl, CHR 44 NHR 45 , and guanidino;
• R 44 is chosen from any naturally occurring amino acid sidechain
• R 45 is chosen from H, methyl, and (Ci-C 4 )alkoxycarbonyl; and R 40 and R 41 are chosen independently from hydrogen and (Ci-C 6 )hydrocarbyl;
• R 42 is (Ci-C 5 )alkyl
• R 43 is (Ci-C 3 )alkyl
• R 50 is H or (Ci-C 3 )alkyl
• R 6 and R 10 are chosen independently from hydrogen, deuterium, halo, (Ci-C 3 )alkyl, perfluoro(Ci-C 3 )alkyl, hydroxy, (Ci-C 3 )alkoxy, perfluoro(Ci-C 3 )alkoxy, and amino;
• R 7 and R 9 are chosen independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, and halo(Ci- C 4 )alkoxy; and
• R 8 is chosen from hydrogen, deuterium, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci- C 4 )alkoxy, halo(Ci-C 4 )alkoxy, cyano, phenyl, phenoxy, benzyl oxy, and amino;
• R 8 is not hydrogen or (Ci-C 4 )alkyl when:
• R 1 is hydrogen
• W 8 is C-R 8 ;
• R 9 and R 10 are hydrogen.
• the invention relates to methods and uses of the above-described compounds of formulas I, II, or III, or pharmaceutical compositions comprising a compound of formulas I, II, or III, in medicine, particularly for the treatment of a neurodegenerative disease.
• neurodegenerative diseases include amyotrophic lateral sclerosis (ALS),
• the method includes administering an effective amount of a compound or pharmaceutical composition described herein.
• the invention relates to methods and uses of the above-described compounds of formulas I, II, or III, or pharmaceutical compositions comprising a compound of formulas I, II, or III, in medicine, particularly for treating aging-associated cognitive impairment and neuroinflammation in a patient. These methods include administering to a patient a therapeutically effective amount of a compound pharmaceutical composition described herein.
• FIG. 1 shows the plasma levels of API for prodrug examples 6-P, 8-P, and ll-P.
• FIG. 2 shows the brain levels of API for prodrug examples 6-P, 8-P, and ll-P.
• FIG. 3 shows the liver levels of API for prodrug examples 6-P, 8-P, and ll-P.
• the compound may be of formula I, II, or III, unless otherwise indicated.
• W 1 is N-R 1 . In other embodiments of formulas II, and III, W 1 is O. In yet other embodiments of formulas II and III, W 1 is S. In still other embodiments of formulas II and III, W 1 is C-R 50 , preferably when W 9 is N. In some embodiments where W 1 is C-R 50 , R 50 is H. In other embodiments where W 1 is C-R 50 , R 50 is (Ci-C 3 )alkyl.
• R 30 is chosen from: (a) (Ci- C 6 )alkyl; (b) phenyl substituted with (Ci-C 4 )alkylamino; (c) the descarboxy residue of a natural amino acid; (d) (Ci-C3)hydrocarbyl substituted with carboxyl; (e) (Ci-C5)oxaalkyl; and (d) pyridyl.
• R 1 is H. In other embodiments of formulas alkyl.
• W 2 is N. In other embodiments of formulas I, II, and III, W 2 is C-R 2 . In some embodiments, W 2 is chosen from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C-OCF 3 , C-OCF 2 H, C-CD 3 , and C-CONH 2 , In some embodiments, W 2 is chosen from C-H, C-F, C-D, C-CF 2 H, C-CD 3 , and C-CF3.
• R 2 is chosen from hydrogen, perfluoro(Ci- C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, perfluoro(Ci-C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
• R 2 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
• R 2 is chosen from hydrogen, halo, and perfluoro(Ci-C3)alkyl.
• W 3 is N. In other embodiments of formulas I, II, and III, W 3 is C-R 3 . In some embodiments, W 3 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C-D, C-OCH 3 , C-CN, C-OH, C-Cl, C-CH 3 , C-CF 2 H, C-OCF 3 , C-OCF 2 H, C- CD 3 , and C-Br. In some embodiments, W 3 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C- CF 2 H, C-CD 3 , and C-D.
• R 3 is chosen from hydrogen, perfluoro(Ci- C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, perfluoro(Ci-C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide. In some embodiments where W 3 is C-R 3 , R 3 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide. In some embodiments where W 3 is C-R 3 , R 3 is chosen from H, halo, and perfluoro(Ci-C 3 )alkyl.
• W 4 is N. In other embodiments of formulas I, II, and III, W 4 is C-R 4 . In some embodiments, W 4 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C-D, C-OCH 3 , C-CN, C-OH, C-Cl, C-CFF, C-CF 2 H, C-OCF 3 , C-OCF 2 H, C- CD 3 , and C-Br. In some embodiments, W 4 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C- CF 2 H, C-CD 3 , and C-D.
• R 4 is chosen from hydrogen, perfluoro(Ci- C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, perfluoro(Ci-C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide. In some embodiments where W 4 is C-R 4 , R 4 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide. In some embodiments where W 4 is C-R 4 , R 4 is chosen from H, halo, and perfluoro(Ci-C 3 )alkyl.
• W 5 is N. In other embodiments of formulas I, II, and III, W 5 is C-R 5 . In some embodiments, W 5 is chosen from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C-OCF 3 , C-OCF 2 H, C-CD 3 , and C-CONH 2 , In some embodiments, W 5 is chosen from C-H, C-F, C-D, C-CF 2 H, C-CD 3 , and C-CF3.
• R 5 is chosen from hydrogen, perfluoro(Ci- C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, perfluoro(Ci-C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
• R 5 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
• R 5 is chosen from hydrogen, halo, and perfluoro(Ci-C3)alkyl.
• W 6 is N. In other embodiments of formulas I and III, W 6 is C-R 6 , preferably C-H.
• R 6 is chosen from hydrogen, deuterium, halo, (Ci-C3)alkyl, perfluoro(Ci-C3)alkyl, hydroxy, (Ci-C3)alkoxy, perfluoro(Ci-C3)alkoxy, and amino.
• W 7 is N. In other embodiments of formulas I and III, W 7 is C-R 7 . In some embodiments where W 7 is C-R 7 , R 7 is chosen from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci- C 4 )alkoxy, and halo(Ci-C 4 )alkoxy. In some embodiments where W 7 is C-R 7 , R 7 is hydrogen or (C3-C 4 )alkyl.
• W 8 is N. In other embodiments of formulas I and III, W 8 is C-R 8 . In some embodiments where W 8 is C-R 8 , R 8 is chosen from hydrogen, deuterium, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci- C 4 )alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino.
• R 8 is chosen from H, (Ci-C 4 )alkyl, amino, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, and hydroxy. In some embodiments where W 8 is C-R 8 , R 8 is chosen from H, tert-butyl, amino, and methoxy, preferably tert-butyl when W 7 is N or R 7 is hydrogen.
• W 9 is N. In other embodiments of formulas II and III when W 1 is NR 1 , O, or S, W 9 is C.
• R 9 is chosen from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, and halo(Ci- C 4 )alkoxy.
• R 7 is hydrogen and R 8 is H
• R 9 is tert-butyl.
• R 10 is chosen from hydrogen, deuterium, halo, (Ci-C 3 )alkyl, perfluoro(Ci-C3)alkyl, hydroxy, (Ci-C 3 )alkoxy, perfluoro(Ci-C 3 )alkoxy, and amino, preferably H.
• salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
• Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric,
• ethanedi sulfonic ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like.
• suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine,
• chloroprocaine choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
• the present invention provides a pharmaceutical composition comprising a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
• the most suitable route may depend upon the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula I, II or III, or a pharmaceutically acceptable salt thereof ("active ingredient”), with the carrier which constitutes one or more accessory ingredients.
• active ingredient a compound of formula I, II or III, or a pharmaceutically acceptable salt thereof
• the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
• Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti -oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
• Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 ⁇ 4, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 Cl, respectively.
• Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
• Tritiated, i.e. 3 ⁇ 4, and carbon-l4, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
• Compounds that contain isotopes U C, 13 N, 15 0 and 18 F are well suited for positron emission tomography.
• Radiolabeled compounds of formulas I, II, and III of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
• the compounds provided herein can be used for treating neurodegenerative diseases in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formulas I, II, or III.
• A“patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary
• the patient is a mammal, for example, a primate. In some embodiments, the patient is a human.
• Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the
• compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
• the terms“administer”,“administering” or“administration” in reference to a dosage form of the invention refers to the act of introducing the dosage form into the system of subject in need of treatment.
• “administration” and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents.
• Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration.
• the therapies are administered at approximately the same time, e.g ., within about a few seconds to a few hours of one another.
• A“therapeutically effective” amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. A therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
• Ci to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthyl ethyl. Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
• Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc.
• Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
• alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof.
• Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s- butyl, t-butyl and the like.
• Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.
• carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
• C3-C 10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene;
• Cs-Co carbopolycycle refers to such systems as norbomane, decalin, indane and naphthalene.
• Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
• Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S.
• the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
• a heterocycle may be non aromatic (heteroaliphatic) or aromatic (heteroaryl).
• heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
• heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl,
• thiazolidinyl isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and
• Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include
• Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9- trioxadecyl and the like.
• the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
• thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethyl aminoethyl and methylthiopropyl .
• halogen means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
• acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl and the like. Lower- acyl refers to groups containing one to four carbons.
• the double bonded oxygen, when referred to as a substituent itself is called“oxo”.
• the term“optionally substituted” may be used interchangeably with “unsubstituted or substituted”.
• the term“substituted” refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc.
• cycloalkylaminoalkyl dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclyl alkoxy, mercapto, alkylthio, sulfoxide, sulfone, sulfonyl amino, alkylsulfmyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryl oxy, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, benzyloxyphenyl, and benzyloxy.
• Oxo is also included among the substituents referred to in“optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
• 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
• more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
• Preparation of compounds can involve the protection and deprotection of various chemical groups.
• the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry , I st Ed., Oxford University Press, 2000; and in March’s Advanced Organic chemistry: Reactions, Mechanisms, and Structure , 5 th Ed., Wiley-Interscience Publication, 2001.
• Benzimidazole compounds were synthesized by either: i) reaction of optionally substituted 2-nitroanilines with aryl aldehydes in the presence of sodium hydrosulfite (D. Fokas et al. Synthesis. 2005, 1, 47-56.); or ii) reaction of acid chlorides with optionally substituted 1, 2-phenyl enediamines followed by cyclocondensation of the intermediate amides.
• Benzoxazole compounds were synthesized by reacting an optionally substituted 2- aminophenol with an acid chloride followed by heat.
• Imidazo[l,2-a]pyri dines were synthesized by heating a 2-aminopyridine with a 2- bromo-l-phenylethan-l-one in the presence of a base.
• Benzimidazole prodrugs were synthesized by methods G and H as described below. Method G - Benzimidazole Prodrugs from Reaction with Halomethylesters and
• Benzimidazole prodrugs are prepared by heating benzimidazoles with chloromethyl esters in the presence of sodium iodide and sodium carbonate in refluxing acetone or, alternatively, they can be prepared by heating benzimidazoles with chloromethyl carbonates in the presence of sodium iodide and sodium carbonate in refluxing acetone (Examples 6-P to 9-P and l l-P).
• Example l-P (2-(4-(fer/-Butyl)phenyl)-liT-benzo[ ⁇ i]imidazol-l-yl)m ethyl acetate.
• Example 2-P (2-(4-(ter/-Butyl)phenyl)-liT-benzo[i/]imidazol-l-yl)m ethyl butyrate.
• Example 4-P (2-(4-(ter/-Butyl)phenyl)-liT-benzo[i/]imidazol-l-yl)m ethyl pivalate.
• Example 6-P 4-((2-(4-(/er/-Butyl)phenyl)-liT-benzo[i/]imidazol-l-yl)methoxy)-4- oxobutanoic acid.
• Example 7-P (2-(4-(ter/-Butyl)phenyl)-liT-benzo[i/]imidazol-l-yl)m ethyl 4-(((lerl- butoxycarbonyl)amino)methyl)benzoate.
• Example 8-P (4-(((2-(4-(/er/-butyl)phenyl)-l77-benzo[ ⁇ 7]imidazol-l-yl)methoxy)carbonyl)- phenyl)methyl amm onium hy drochl ori de .
• Benzimidazole prodrugs are prepared by treating benzimidazoles with an excess of sodium hydride, followed by treatment with dialkyl chloromethylphosphates. In the case of di-tert-butyl chloromethylpshophates, the resultant product may be subjected to acid- mediated hydrolysis to afford the dihydrogen phosphate pro-drug. These procedures are adapted from those reported by Chassaing et al. (J Med Chem. 2008, 57, 1111), and Flores- Ramos et al. (Bioorg Med Chem Lett. 2014, 24, 5814).
• Example 9-P Di-fe/V-butyl ((2-(4-(/er/-butyl)phenyl)-li7-benzo[ ⁇ i]imidazol-l-yl)methyl) phosphate.
• Example 10-P Dihydrogen ((2-(4-(/er/-butyl)phenyl)-li7-benzo[ ⁇ i]imidazol-l-yl)methyl) phosphate.
• reaction mixture was diluted with l,4-dioxane (1.0 mL), and the precipitate was filtered, washed with cold dioxane (1.0 mL), cold diethyl ether (1.0 mL), and dried under high-vacuum to give a white crystalline solid (69 mg, 73%).
• Example l l-P Disodium ((2-(4-(/er/-butyl)phenyl)-liT-benzo[ ⁇ i]imidazol-l-yl)m ethyl) phosphate.
• prodrug derivatives synthesized are as shown below. Carbamate examples were typically formed by treatment of the benzimidazole precursor with the appropriate chloroformate in pyridine/dichlormethane.
• Example 12-P (2-(4-(ter/-Butyl)phenyl)-lH-benzo[d]imidazol-l-yl)methyl (tert- butoxycarbonyl)-L-alaninate.
• Example 13-P Ethyl 2-(4-(/er/-butyl)phenyl)-lH-benzo[d]imidazole-l-carboxylate.
• Example 14-P Methyl 2-(4-(/er/-butyl)phenyl)-lH-benzo[d]imidazole-l-carboxylate.
• Example 15-P Ethyl 2-(4-(/er/-butyl)phenyl)-lH-benzo[d]imidazole-l-carboxylate.
• Example 16-P Propyl 2-(4-(/er/-butyl)phenyl)-lH-benzo[d]imidazole-l-carboxylate.
• Example 17-P l-(2-(4-(/er/-Butyl)phenyl)-lH-benzo[d]imidazol-l-yl)ethan-l-one.
• the murine myeloid cell line BV2 or human peripheral blood mononuclear cells are cultured in RPMI 1640 media (Cat# 11875119, Gibco) supplemented with 10% fetal bovine serum and 1% L-glutamine 1% penicillin. These cells are then stimulated with lOOng/ml of lipopolysaccharide (LPS, 0111 :B4, Cat# L2630, Sigma) over 24 hours.
• LPS stimulation results in the secretion of the inflammatory cytokine TNF-a by BV2 cells or PBMC, which can be quantified by ELISA in culture supernatant samples per manufacturer's protocol (Cat# 558273 for BV2 and Cat# 558299 for PBMC, BD Biosciences).
• BV2 cells or PBMC adenosine-phosphate-containing cells
• PBMC PBMC-derived cytokine TNF-a by PBMC
• Example compounds 1-78 inhibit TNF-a production by BV2 cells or PBMC
• the cells were cultured in the presence of the compounds at different concentrations, and fold reduction in TNF-a production relative to TNF-a production by the same cells cultured in the presence of dimethylsulfoxide (as vehicle control) was determined. The results are shown in Table 2.
• Caco-2 cells were maintained in DMEM in an atmosphere of 5% C0 2 .
• 5 c 10 5 cells/well of were seeded on polycarbonate filter inserts and allowed to grow and differentiate for 21 ⁇ 4 days before the cell monolayers were used for experiments.
• Apparent permeability coefficients were determined for A B and B A directions with and without the presence of elacridar as a transporter inhibitor.
• Up to three test items and reference compounds were dissolved in Hank’s balanced salt solution at pH 7.4 to yield a final concentration of 10 mM.
• the assays were performed in HBSS containing 25 mM HEPES (pH 7.4) at 37 °C. Prior to the study, the monolayers were washed in prewarmed HBSS.
• HBSS containing the test items was added to the donor side of the monolayer and HBSS without test items was added to the receiver side. Aliquots of the receiver side were taken over the 2 h incubation period; aliquots of the donor side were taken at 0 h and 2 h. Aliquots were diluted with an equal volume of methanol/water with 0.1% formic acid containing the internal standard. The mixture was analyzed by LC-MS/MS.
• FIG. 1 shows the plasma levels of API for prodrug examples 6-P, 8-P, and ll-P.
• FIG. 2 shows the brain levels of API for prodrug examples 6-P, 8-P, and ll-P.
• FIG. 3 shows the liver levels of API for prodrug examples 6-P, 8-P, and ll-P.
• FIGs 1-3 show that prodrug examples 6-P, 8-P, and ll-P led to measurable amounts of API in plasma, brain, and liver in the mouse PK study.

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