Imidazo [1,5-a]pyridine compounds and their use
Inventors
Bond, Silas • Huggins, Penelope Jane • Parsons, Jack Gordon
Assignees
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Publication Number
US-10941143-B2
Publication Date
2021-03-09
Expiration Date
Abstract
The present invention provides compounds that modulate biological metals and to pharmaceutical compositions containing such compounds. The invention particularly relates to imidazo[1,5-a]pyridine compounds of formula (I) that modulate iron and are useful for the treatment of diseases, particularly neurological diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Alzheimer-type dementia, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and multiple system atrophy (MSA). The compounds of formula (I) being where variables are defined herein.
Core Innovation
The invention relates to compounds of formula (I) in which each of X1 through X12 is independently N or CR3, with a limitation that 0, 1, 2 or 3 of X1 through X12 are N. The compounds further define R1 and R2 from specified functional-group sets, and each R3 is independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, and multiple functionalized variants, with optional substitution. The disclosure also includes R4, R5, R6, and R7 selection rules and permits pharmaceutically acceptable salts or solvates.
The definitions for R4, R5, R6 and R7 further delimit the permitted chemical space, including hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, ring systems, OR5, SR5, N(R6)2, carbonyl and thiocarbonyl derivatives, and S(O)n-related options, with m limited to 0 or an integer from 1 to 6 and n limited to 1 or 2. The provided content also describes related structural embodiments and example compounds showing substituted polyaromatic heterocycle scaffolds, including imidazo[1,5-a]pyridine and imidazo[1,5-b]pyridine-containing compounds.
The invention is also described in connection with imidazo[1,5-a]pyridine iron-modulating compounds and related structural forms, with stated therapeutic use for metal ion-associated neurological disease. The partial content further presents compound examples and analytical characterization, and describes administration through pharmaceutical compositions containing a compound of formula (I) and a pharmaceutically acceptable carrier and/or excipient.
Claims Coverage
The consolidated claim coverage centers on a compound of formula (I) with defined X1–X12 N/CR3 selection and a maximum of 0–3 N atoms, together with constrained substituent sets for R1 and R2 and a broad independently selectable R3 substituent set. The coverage also includes pharmaceutically acceptable salts or solvates, and a pharmaceutical composition comprising a formula (I) compound with a pharmaceutically acceptable carrier and/or excipient. One part of the provided content also refers to related formula (III) embodiments.
Compound of formula (I) with limited N substitution
Each of X1 through X12 is independently N or CR3, with 0, 1, 2 or 3 of X1 through X12 being N.
R1 and R2 functional-group constraints
R1 is selected from hydrogen, alkyl, alkenyl, alkynyl, C(O)R4 and C(S)R4; R2 is selected from OH, SH, halo, OR5, SR5, C(O)R4, C(S)R4, NO2, CN, N(R6)2, OS(O)nN(R6)2 and OS(O)nR4.
Broad independently selectable R3 substituents
Each R3 is independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, and multiple functionalized variants, with optional substitution and the stated constraints on R4, R5, R6, R7, m and n.
Formula (III) positional refinement
A compound having formula (III) with X5, X7, and X9 limited to N or CR3e/CR3g/CR3i, with none, one, or two of X5, X7, and X9 being N, while R1, R2, and R3b–R3l follow the defined selection rules.
Pharmaceutical composition containing compound of formula (I)
A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate of it, together with a pharmaceutically acceptable carrier and/or excipient.
The consolidated claim coverage is anchored on formula (I) compounds defined by an N/CR3 scaffold across X1–X12 with 0–3 N atoms, constrained R1 and R2 groups, and a broad R3 substituent definition with additional variable constraints. It also includes pharmaceutically acceptable salts or solvates and a pharmaceutical composition containing the compound with a carrier and/or excipient.
Stated Advantages
Oral delivery and CNS availability for metal ion-associated neurological disease.
Inhibition of iron-mediated toxicity.
Low liver extraction.
Non-toxicity.
Documented Applications
Treatment and prevention of metal ion-associated disorders, including iron-ion associated disorders and neurological disorders.
Treatment and prevention of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Alzheimer-type dementia, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple system atrophy.
Medicaments manufactured for use in treating or preventing a metal ion associated disorder via administration.
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