Compounds for and methods of treating diseases
Inventors
Bond, Silas • Huggins, Penelope Jane • Parsons, Jack Gordon
Assignees
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Publication Number
US-11155547-B1
Publication Date
2021-10-26
Expiration Date
Abstract
The present invention provides heterocyclic compounds of formula (I) that modulate biological metals and to pharmaceutical compositions containing such compounds. The invention particularly relates to compounds that modulate iron and to compounds 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).
Core Innovation
The invention relates to compounds of formula (I), including pharmaceutically acceptable salts, stereoisomers and solvates, and describes heterocyclic metal modulators defined by positions X1 to X8 that are independently selected from N and CR3, with 0, 1, 2, 3 or 4 of X1 to X8 being N. The compound definitions further specify substituent groups R1 to R7 and integer parameters m, n, and p, together with additional structural formulas and variants.
The disclosed subject matter includes imidazo[1,5-a]pyridine-containing tetrahydroimidazo[1,5-a]pyridine scaffolds and related fused ring systems, with examples bearing hydroxyl, methoxy, halogenated aryl, fluoro and methyl substitutions, benzyloxy substituents, and morpholinomethyl substituents. The examples are reported with analytical data such as HPLC, 1H NMR, MS, and m/z values, and include described preparation and ring-conversion chemistry.
The invention is directed to methods of treating and/or preventing metal-ion-associated neurological disorders, and it emphasizes iron modulators that remove iron from cells. The mechanistic rationale includes modulation of iron, iron(II)/iron(III), reactive oxygen species, and hydroxyl radical chemistry, including references to Fenton reaction chemistry, and includes pharmaceutical compositions with pharmaceutically acceptable carrier and/or excipients.
Claims Coverage
The consolidated claim coverage centers on compound claims for formula (I) with tightly constrained X1–X8 heteroatom patterns and enumerated substituent sets for R1 to R7, including integer constraints on m, n, and p. The scope also expressly includes pharmaceutically acceptable salts, stereoisomers, and solvates, and includes pharmaceutical composition claims with pharmaceutically acceptable carrier and/or excipient. Across the input items, three inventive feature groupings are consistently supported.
Formula (I) compound scaffold with constrained X1–X8 heteroatom pattern
A compound of formula (I) wherein each of X1 to X8 is independently selected from N and CR3, with 0, 1, 2, 3 or 4 of X1 to X8 being N.
Enumerated substituent sets for R1 to R7 with parameter constraints
R1, R2, R3, R4, R5, R6 and each R7 are selected from defined option sets, with m equal to 0 or an integer from 1 to 6, n equal to 1 or 2, and p equal to an integer from 1 to 4.
Pharmaceutically acceptable salts, stereoisomers and solvates
Coverage includes a pharmaceutically acceptable salt, stereoisomer or solvate thereof.
Pharmaceutical composition with carrier and/or excipient
A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier and/or excipient.
Overall, claim coverage is directed to formula (I) compounds defined by constrained heteroatom selection and substituent option sets, with coverage for pharmaceutically acceptable salts, stereoisomers, and solvates, and a pharmaceutical composition aspect using a pharmaceutically acceptable carrier and/or excipient.
Stated Advantages
Oral delivery.
CNS iron modulation.
Low liver extraction.
Non-toxicity.
Kinetic stability/selectivity of metal complexes.
Treating and/or preventing metal-ion-associated neurological disorders, including Parkinson’s disease.
Acting as iron modulators that remove iron from cells.
Providing pharmaceutical compositions suitable for multiple routes of administration (oral, rectal, nasal, topical, parenteral, inhalation/aerosol).
Documented Applications
Treating or preventing metal-associated or metal-ion associated neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, ALS, multiple sclerosis, frontotemporal dementia, multiple system atrophy, tardive dyskinesia, Hallervorden-Spatz syndrome, Friedreich’s ataxia, epilepsy, and multiple sclerosis.
Biological testing of Fe efflux from BE(2)-M17 cells using 57Fe and ICP-MS.
MS/NMR characterization of phenol-containing small molecules, including fluorinated variants.
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