3-(5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl) propanoic acid derivatives as KMO inhibitors
Inventors
Bouillot, Anne Marie Jeanne • Mirguet, Olivier • Liddle, John • WALKER, Anne Louise
Assignees
Dr Falk Pharma GmbH • Kynos Therapeutics Ltd • GlaxoSmithKline Research and Development Ltd
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Publication Number
US-11352334-B2
Publication Date
2022-06-07
Expiration Date
Abstract
A compound of formula (I) or a salt thereof are provided: wherein R1, X and R3 are defined in the specification, useful in the treatment of disorders mediated by KMO such as acute pancreatitis, chronic kidney disease, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure.
Core Innovation
The invention relates to benzo[d]oxazole-propanoic acid derivatives defined by a Formula (I) scaffold and to stereochemically defined benzo[d]oxazole-propanoic acid compounds. The scaffold specifies a benzo[d]oxazol-3(2H)-yl propanoic acid/propanoate framework with defined X, R1, R2 and R3 substituents, optional heteroaryl substitution patterns, and pharmaceutically acceptable salts.
The disclosed compound set includes enantiomers, racemic variants, and specific named examples within the remaining structural coverage. The Formula (I) scope includes explicit exclusions of named substituted propanoic acid derivatives, while the compound set also enumerates specific 5-chloro-2-oxo benzo[d]oxazole-propanoic acid structures, including pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyridine N-oxide, cycloalkoxy, and oxetaneyloxy variants.
The document further provides example compounds, salt forms, and adduct forms tied to the benzo[d]oxazole-propanoic acid core, including sulfuric acid 1:1, methanesulfonic acid 1:1, sodium carboxylate, 4-methylbenzenesulfonic acid 1:1, and tris salt formation with 2-amino-2-(hydroxymethyl)-1,3-propanediol. Analytical characterization is also described, including LCMS/HPLC and chiral-HPLC.
Claims Coverage
The consolidated claim set includes two independent claim groupings: a Formula (I) compound claim with defined substituent options and explicit exclusions, and an enumerated benzo[d]oxazole-propanoic acid compound claim covering specific structures, stereoisomers, and pharmaceutically acceptable salts. In addition, the document includes dependent coverage for pharmaceutical composition and acute pancreatitis treatment. The inventive coverage centers on 2 main feature groupings.
Formula (I) benzo[d]oxazole-propanoic acid scaffold with defined substituent options and exclusions
A compound of Formula (I), or a pharmaceutically acceptable salt, wherein the benzo[d]oxazol-3(2H)-yl propanoic acid/propanoate scaffold has defined X, R1, R2 and R3 substituents, including heteroaryl options optionally additionally substituted by halo, methyl, ethyl or O, and excludes named substituted propanoic acid derivatives.
Enumerated benzo[d]oxazole-propanoic acid compounds including stereoisomers and alternative heteroaryl or alkoxy variants
A compound selected from explicitly listed 3-(5-chloro-2-oxo-6-substituted) benzo[d]oxazol-3(2H)-yl)propanoic acid structures, including (R) and (S) stereoisomers and a racemic example, together with variants such as pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, cycloalkoxy, and oxetaneyloxy substituents, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including a Formula (I) compound
A pharmaceutical composition comprising a compound of Formula (I), optionally as a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients.
Treatment method for acute pancreatitis
A method for treating acute pancreatitis by administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a corresponding method using a pharmaceutical composition.
Claim coverage focuses on benzo[d]oxazole-propanoic acid compounds defined either by a general Formula (I) with specified substituent selections and explicit exclusions, or by an extensive enumeration of specific substituted compounds and stereoisomers with pharmaceutically acceptable salts. The document also recites pharmaceutical composition and acute pancreatitis treatment use.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or prophylaxing disorders mediated by KMO.
Inhibition of kynurenine 3-monooxygenase (KMO) using an MS Rapidfire functional assay.
Treating acute pancreatitis by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes the Formula (I) compound.
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