N-acylethanolamide derivatives and uses thereof
Inventors
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Publication Number
US-11547681-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present disclosure provides certain N-Acylethanolamide derivatives, and uses relating thereto.
Core Innovation
The invention relates to N-acylethanolamide derivatives and compound or salt definitions in which substituents R4a, R4b, and R4c are acyl/ester-containing side chains attached via carbonyl groups. The disclosed motifs include —C(O)—Y—C(O)OR′ and —C(O)R′, with Y as a straight or branched bivalent hydrocarbon chain and OR′ as hydrogen or an optionally substituted C1–C20 aliphatic group.
The invention also relates to stereochemically and positionally defined glycerol-derived N-acylethanolamide conjugates in which conjugation at the glycerol 2-position (—OR2) is distinguished from the 1- or 3-positions (—OR1/—OR3). The disclosure provides broad scaffold families via formulas II, III, III′/III″, IV, IV′/IV″, and V, including variable groups Y and R4 and substitution options for R′.
The disclosure further includes N-acylethanolamide prodrug or derivative compounds selected from Formula I-a, Formula I, Formula I-b, Formula II, and Formula III, including variants I′/I″ and III′/III″. The disclosed approach conjugates N-acylethanolamide moieties via linkers to phosphate, butyric acid, glycerol, succinate, caprylic acid, gluconoic acid, eicosapentaenoic acid, linoleic acid, and sucrose, and includes positional isomerism on the glycerol backbone. It also includes deuterium-substituted variants and non-isomerizing compounds such as compound I-16.
The embodiments state improved or comparable pharmacologic activity versus parent N-acylethanolamides, improved aqueous solubility and stability, altered metabolism associated with delivery of the parent PEA or active metabolites, and improved oral bioavailability. Positional isomer interconversion can occur pre- or post-administration depending on whether the glycerol bears a free alcohol, and oral performance is characterized by plasma pharmacokinetics and PEA exposure following administration.
Claims Coverage
The consolidated claim coverage includes compound or salt claims and related composition and use claims. Five inventive feature groupings are consistently present across the provided claim material: compound or salt form, pharmaceutically acceptable salt, pharmaceutical composition with excipient, oral capsule formulation, and treatment of pain including inflammatory pain and neuropathic pain where stated.
Compound or salt form
A compound or a salt thereof, including embodiments defined by R4a, R4b, and R4c as acyl/ester-containing carbonyl-linked side chains and by the disclosed glycerol-derived N-acylethanolamide scaffold families.
Positionally defined glycerol-derived N-acylethanolamide conjugates
A compound characterized by stereochemically and positionally defined glycerol-derived N-acylethanolamide conjugates, including conjugation at the glycerol 2-position versus the 1- or 3-positions, with broad scaffold families defined via formulas II, III, III′/III″, IV, IV′/IV″, and V.
Pharmaceutically acceptable salt
The compound is a pharmaceutically acceptable salt.
Pharmaceutical composition with excipient
A pharmaceutical composition including the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Oral delivery capsule formulation
The pharmaceutical composition is formulated for oral delivery and is a solid formulation in a capsule.
Treatment of inflammatory pain by administration
A method of treating inflammatory pain by administering the compound, or a pharmaceutically acceptable salt of it, to a patient in need of treatment.
Treatment of pain
Treatment of pain, including chronic lower back pain, sciatica/radiculopathy, and neuropathic pain, by administering the compound or a pharmaceutical composition.
The claim coverage centers on the compound or salt itself, with refinements to pharmaceutically acceptable salts, pharmaceutical compositions with excipients, oral capsule formulations, and treatment of pain, including explicit treatment of inflammatory pain and neuropathic pain.
Stated Advantages
Addresses poor pharmacological properties of N-acylethanolamides, including limited oral bioavailability and limited exposure to GI/lower bowel target sites.
Improves pharmacological properties versus 1- or 3-position conjugation as proposed for 2-position conjugation.
Improved or comparable pharmacologic activity versus parent N-acylethanolamides.
Improved aqueous solubility and stability.
Altered metabolism associated with delivery of the parent PEA or active metabolites.
Improved oral bioavailability.
Documented Applications
Treating pain, including inflammatory pain and neuropathic pain, by administering the compound or a pharmaceutical composition.
Treating chronic lower back pain, sciatica/radiculopathy, and neuropathic pain.
Treating anxiety.
Treating depression.
Treating schizophrenia.
Treating Huntington's disease.
Treating Parkinson's disease.
Treating Alzheimer's disease.
Treating ALS.
Treating multiple sclerosis.
Treating cerebral ischemia.
Treating epilepsy.
Treating IBS-D.
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