Methods for making valerenic acid derivatives and their use
Inventors
Mulzer, Johann • Ramharter, Jürgen • Hering, Steffen • Khom, Sophia
Assignees
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Publication Number
US-8809395-B2
Publication Date
2014-08-19
Expiration Date
Abstract
The present invention is directed to compounds, intermediates and methods for making valerenic acid and its derivatives as well as the use of such compounds as GABAA receptor ligands.
Core Innovation
The invention relates to valerenic acid derivative compounds of formula (IA2) and variants including general formulas (I), (IA1), (IA2), (IB), (IC), and (ID), including pharmaceutically acceptable salts, solvates, and prodrugs. The compounds are defined by specific substituent options for R1, R2 to R4, R7 to R9, and R10 to R12, with the dotted line between C10 and C11 representing an optional double bond in at least one general formula embodiment.
The structure is further constrained by excluding certain Z- or E-isomers and excluding specific compounds, including cases without a defined double-bond feature and certain bicyclic or double-bond-free ring cases, as stated in the claim exclusions. Preferred embodiments are stated using structural constraints such as the optional C10=C11 double bond and preferred substituent patterns, together with isomer and ring-structure exclusions.
The invention positions the valerenic acid derivative compounds as GABA_A receptor ligands with the intended therapeutic use for anxiety and insomnia treatment. It further describes ester prodrugs and double ester prodrugs to improve oral delivery and blood-brain barrier penetration, together with pharmaceutical use and medicament manufacture.
Claims Coverage
The independent claims cover one primary inventive structural space for a valerenic acid derivative compound of formula (IA2), defined by an optional C10-C11 double bond, specified substituent classes for R1 and for multiple substituents R2-R4, R7-R9, and R10-R12, plus inclusion of pharmaceutically acceptable derivatives and explicit exclusions of specific compounds and Z- or E-isomers. In total, the claim coverage centers on these 2 independent claim themes, with dependent claims refining double-bond presence, bundled substituent selections, and enumerated E-configured and stereodefined members.
Compounds of formula (IA2) with optional C10-C11 double bond
A compound of formula (IA2) wherein the dotted line between C10 and C11 represents an optional double bond, with R1 selected from the listed substituent classes and R10, R11, and R12 independently selected from the listed substituent classes; R2, R3, R4, R7, R8, and R9 independently selected from the listed substituent classes; and wherein the compound is a pharmaceutically salt, solvate, or prodrug thereof, excluding the following compounds and Z- or E-isomers thereof.
Pharmaceutical composition containing the formula (IA2) compound
A pharmaceutical composition containing a pharmaceutically effective amount of the compound of claim 1, optionally formulated as an ester prodrug.
Specific substituent and stereochemical refinements
Dependent claims further specify whether the C10-C11 bond is a double bond, impose bundled selections for certain R groups, and enumerate specific (E)-stereodefined compound members within the claimed formula space.
The claims cover a broad IA2 valerenic acid derivative compound space with an optional or specified C10-C11 double bond and extensive independently selectable substituent groups, including salts, solvates, and prodrugs. The claim set also includes narrower embodiments that specify the double bond and combine particular R-group constraints, as well as a pharmaceutical composition embodiment.
Stated Advantages
Improved bitter taste.
Improved absorption.
Improved solubility.
Improved oral delivery.
Improved blood-brain barrier penetration.
GABA_A receptor ligand intended for treating anxiety and insomnia.
Documented Applications
Treatment or use in relation to anxiety.
Treatment or use in relation to insomnia.
Modulation of GABA_A receptor pharmacological response.
Use as GABA_A receptor ligands for treating anxiety and insomnia.
Pharmaceutical use including medicament manufacture, including ester prodrug and double ester prodrug forms to improve oral delivery and blood-brain barrier penetration.
Concentration-response evaluation of VA-IPA/VA-A using oocytes for GABA-A receptor α1β2γ concentration-response.
Behavioral evaluation in an elevated plus maze test of mice dosed with VA or VA-derivatives, including open arm time.
Seizure threshold modulation via PTZ.
Use of VA and derivatives to modulate GABA-A pharmacodynamics.
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