3.alpha.-ethynyl, 3.beta.-hydroxy-5.alpha.-pregnan-20-oxime for use in the treatment of CNS disorders
Inventors
Bäckström, Torbjörn • Ragagnin, Gianna
Assignees
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Publication Number
US-10351589-B2
Publication Date
2019-07-16
Expiration Date
Abstract
The invention relates to 3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-oxime, represented by the following structural formula: or a pharmaceutically acceptable salt thereof, which compounds and/or salts are useful as modulators of the mammal brain excitability via the gamma-aminobutyric acid receptor-chloride ionophore (GABAA-R) complex and in the treatment of disorders such as hepatic encephalopathy, Down's syndrome and Alzheimer's disease.
Core Innovation
The invention describes the steroidal compound 3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-oxime, and pharmaceutically acceptable salts, as a central nervous system therapeutic modulator acting via the GABAA receptor complex. The compound is positioned as an antagonist/blocker of steroid (GAMS) enhancement of GABAA receptor signaling, with selective antagonism for the subtype containing the γ and β and α elements (i.e., the ι-containing subtype, ιβ3β2 subtype combination) in contrast to no major effect on chloride flux for the α-containing subtype (α1β2β3β2).
The problem addressed is steroid (GAMS) enhancement of GABAA receptor signaling and its modulation in steroid-related CNS disorders, including cognitive and memory and mood disorders. The patent indicates that the compound provides antagonistic activity in the presence of THDOC/GAMS at the ιβ3β2 subtype receptor complex while showing no antagonistic effect at the α-containing subtype receptor complex, with only minor/vehicle-range activity.
The document describes supported therapeutic indications for the compound in steroid-related CNS disorders, notably hepatic encephalopathy, Down’s syndrome, Alzheimer’s disease, and related cognitive impairment/memory and mood disorders. It also includes composition/administration concepts, including oral and parenteral routes, and mentions pharmaceutically acceptable salt types such as hydrochloride salt and sodium salt.
Claims Coverage
The partial content includes one independent claim directing protection to the specific steroidal compound or its pharmaceutically acceptable salt. The independent claim is supported by dependent claims that add formulation, combination product, kit-of-parts, and preparation or association processes, while the core inventive subject matter remains the compound identity in the independent claim.
Stated steroidal compound and pharmaceutically acceptable salt
3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-oxime or a pharmaceutically acceptable salt thereof.
Pharmaceutical formulation with adjuvant, diluent, or carrier
A pharmaceutical formulation including the compound mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.
Combination product with additional therapeutic agent for steroid-related CNS disorders
A combination pharmaceutical product including the compound together with at least one additional therapeutic agent for treating a steroid-related CNS disorder, where both components are formulated with a pharmaceutically acceptable adjuvant, diluent, or carrier.
Kit-of-parts combination product with separately formulated components
A kit containing two separate pharmaceutical formulations: one containing a compound of formula I with a pharmaceutically acceptable adjuvant, diluent, or carrier, and another containing at least one additional therapeutic agent for treating a steroid-related CNS disorder, with both formulations provided in administration-suitable forms together.
Chemical preparation by reacting with hydroxylamine
A process preparing a compound of formula I by reacting 3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-one with hydroxylamine.
Process for preparing a combination product by associating components and formulation aids
A process preparing a combination product by associating 3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-oxime with another therapeutic agent for treating a steroid-related CNS disorder and with at least one pharmaceutically acceptable adjuvant, diluent, or carrier.
Overall claim coverage centers on the compound 3α-ethynyl, 3β-hydroxy, 5α-pregnan-20-oxime, or pharmaceutically acceptable salts, and extends to pharmaceutical formulations, combination products including kit-of-parts, and processes that prepare the compound or associate the compound with an additional therapeutic agent and formulation components for steroid-related CNS disorders.
Stated Advantages
Selective antagonism for the subtype containing the ι element (ιβ3β2) while having no major effect on α1β2β3β2 subtype chloride flux.
Antagonist activity in the presence of THDOC/GAMS with concentration-dependent antagonism.
Documented Applications
Treatment of hepatic encephalopathy (Type A/B/C, minimal/overt).
Treatment of Down’s syndrome.
Treatment of Alzheimer’s disease.
Treatment of related cognitive impairment, memory and mood disorders.
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