Steroids having increased water solubility and resistance against metabolism and methods for their production
Inventors
Bäckström, Torbjörn • Ragagnin, Gianna
Assignees
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Publication Number
US-9200028-B2
Publication Date
2015-12-01
Expiration Date
Abstract
Steroid compounds having increased resistance against metabolism and increased water solubility are disclosed, together with methods for their production. These substances are suitable for the manufacture of pharmaceuticals for the treatment of steroid related or steroid induced CNS disorders and for use in methods of prevention, alleviation or treatment of such disorders.
Core Innovation
The invention relates to steroid drug candidates that target the GABA-A receptor chloride ionophore for central nervous system disorders. The disclosed steroid compounds are gamma-aminobutyric acid receptor-chloride ionophore targeting agents based on steroid scaffolds, with structural features intended to increase metabolic resistance and improve water solubility.
The steroid core includes a double bond, and the 20-keto group is replaced with an oxime or oxime-related features. Additional 3-position modifications are used to prolong half-life by reducing metabolic oxidation and degradation at the 3-position.
The disclosure describes steroidal ethynyl/hydroxyl and oxime derivatives and specific examples of compounds including 3α-ethynyl, 3β-hydroxyl, androstan-17-one oxime and related structures. The compounds are characterized by properties related to water solubility and hydrophilicity, and are described as pharmaceutically acceptable derivatives, including salts, prodrugs, solvates, ethers, esters, oxime forms, sulfates, acetates, and glycosylations.
Claims Coverage
The provided content includes one independent claim family member and one dependent claim. The independent claim centers on a specifically defined steroid oxime compound with 3α/3β substitution, and the dependent claim adds a pharmaceutically acceptable carrier for formulation.
Specific steroidal compound defined by 3α-ethynyl, 3β-hydroxyl and androstan-17-one oxime
A compound which is 3α-ethynyl, 3β-hydroxyl, androstan-17-one oxime or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition that includes the compound together with a pharmaceutically acceptable carrier.
Protection is directed to a specifically defined steroid oxime compound featuring 3α-ethynyl, 3β-hydroxyl, and androstan-17-one oxime, or a pharmaceutically acceptable salt, with a dependent claim covering a pharmaceutical composition including a pharmaceutically acceptable carrier.
Stated Advantages
Increased metabolic resistance, notably at the 3-position, is described for the steroid scaffolds.
Increased water solubility is described, including as associated with oxime introduction.
Prolonged half-life is described via reduced metabolic oxidation and degradation at the 3-position.
Higher hydrophilicity is indicated by shorter HPLC retention times for inventive compounds compared to the reference.
Documented Applications
Use of the steroid compounds as GABA-A receptor chloride ionophore targeting agents for central nervous system disorders.
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