Pleuromutilin derivatives for the treatment of diseases mediated by microbes
Inventors
Mang, Rosemarie • Heilmayer, Werner • Badegruber, Rudolf • Strickmann, Dirk B. • Novak, Rodger • Ferencic, Mathias • Bulusu, Atchyuta Rama Chandra Murty
Assignees
Hong Kong King Friend Industrial Co Ltd • Kreos Capital IV UK Ltd
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Publication Number
US-8153689-B2
Publication Date
2012-04-10
Expiration Date
Abstract
Disclosed are pleuromutilin derivatives of formula (I) and their use in the treatment of diseases mediated by microbes.
Core Innovation
The invention relates to pleuromutilin derivatives in which a cyclohexylsulfanyl-acetyl side chain is installed at the 14-O position. The disclosed compounds include 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and related 14-O derivatives bearing amino-substituted, hydroxy-functionalized cyclohexylsulfanyl-acetyl side chains.
The document discloses multiple synthetic examples of 14-O pleuromutilin or mutilin derivatives in which the C5 amino substituent on a hydroxy-cyclohexylsulfanyl side chain is varied, including amino, ethylamino, and azido-to-amino functional variants, as well as variants at different stereocenters. The core structural motif is an acetylated 14-O linkage to a pleuromutilin or mutilin framework, incorporating a hydroxy-cyclohexylsulfanyl substituent bearing an amino-containing substituent at the indicated cyclohexyl position.
The invention emphasizes unexpected metabolic stability achieved by placing an R3 substituent, preferably a hydroxy group, vicinal to the sulfur substituent on the cyclohexyl side chain. This effect is supported by a hepatocyte incubation comparison in which the parent compound remaining is substantially higher for the hydroxy vicinal analog than for an analog lacking the hydroxy group.
The pleuromutilin derivatives are further described as having antimicrobial utility against multiple bacterial groups, including Gram+/Gram− bacteria, Mycoplasms, Chlamydia, and anaerobes. The document also provides use for conditions including acne and includes pharmaceutically acceptable salt forms such as hydrochloride.
Claims Coverage
The provided independent claim coverage comprises 1 independent claim. Across the claim set shown, there are 1 core inventive composition definition and 2 refinement directions focused on pharmaceutically acceptable salt selection and optional formulation with pharmaceutically acceptable excipients.
Specific pleuromutilin derivative composition with formula (I) structure
A composition comprising 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, wherein the compound has the structure of formula (I).
Composition in a pharmaceutically acceptable salt form
The composition of the specific pleuromutilin derivative is provided as a pharmaceutically acceptable salt.
Salt selected from a specified list of salt types
The pharmaceutically acceptable salt is selected from a list including inorganic and organic acid salts and ammonium salts, such as sodium, potassium, calcium, magnesium, trimethylammonium, hydrochloric acid salt, hydrogen fumarate, fumaric acid salt, and tartaric acid salt.
Optional inclusion of a pharmaceutically acceptable excipient
The composition further includes at least one pharmaceutically acceptable excipient.
Overall, the claim coverage centers on a defined pleuromutilin derivative composition specified by the compound identity and formula (I) structure, with refinements allowing formulation as a pharmaceutically acceptable salt selected from an explicit list and optional addition of pharmaceutically acceptable excipients.
Stated Advantages
Unexpected metabolic stability from placing an R3 substituent, preferably hydroxy, vicinal to the sulfur substituent on the cyclohexyl side chain.
Documented Applications
Treating microbe-mediated diseases.
Use for acne.
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