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-8071643-B2
Publication Date
2011-12-06
Expiration Date
Abstract
A pleuromutilin derivative compound of general formula (I)
Core Innovation
The invention relates to pleuromutilin derivatives for treating microbe-mediated diseases. The compounds are defined by formula (I) with limited values of n and m, and with a sulphur atom and R3 required to be in vicinal position with position-dependent constraints. The substituent pattern specifies R as ethyl or vinyl, and defines R1 and R2 in terms of hydrogen, (C1-6)alkyl, (C3-6)cycloalkyl, permissible substitution, or formation of a 5 to 7 membered heterocyclic ring containing at least 1 nitrogen atom or 1 nitrogen and 1 additional heteroatom selected from N or O.
R3 is defined as OH, OR4, or a halogen atom, or as being bound to 2′ where R3 represents —O—(CH2)p—O— with p being 2 or 3. R4 is defined as unsubstituted (C1-6)alkyl or (C3-6)cycloalkyl, and preferred subclasses are indicated by formulae (II) to (VI). The disclosed examples include specific 14-O-substituted pleuromutilin and mutilin derivatives, including 19,20-dihydro-mutilin analogs and defined diastereomeric forms.
The text states an unexpected improvement in metabolic stability when R3, preferably hydroxy, is introduced in vicinal position to the sulphur substituent. The document further provides pharmaceutical and veterinary use statements and includes antimicrobial activity statements together with metabolic stability evaluation using primary human hepatocytes and LC/MS parent compound disappearance.
Claims Coverage
The consolidated claim coverage identifies one independent compound claim defining a broad formula (I) class with strict positional and substituent constraints, plus dependent claims that refine formula variants, salt forms, pharmaceutical composition forms, and selected named derivatives. The inventive features are centered on the vicinal sulphur and R3 requirement and the defined R/R1/R2/R3/R4 substitution patterns.
Vicinal sulphur and R3 positional requirement
A compound of formula (I) where n is 0 to 4 and m is 0 or 1, with the proviso that the sulphur atom and R3 are in vicinal position, and with position-dependent constraints for R3 when m is 0 or 1.
Ethyl or vinyl substituent with constrained R1 and R2
R is ethyl or vinyl; R1 is hydrogen or (C1-6)alkyl; and R2 is hydrogen or (C3-6)cycloalkyl, or unsubstituted (C1-6)alkyl, or (C1-6)alkyl substituted by one or more of hydroxy, methoxy, halogen, or (C3-6)cycloalkyl, or R1 and R2 together with the nitrogen atom form a 5 to 7 membered heterocyclic ring containing at least 1 nitrogen atom or 1 nitrogen and 1 additional heteroatom selected from N or O.
Defined R3 and constrained R4
R3 is OH, OR4, or a halogen atom, or R3 is bound to 2′ and represents —O—(CH2)p—O— with p being 2 or 3; and R4 is unsubstituted (C1-6)alkyl or (C3-6)cycloalkyl.
Formula variants and selected derivative forms
Dependent claims refine the class by formula variants (II) to (VI), salt forms, pharmaceutical compositions with at least one pharmaceutical excipient or an additional pharmaceutically active agent, and selected mutilin and 19,20-dihydro-mutilin derivatives including specific 14-O-substituted pleuromutilin/mutilin derivatives and diastereomers.
The claim set primarily covers a formula (I) compound class defined by strict vicinal positioning of the sulphur atom and R3, defined substitution for R, R1, R2, R3, and R4, and optional heterocycle formation for R1 and R2. Dependent claims then refine this coverage to formula variants, salt forms, pharmaceutical compositions, and selected named mutilin or 19,20-dihydro-mutilin derivatives including diastereomeric selections.
Stated Advantages
Unexpected improvement in metabolic stability when R3, preferably hydroxy, is introduced in vicinal position to the sulphur substituent.
Documented Applications
Treating microbe-mediated diseases, including bacterial infections, Helicobacter-associated diseases, Mycobacterium-associated diseases, and acne.
Antimicrobial activity is stated together with metabolic stability evaluation in the context of the claimed pleuromutilin derivatives.
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