(+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives
Inventors
Grote, Christopher W. • Cantrell, Gary L. • Wang, Peter X. • Trawick, Bobby N. • Berberich, David W.
Assignees
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Publication Number
US-8563724-B2
Publication Date
2013-10-22
Expiration Date
Abstract
The present invention provides (+)-morphinanium compounds comprising substituted 6-hydroxy or 6-amine groups. The invention also provides methods for inhibiting microglial activation by administering the compounds of the invention.
Core Innovation
The invention relates to (+)-6-hydroxy-morphinan and (+)-6-amino-morphinan derivatives defined by morphinan structure formulas, including Formula (II) with additional variants referenced as Formulas (IIa) and (IIb), and related variants referenced as Formulas (I) and (Ia)/(Ib). The compounds are described as mirror-image enantiomers with specified stereochemical orientation, including chiral centers at positions 5, 9, 13, and 14 and beta/alpha placement.
A central aspect of the disclosed compound family is explicit structural parameterization using substituent classes for A, R1, R3/R4/R8/R9, R5/R6, Y, and Z. The dashed line between the carbon atoms at positions 7 and 8 is stated to represent a single bond or a double bond, and additional conditional limitations are provided on the allowed substituent choices, including prohibitions on certain R1 identities depending on the selected group for A.
Representative embodiments identified in the disclosure include (+)-nalbuphine and (+)-nalfurafine. The disclosed framework is tied to a pharmacological objective stated in the partial content: inhibiting microglial activation in the central nervous system using the claimed (+)-morphinan compounds, including pharmaceutically acceptable salts and general salt forms and chiral/isomeric inclusions referenced in the description.
Claims Coverage
The partial content provides one independent claim covering a (+)-morphinan compound defined by Formula (II) or a pharmaceutically acceptable salt with multiple classes of substituents and a selectable single or double bond between positions 7 and 8, together with conditional restrictions on R1 based on the selection of A. Dependent claims further narrow to alternative formula structures (IIa/IIb), add stereochemical constraints, and specify named embodiments (+)-nalbuphine and (+)-nalfurafine.
Formula (II) (+)-morphinan framework with conditional substituent limitations
A (+)-morphinan compound of Formula (II) or a pharmaceutically acceptable salt, where A is chosen from —OR8 and —NR8R9; R1 is chosen from hydrocarbyl and substituted hydrocarbyl; R3, R4, R8, and R9 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl; R5 and R6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, —OH, —NH2, and —OR7; R7 is chosen from hydrocarbyl and substituted hydrocarbyl; Y and Z are chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and the dashed line between positions 7 and 8 represents a single bond or a double bond, with provided conditional restrictions on R1 depending on the selection of A.
Alternative Formula (IIa) substituent pattern
A compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, where the variables A, R1, R8, R9, Y, and Z are defined by the stated substituent choices in Formula (IIa).
Alternative Formula (IIb) substituent pattern with A-dependent condition
A compound of Formula (IIb) or a pharmaceutically acceptable salt thereof, where substituents A, R1, R8, R9, Y, and Z are defined as stated, including a condition when A is —OC(═O)R such that R is H or heterocyclo.
Stereochemical constraint tied to (+) optical activity and specified positional stereochemistry
A compound having (+) optical activity with defined stereochemistry at specified carbon positions or ring substituent stereochemistry at positions 5 and 14 (including stated S/R configurations or beta/alpha placement).
Named embodiments selected from (+)-nalbuphine and (+)-nalfurafine
A compound is selected to be either (+)-nalbuphine or (+)-nalfurafine.
Across the provided independent claim set, coverage is directed to (+)-morphinan compounds defined by Formula (II) with a tunable 7–8 bond state and multiple substituent classes, further constrained by conditional limitations on R1 based on A. Dependent claims refine this coverage using alternative structural formulas (IIa/IIb), add stereochemical constraints associated with (+) optical activity and specified positional stereochemistry, and narrow embodiments to (+)-nalbuphine or (+)-nalfurafine.
Stated Advantages
Inhibiting microglial activation in the central nervous system.
Documented Applications
Use of the (+)-morphinan compounds to inhibit microglial activation in the central nervous system.
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