(+)-morphinanium N-oxides and processes for their production
Inventors
Cantrell, Gary L. • Wang, Peter X. • Trawick, Bobby N. • Grote, Christopher W. • Berberich, David W. • Sun, Hang • Liao, Subo
Assignees
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Publication Number
US-8563727-B2
Publication Date
2013-10-22
Expiration Date
Abstract
The present invention provides (+)-morphinanium N-oxide compounds or pharmaceutically acceptable salts thereof. The invention also provides processes for producing (+)-morphinanium N-oxides or pharmaceutically acceptable salts thereof from the corresponding tertiary N-substituted (+)-morphinan compound or pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to (+)-morphinanium N-oxide compounds and pharmaceutically acceptable salts. The disclosed compounds are defined by broad structural Formula (IV) and related alternative formulae, together with variable substituents including A, A1, R1, R3-R8, Y, Z, and Z′, and dashed-line bond patterns that constrain carbon-to-carbon bonds at positions 6, 7, 8, and 14.
The core structural idea is oxidative N-oxidation of tertiary (+)-morphinans, where quaternization at N-17 is involved in forming the quaternary N-oxide products. The process converts a (+)-morphinan comprising a tertiary amine at position 17 (Formula (III)) to a Formula (IV) compound or a pharmaceutically acceptable salt by contact with an oxidizing agent.
The disclosed compound scope includes representative N-oxide compounds such as N-oxides of (+)-dihydromorphine, (+)-morphine, (+)-dextrorphan, (+)-dextromethorphan, and (+)-dihydrosinomenine. Overall, the invention defines VEGF inhibitor candidate structures as (+)-morphinanium N-oxides with specified Formula (IV) or related alternatives and their salts.
Claims Coverage
The independent claims define compounds of Formula (IV) or pharmaceutically acceptable salts with variable substituents and specific carbon-to-carbon bond patterns, and also cover oxidation-based preparation of Formula (IV) compounds from (+)-morphinan tertiary amine precursors. Across the independent claims, there are two inventive features.
Formula (IV) (+)-morphinanium N-oxide compound scope
A compound of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein A is chosen from —C(O)—, —C(≡CH2)—, —(CH2)—, —(CH(A1))—, and —C(A1)≡; A1 is chosen from hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl; R1 and R7 are independently chosen from hydrocarbyl and substituted hydrocarbyl; R3 and R4 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl; R5 and R6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, —OH, and —OR7; R8 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl; Y, if present, is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14 represent carbon to carbon bonds selected from single bonds or specified single and double bond combinations.
Oxidation of a (+)-morphinan tertiary amine to form Formula (IV)
A process prepares a compound of Formula (IV) by contacting a (+)-morphinan comprising a tertiary amine at position 17 (Formula (III)) with an oxidizing agent to form the Formula (IV) compound or its pharmaceutically acceptable salt.
The claim coverage centers on Formula (IV) compounds and pharmaceutically acceptable salts defined by extensive substitution options and constrained bond patterns at carbon positions 6, 7, 8, and 14, together with oxidation-based claims that convert a (+)-morphinan tertiary amine precursor at position 17 into the Formula (IV) product.
Stated Advantages
VEGF inhibition without opiate receptor interaction.
Documented Applications
Use as VEGF inhibitors that do not interact with opiate receptors.
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