(+)-morphinanium quaternary salts and processes for their production
Inventors
Cantrell, Gary L. • Wang, Peter X. • Trawick, Bobby N. • Grote, Christopher W. • Berberich, David W.
Assignees
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Publication Number
US-8436174-B2
Publication Date
2013-05-07
Expiration Date
Abstract
The present invention provides (+)-morphinanium quaternary salts. The invention also provides processes for producing (+)-morphinanium quaternary salts from tertiary N-substituted (+)-morphinan compounds.
Core Innovation
The invention relates to quaternary N-substituted salts formed from quaternizing tertiary N-substituted (+)-morphinan compounds using R2X, where X is an anion having a leaving group character. The resulting compounds are represented by Formula (II) and include sub-classes represented by Formula (IV) and sub-variants represented by Formula (IIa/IIb/IIc) and Formula (IVa/IVb/IVc), with specified stereochemical orientation for (+)-morphinan derivatives.
Formula (II) defines selection sets for structural variable groups including A and A1, substituents A1, R1, R2, R3, R4, R5, R6, R7, and R8, and optional substituents Y and Z when present. The anion X is included as part of the quaternary salt definition, and Y and Z are selected from specified lists, including hydroxy, protected hydroxy, alkoxy, and acyloxy for Y and Z.
The dashed lines between carbon atoms at positions 6, 7, 8, and 14 represent carbon-to-carbon bonds restricted to defined combinations of single and double bonds, with an additional condition that relates the presence of Y to a double bond assignment between positions 8 and 14. The disclosure enumerates representative (+)-morphinan alkaloids and derivatives that can be used as salt-forming targets within the quaternary (+)-morphinanium framework, including (+)-dihydromorphine, (+)-morphine and codeine derivatives, (+)-thebaine and (+)-oripavine, and other (+)-morphinan derivatives such as (+)-dextrorphan and (+)-dextromethorphan, and (+)-dihydrosinomenine.
Claims Coverage
The independent claim is directed to a compound defined by Formula (II), with multiple structural parameters and bond-pattern restrictions. The inventive coverage is refined through dependent claims that narrow substituent choices, specify enumerated salt-anion options, and further limit the claimed compounds to quaternary salt forms of particular (+)-opioid-related stereochemically defined starting compounds.
A compound of Formula (II) quaternary (+)-morphinanium salts
A compound according to Formula (II) in which variable groups A and A1 are selected from the specified carbon/heteroatom patterns, substituents R1, R2, and R7 are independently selected from hydrocarbyl and substituted hydrocarbyl, R3 and R4 are independently selected from hydrogen, hydrocarbyl and substituted hydrocarbyl, R5 and R6 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, —OH, and —OR7, R8 is selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl, X is an anion, optional Y and Z are selected from specified hydroxy/protected hydroxy/alkoxy/acyloxy lists, and the dashed carbon connectivity between positions 6, 7, 8, and 14 is restricted to the specified single/double bond patterns with the condition relating Y presence to a double bond between the carbons at positions 8 and 14.
Constrained substituent selection with enumerated anion/salt options for X
A compound according to the claims in which R1 is selected from alkyl, cycloalkyl, cycloalkylmethyl, allyl, and aryl, R2 is selected from alkyl, allyl, alkenyl, and alkaryl, and X is selected from the listed anion/salt groups including halides and sulfonates and other enumerated counterions.
Quaternary salt of selected (+)-opioid-related compounds bearing (+) stereochemistry
A compound defined as a quaternary salt of one of the listed morphine/opioid-related (+)-stereochemistry compounds, including (+)-dihydromorphine, (+)-dihydrocodeine, (+)-hydrocodone, (+)-hydromorphone, (+)-oxycodone, (+)-oxycodeinone, (+)-oxymorphone, (+)-oxymorphinone, (+)-naloxone, (+)-naltrexone, (+)-nalbuphine, (+)-nalfurafine, (+)-nalmefene, (+)-buprenorphine, and (+)-etorphine.
Quaternary salt defined by Formula (IIc) with restricted Z and other variable sets
A compound defined by Formula (IIc), in which substituents A1, R1, R2, R8, X (anion), and Z are selected from the specified lists, where Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy and other variables are selected from their corresponding hydrocarbyl and substituted hydrocarbyl or hydrogen lists.
Quaternary salt form of (+)-thebaine or (+)-oripavine
A compound specified as a quaternary salt form of a compound selected from (+)-thebaine and (+)-oripavine.
Across the claim set, the inventive coverage centers on quaternary (+)-morphinanium compounds defined by Formula (II) with explicit sets for structural substituents and anion X, further narrowed by dependent claims that specify additional substituent sets and enumerated anions, and that restrict the claimed compounds to quaternary salt forms of particular (+)-opioid-related stereochemistry compounds, including specific endpoints such as (+)-thebaine and (+)-oripavine.
Stated Advantages
Avoiding peripheral opiate receptor interaction while leveraging reported VEGF inhibitory activity.
Documented Applications
Use of the claimed quaternary (+)-morphinanium salts in the context of achieving VEGF inhibitory activity, with an emphasis on avoiding peripheral opiate receptor interaction.
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