3-oxy-hydromorphone derivatives
Inventors
Cantrell, Gary L. • Halvachs, Robert E. • Moser, Frank W. • Berberich, David W. • Wang, Peter X.
Assignees
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Publication Number
US-8623888-B2
Publication Date
2014-01-07
Expiration Date
Abstract
The present invention provides 3-oxy-hydromorphone derivatives, and in particular, 3-ester, 3-carbonate, and 3-sulfonate derivatives of hydromorphone.
Core Innovation
The invention relates to 3-oxy-hydromorphone prodrugs that are 3-carbon substituted derivatives intended to convert to hydromorphone in vivo. The prodrugs are defined by a morphinan core and are expressed as 3-ester, 3-carbonate, and 3-sulfonate derivatives. Each derivative includes a variable hydrophobic substituent R described using hydrocarbyl and substituted hydrocarbyl groups, such that the derivatives are designed to increase hydrophobicity.
The disclosure also describes morphinan-6-one derivatives based on a 4,5α-epoxy-17-methylmorphinan-6-one scaffold with defined stereochemistry. The examples include specific substituent patterns at the 3-position, and the described substituents include thienylacetyl oxy, tetrahydrofuranyloxy, isobutoxycarboxy, nicotinylcarboxy, benzenesulfonyloxy, α-methylthioacetyl, camphanyl, cyclopentylcarboxy, and furanylcarboxy.
The prodrugs are further described with pharmaceutically acceptable salts and pharmaceutical compositions, including transdermal systems and transmucosal delivery contexts. Different stereochemical arrangements are considered within the prodrug designs, and the compounds are characterized by exact mass, mass spectrometry values, elemental analysis, physical form, and chemical formulas tied to the particular 3-position substituent.
Claims Coverage
The consolidated claim coverage includes three independent claims for compounds of Formula (I), Formula (II), and Formula (III), corresponding to 3-ester, 3-carbonate, and 3-sulfonate prodrug compounds. The independent claims define enumerated substituent choices for R with specified optical activity, plus substituent options for R1/R2 and R3-R7, and the dependent refinements add stereochemical constraints at labeled carbon positions.
3-ester prodrug compound defined by Formula (I)
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is selected from specified substituent groups with defined optical activity (- or + depending on the R set), R1 and R2 are independently selected from hydrogen, halogen, —OH, —OR7, hydrocarbyl, and substituted hydrocarbyl, and R3, R4, R5, R6, and R7 are independently selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
3-carbonate prodrug compound defined by Formula (II)
A compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R is selected from specified substituent groups with defined optical activity (- or + depending on the R set), R1 and R2 are independently selected from hydrogen, halogen, —OH, —OR7, hydrocarbyl, and substituted hydrocarbyl, and R3, R4, R5, R6, and R7 are independently selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
3-sulfonate prodrug compound defined by Formula (III)
A compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R is selected from specified substituent groups with defined optical activity (- or + depending on the R set), R1 and R2 are independently selected from hydrogen, halogen, —OH, —OR7, hydrocarbyl, and substituted hydrocarbyl, and R3, R4, R5, R6, and R7 are independently selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
The claims cover three families of 3-oxy-hydromorphone prodrug compounds corresponding to Formula (I), Formula (II), and Formula (III), with R selected from enumerated hydrophobic groups tied to specified optical activity signs and with R1/R2 plus R3-R7 defined by independent substituent-selection sets. Dependent claims further narrow by fixing multiple substituents to hydrogen and by specifying stereochemical configuration constraints at labeled carbon positions, including C-15 and C-16 on the same alpha or beta face.
Stated Advantages
Designed to convert to hydromorphone in vivo.
Designed to increase hydrophobicity.
Documented Applications
Topical transdermal delivery context.
Transmucosal delivery context.
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