Mixed μ agonist/ δ antagonist opioid analgesics with reduced tolerance liabilities and uses thereof
US9422302B2 · kind B2 · utility
Assignee
Inventors
Key dates
| Filing date | Mar 6, 2014 |
| Grant date | Aug 23, 2016 |
| Priority date | — |
| Expiry date | Mar 6, 2034 |
Classification
- Technology area (CPC C)Chemistry; Metallurgy
- CPC primaryC07D489/02
- WIPO fieldOrganic fine chemistry
- WIPO sectorChemistry
Abstract
An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through μ receptors. Although, traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.
Source: USPTO / EPO open patent data. Objective bibliographic and citation counts.