- The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments
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(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body"and "tail"interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address"can be considered the "body"of the hydromorphone molecule and the "message"delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chlorophenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro- 1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer sideeffects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.
- Adler, Martin W.,Bergman, Jack,Chadderdon, Aaron M.,Crowley, Rachel Saylor,Geller, Ellen B.,Hanna, Ramsey D.,Hassan, Sergio A.,Herdman, Christine A.,Inan, Saadet,Irvin, Thomas C.,Jacobson, Arthur E.,Kaska, Sophia,Katz, Jonathan L.,Kopajtic, Theresa A.,Lee, Yong-Sok,Paronis, Carol A.,Prisinzano, Thomas E.,Rice, Kenner C.,Traynor, John R.,Wang, Meining,Withey, Sarah L.
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supporting information
(2020/07/02)
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- Method for synthesizing hydromorphone
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The invention discloses a method for synthesizing hydromorphone by using a continuous flow microchannel reactor. According to the method, by the temperature and the reaction speed of each module of the continuous flow microchannel reactor are controlled, a quenching is integrated into the continuous flow microchannel reactor, and by control of optimal reaction state of hydromorphone synthesis rawmaterials and a catalyst and the reaction speed, the reaction speed is improved. At the same time, through addition of the quenching module, the reaction can be promptly quenched, the precise controlof the reaction time can be achieved, over oxidation in a key step of Oppenauer Oxidation during hydromorphone synthesis can be reduced, production of by-products can be reduced, and reaction yield and hydromorphone product purity can be improved.
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Paragraph 0041; 0042; 0043; 0047; 0048; 0049; 0050; 0054
(2018/07/07)
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- NEW PROCESS FOR PREPARING HYDROMORPHONE AND DERIVATIVES THEREOF
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There is provided a novel process for the preparation of a compound of formula (I), wherein R1 is as described in the description, by demethylation of a corresponding O-methyl derivative.
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Page/Page column 22; 23; 24; 25; 26; 27; 28; 29; 30
(2017/02/24)
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- SUPPORTED METAL CATALYST FOR THE PRODUCTION OF HYDROCODONE AND HYDROMORPHONE
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The present invention relates to the process for the manufacture of hydrocodone or hydromorphone from their enol derivatives codeine and morphine respectively. Particularly, the invention discloses a metal catalyst that is used in low amount, leads to high yields and can easily be reused.
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Page/Page column 5; 6; 7
(2018/01/15)
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- General, Simple, and Chemoselective Catalysts for the Isomerization of Allylic Alcohols: The Importance of the Halide Ligand
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Remarkably simple IrIIIcatalysts enable the isomerization of primary and sec-allylic alcohols under very mild reaction conditions. X-ray absorption spectroscopy (XAS) and mass spectrometry (MS) studies indicate that the catalysts, with the general formula [Cp*IrIII], require a halide ligand for catalytic activity, but no additives or additional ligands are needed.
- Erbing, Elis,Vázquez-Romero, Ana,Bermejo Gómez, Antonio,Platero-Prats, Ana E.,Carson, Fabian,Zou, Xiaodong,Tolstoy, P?ivi,Martín-Matute, Belén
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supporting information
p. 15659 - 15663
(2016/10/25)
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- METHODS FOR THE PREPARATION OF HYDROMORPHONE
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The present application relates to methods for the preparation of morphine derivatives. In particular, the present application relates to methods for the preparation of hydromorphone from oripavine and oripavine from thebaine.
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- On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships
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Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.
- Musazzi, Umberto M.,Matera, Carlo,Dallanoce, Clelia,Vacondio, Federica,De Amici, Marco,Vistoli, Giulio,Cilurzo, Francesco,Minghetti, Paola
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p. 177 - 185
(2015/05/20)
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- PROCESSES FOR MAKING HYDROCODONE, HYDROMORPHONE AND THEIR DERIVATIVES
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Improved processes for making hydrocodone and hydromorphone as well as their 8,14-dihydrothebaine and 8,14-dihydrooripavine derivatives and salts are disclosed.
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Paragraph 0091; 0092
(2015/09/28)
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- PROCESSES FOR MAKING HYDROCODONE, HYDROMORPHONE AND THEIR DERIVATIVES
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Improved processes for making hydrocodone and hydromorphone as well as their 8,14-dihydrothebaine and 8,14-dihydrooripavine derivatives and salts are disclosed.
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Page/Page column 22
(2015/09/28)
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- PREPARATION OF SATURATED KETONE MORPHINAN COMPOUNDS BY CATALYTIC ISOMERISATION
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There is provided a novel process for the preparation of a compound of formula I, wherein R1, R2 and R3 are as described in the description, by conversion of a corresponding allylic alcohol.
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Page/Page column 46; 48
(2015/02/19)
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- Conversion of thebaine to oripavine and other useful intermediates for the semisynthesis of opiate-derived agents: Synthesis of hydromorphone
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Thebaine was converted to oripavine in three steps by employing two different modes of protection of the diene moiety; as an iron tricarbonyl complex and as a Diels-Alder adduct with thioformyl cyanide. The two C-ring-protected thebaine derivatives were subjected to 3-O-demethylation by four different protocols, providing oripavine derivatives, which yielded oripavine after deprotection. Oripavine was then converted to hydromorphone by a three-step process of ketalization, hydrogenation, and deprotection, without the isolation of intermediates.
- Murphy, Brennan,Snajdr, Ivan,Machara, Ales,Endoma-Arias, Mary Ann A.,Stamatatos, Theocharis C.,Cox, D. Phillip,Hudlicky, Tomas
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supporting information
p. 2679 - 2687
(2014/09/30)
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- METHOD OF PREPARING BUPRENORPHINE
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An improved process for preparing buprenorphine and a method for increasing the yield of buprenorphine or a derivative thereof.
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Paragraph 0143; 0154
(2014/09/03)
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- Transition metal-catalyzed redox isomerization of codeine and morphine in water
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A water-soluble rhodium complex formed from commercially available [Rh(COD)(CH3CN)2]BF4 and 1,3,5-triaza-7- phosphaadamantane (PTA) catalyzes the isomerization of both codeine and morphine into hydrocodone and hydromorphone with very high efficiency. The reaction is performed in water, allowing isolation of the final products by simple filtration, which results in very high isolated yields. The reactions can be easily scaled up to 100 g.
- Gomez, Antonio Bermejo,Holmberg, Paer,Baeckvall, Jan-E.,Martin-Matute, Belen
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p. 39519 - 39522
(2014/11/08)
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- Towards an efficient preparation of hydromorphone
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Dihydromorphone was prepared from morphine in high yield, excellent purity, and low residual metal content. The key steps used palladium on porous glass and a modified Oppenauer oxidation, or Wilkinson's catalyst. Georg Thieme Verlag Stuttgart ? New York.
- Csuk, Rene,Vasileva, Galina,Barthel, Alexander
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p. 2840 - 2842
(2012/10/29)
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- COMPOSITIONS COMPRISING ENZYME-CLEAVABLE OPIOID PRODRUGS AND INHIBITORS THEREOF
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Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an opioid prodrug that provides enzymatically-controlled release of an opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the opioid from the opioid prodrug so as to attenuate enzymatic cleavage of the opioid prodrug.
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- Methods for Producing Hydrocodone, Hydromorphone or a Derivative Thereof
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The present disclosure generally relates to methods for producing opioid derivatives. More particularly, the present disclosure relates to the preparation of hydromorphone, hydrocodone, or a derivative thereof, by means of a non-catalytic hydrogenation reaction of thebaine, oripavine or a derivative thereof, respectively, using a hydrazide reagent, followed by hydrolysis of the hydrogenated intermediate at a low temperature and for a short period of time. Additionally, the present disclosure relates to a composition comprising the desired hydromorphone, hydrocodone, or a derivative thereof, in combination with a 6-beta compound that is structurally related thereto.
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Page/Page column 13
(2011/04/18)
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- Preparation of Saturated Ketone Morphinan Compounds Having Low Metal Content
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The present invention provides processes for the preparation of saturated ketone morphinan compounds from a morphinan comprising an allyl alcohol ring moiety, wherein the final product has a low metal content. In particular, the invention provides processes that utilize isomerization reactions catalyzed by transition metal catalysts and the subsequent removal of the transition metal using metal scavengers.
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Page/Page column 8
(2011/11/12)
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- Heterogeneous Ruthenium Metal Catalyst for the Production of Hydrocodone, Hydromorphone or a Derivative Thereof
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The present disclosure generally relates to catalytic methods for producing opioid derivatives. More particularly, the present disclosure relates to the preparation of hydrocodone, hydromorphone, or a derivative thereof, by means of a conversion or an isomerization of codeine, morphine, or a derivative thereof, respectively, using a heterogeneous ruthenium metal catalyst.
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Page/Page column 8
(2011/04/18)
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- Preparation of Saturated Ketone Morphinan Compounds by Catalytic Isomerization
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The present invention provides processes for the preparation of saturated ketone morphinan compounds by catalytic isomerization. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an allyl-transition metal catalyst.
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Page/Page column 8
(2010/11/03)
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- Method for catalytic preparation of hydromorphone and hydrocodone
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The present invention generally relates to catalysts of formula (III) [in-line-formulae][M(P(Ra)(Rb)N(Rc)(Rd))2Xn]mYp [/in-line-formulae]that selectively convert morphine/codeine to hydromorphone/hydrocodone, and methods of use thereof.
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Page/Page column 8
(2008/12/06)
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- Preparation of opioid analgesics by a one-pot process
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A one-pot process for preparing opioid analgesics such as hydrocodone, hydromorphone, and analogues thereof by reacting codeine, morphine, and analogues thereof with hydrogen in a solvent system of benzophenone and neutral solvent in the presence of a metal catalyst followed by oxidation in the presence of potassium tert-alkylate.
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Page/Page column 6
(2008/06/13)
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- METHOD FOR THE CATALYTIC PRODUCTION OF HYDROCODONE AND HYDROMORPHONE
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A method for the catalytic conversion of codeine, morphine or analogs thereof into hydrocodone, hydromorphone or analogs thereof utilizing a transition metal complex of a tertiary phosphine halide as catalyst.
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Page/Page column 6
(2008/06/13)
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- Combination of selected opioids with muscarine antagonists for treating urinary incontinence
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Active compound combinations of compounds of group A, particularly opioids, and compounds of group B, particularly anti-muscarine agents and other substances suitable for treatment of an increased urge to urinate or urinary incontinence. Related pharmaceutical formulations and methods of treatment of an increased urge to urinate or urinary incontinence are also provided.
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- Preparation of narcotic analgesics
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A novel process for preparing narcotic analgesics such as hydrocodone and hydromorphone using catalytic amounts of homogeneous organometallic complexes is disclosed.
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- Transformations of morphine, codeine and their analogues by Bacillus sp
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A bacterial strain belonging to the genus Bacillus islolated by enrichment culture technique using morphine as a sole source of carbon transforms morphine and codeine into 14-hydroxymorphinone and 14-hydroxycodeinone as major and 14-hydroxymorphine and 14-hydroxycodeine as minor metabolites, respectively. When the N-methyl group in morphine and codeine are replaced by higher alkyl groups, the organism still retains its ability to carry out 14-hydroxylation as well as oxidation of the C6-hydroxyl group in these N-variants, although the level of metabolites formed are considerably low. The organism readily transforms dihydromorphine and dihydrocodeine into only dihydromorphinone and dihydrocodeinone, respectively, suggesting that the 7,8-double bond is a necessary structural feature to carry out 14-hydroxylation reaction. The cell free extract (20,000 × g supernatant), prepared from morphine grown cells, transforms morphine into 14-hydroxymorphinone in the presence of NAD+, but fails to show activity against testosterone. However, the cell free extract prepared from testosterone grown cells contains significant levels of 17β- hydroxysteroid dehydrogenase but shows no activity against morphine.
- Madyastha,Reddy,Sridhar
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p. 749 - 753
(2007/10/03)
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- An improved synthesis of noroxymorphone
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A brief synthesis of noroxymorphone is described which involves the oxidation of 3-O-(t)butyldimethylsilylmorphine by manganese dioxide. The initial product is the corresponding morphinone which is further oxidised to the 14-hydroxymorphinone. After hydrogenation the 7,8-dihydro-14-hydroxymorphinone is acetylated and N-demethylation of the 14-O-acetylated product is achieved using vinyl chloroformate as the reagent. The overall yield from morphine is 40-45%.
- Ninan,Sainsbury
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p. 6709 - 6716
(2007/10/02)
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