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Phenotypic differences in analgesic sensitivity to codeine (3-methoxymorphine) results from polymorphisms in cytochrome P450-2D6, which catalyzes O-demethylation of codeine to morphine. However, O-demethylation reportedly is not required for analgesic activity of the 7,8-saturated codeine congeners dihydrocodeine, hydrocodone, and oxycodone. This study determined the potency and efficacy of these compounds and their demethylated derivatives to stimulate μ- and δ-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating μ-receptors, but only dihydrocodeine was more efficacious at δ-receptors. Hydrocodone and oxycodone were ～10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were ～30- to 100-fold more potent than their 3-methoxy analogs at the μ-receptor, and these compounds generally exhibited greater efficacy (e.g., morphine produced 2-fold greater maximal stimulation than codeine). Removal of the N-methyl group did not affect efficacy or potency of codeine congeners to activate μ-receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the δ receptor, morphine congeners showed greater potency and structure-dependent differences in efficacy compared with codeine congeners, whereas removal of the N-methyl group had effects similar to those observed at the μ-receptor. These results demonstrate that 7,8-saturated codeine congeners are more efficacious than codeine, which may explain their lack of requirement for 3-O-demethylation in vivo. Nonetheless, because all 7,8-saturated codeine congeners were significantly less potent than their morphine derivatives, further research is needed to understand the relationship between metabolism and in vivo activity of these compounds.

N-Cubylmethylnormorphine (1) and N-cubylmethylnoroxymorphone (2) have been synthesized and found to be more potent ligands at the μ and κ opioid receptors than morphine and oxymorphone respectively. In the guinea-pig ileum preparation, compounds 1 and 2 were characterized as opioid μ antagonists (Ke=68 and 16 nM, respectively). Compound 2 also showed effective κ-antagonism (Ke=22 nM). The narcotic antagonism activity of 1 has been confirmed by in vivo assays.

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 min after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1–2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

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Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to in

The cyclopropylmethyl group in classical δopioid receptor (DOR) antagonist NTI, BNTX, and NTB was replaced with various electron-withdrawing groups to develop DOR inverse agonists. N-Benzyl NTB derivative SYK-657 was a potent DOR full inverse agonist and its potency was over 10-fold potent than that of a reference compound ICI-174,864. Intraperitoneal administration of SYK-657 induced the short-term memory improving effect in mice without abnormal behaviors.

The invention provides haptens and methods of preparation thereof, for producing immunoconjugates of oxycodone and hydrocodone suitable for raising antibodies in animals specific for the opioid drugs. Adminislration of the opioid-speeific antibodies to humans having the opioid drugs in a body fluid such as blood serum, binds the opioid drugs to the antibody, making the opioids unavailable for producing a drug effect. Accordingly the antibodies can be used to reverse the effects of a drug overdose of oxycodone and hydrocodone, or to reverse a perceived mental effect of the. drugs, such as euphoria.

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Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.

The invention belongs to the technical field of medicament synthesis, and relates to a synthetic method of naloxone hydrochloride. The method comprises the following steps: by adopting thebaine as a starting material, oxidizing and then reducing thebaine to obtain a compound 2, reacting the compound 2 with acetic anhydride to obtain an ester compound 3, then removing methyl and performing hydrolysis to obtain a compound 4, reacting the compound 4 with an alkylating reagent (such as the reagent selected from chloropropene, bromopropene, iodopropylene or the combination thereof), performing allylation on the Nth bit of a mother nucleus structure to obtain a compound 5, then removing methyl to obtain naloxone free alkali, then forming acid addition salts with hydrochloric acid, and then refining to obtain naloxone hydrochloride which can be used as a medicinal raw material medicament. By adopting the method disclosed by the invention, a high-quality medicinal raw material medicament can be prepared.

The application is directed to compounds of Formula I: and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4a, and R4b are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

The application is directed to compounds of Formula I-A and pharmaceutically acceptable salts and solvates thereof, wherein Cy, R1a-R3a, R4a, and R4b are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I-A to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, 1H NMR and 13C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G* * level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm-1, for the 1H NMR peaks are 0.87 and 0.17 ppm and for those of 13C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone.

Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.

(Figure Presented) A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

Morphine alkaloids and some of its derivatives (morphine, codeine, thebaine, oripavine, hydrocodone, and oxycodone) were subjected to fermentations with six fungal strains. The alkaloids were transformed to a variety of products via biological oxidations, reductions, and oxidative demethylations. The strain Cunninghamella echinulata proved to be the most effective for demethylations of all of the above compounds, except for morphine. The time profile of the conversion of 3-[14CH3]thebaine to 3-[ 14CH3]northebaine by C. echinulata cultures was also determined.

The present invention relates to a process for the preparation of an N-demethyl morphinane or a protected form thereof. In one form the preparation of the N-demethyl morphinane or a protected form thereof involves the N-demethylation of an N-methyl morphinane or protected form thereof. In particular the present process is useful in the preparation N-demethyl morphinane or a protected form thereof by N-demethylation of N-methyl morphinanes or protected forms thereof extracted from plants of the genus Papaver of the family Papaveraceae. An example of a suitable N-methyl morphinane that may be usefully subjected to the process of the present invention is thebaine.

The invention generally provides processes and intermediate compounds useful for the production of normorphinans and derivatives of normorphinans.

A process is provided for the N-demethylation of certain morphinans by reaction with α-chloroethyl chloroformate followed by hydrolysis of the resulting intermediate.

A 14-hydroxy group is introduced into a morphinan structure by singlet oxygen reaction with a novel dienol ester of an N-substituted-3-O-alkylnormorphinone. To carry out the singlet oxygen reaction, the enolate substrate may be contacted with molecular oxygen in the presence of light and a light sensitizing agent or in the presence of a chemical reagent for forming singlet oxygen from molecular oxygen.

Secondary amine hydrochlorides are obtained in high yield by reaction of tertiary amines with α-chloroethyl chloroformate followed by warming the intermediate carbamate in methanol.

17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone compounds corresponding to the formula STR1 The compounds exhibit narcotic antagonistic properties.

Codeine is converted to 7,8-dihydro-14-hydroxynorcodeinone (noroxycodone) in six steps and 52percent overall yield or to noroxymorphone in seven steps and 43percent overall yield.N-Demethylation and oxidation of codeine afford N-(ethoxycarbonyl)norcodeinone, which is converted to its dienol acetate derivative and oxidized with singlet oxygen to give N-(ethoxycarbonyl)-14-hydroxynorcodeinone in the key step.Hydrogenation of the latter affords N-(ethoxycarbonyl)noroxycodone, which upon acid hydrolysis yields noroxycodone.Alternatively, O-demethylation of N-(ethoxycarbonyl)noroxycodone with boron tribromide and subsequent acid hydrolysis gives noroxymorphone.The results of the singlet oxygen oxidation of the pyrrolidine dienamine derived from N-(ethoxycarbonyl)norcodeinone are also described.

There is provided a novel, high yield, method of dealkylating N-alkylated 14-hydroxymorphinans and derivatives thereof including, inter alia, oxymorphone and oycodone. There are thus provided, inter alia, more efficient routes for the formation of naloxone, naltrexone, and nalbuphine. In the principal step of the process, the dealkylation using certain oxycarbonyl halides (or haloformates) is carried out on the N-alkyl-14-acyloxy-morphinan which it is desired to dealkylate.