Concise Total Synthesis of (-)-Codeine.

Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate.

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Preparation, Characterization and Pharmacokinetics Evaluation of the Compound Capsules of Ibuprofen Enteric-Coated Sustained-Release Pellets and Codeine Phosphate Immediate-Release Pellets.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13 mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans.

"Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil.

"Tampering to Death": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.

Many homemade tamper processes of medical codeine formulations are available on selected "forums" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called "cold water extraction." Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event.

Total Synthesis of Codeine.

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.

The harmful chemistry behind "krokodil": Street-like synthesis and product analysis.

"Krokodil" is the street name for a drug, which has been attracting media and researchers attention due to its increasing spread and extreme toxicity. "Krokodil" is a homemade injectable mixture being used as a cheap substitute for heroin. Its use begun in Russia and Ukraine, but it is being spread throughout other countries. The starting materials for "krokodil" synthesis are tablets containing codeine, caustic soda, gasoline, hydrochloric acid, iodine from disinfectants and red phosphorus from matchboxes, all of which are easily available in a retail market or drugstores. The resulting product is a light brown liquid that is injected without previous purification. Herein, we aimed to understand the chemistry behind "krokodil" synthesis by mimicking the steps followed by people who use this drug. The successful synthesis was assessed by the presence of desomorphine and other two morphinans. An analytical gas chromatography-electron impact/mass spectrometry (GC-EI/MS) methodology for quantification of desomorphine and codeine was also developed and validated. The methodologies presented herein provide a representative synthesis of "krokodil" street samples and the application of an effective analytical methodology for desomorphine quantification, which was the major morphinan found. Further studies are required in order to find other hypothetical by-products in "krokodil" since these may help to explain signs and symptoms presented by abusers.

Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.

Enantioselective synthesis of (-)-dihydrocodeine and formal synthesis of (-)-thebaine, (-)-codeine, and (-)-morphine from a deprotonated α-aminonitrile.

The α-benzylation of a deprotonated bicyclic α-aminonitrile, followed by Noyori's asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring precursor, are the key steps of a short and high-yielding enantioselective synthesis of the morphinan (-)-dihydrocodeine. This compound can be converted to (-)-thebaine in high yield by known transformations, while (-)-codeine and (-)-morphine are available from an advanced intermediate.

Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat.

We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 µM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC50 20.91 vs 4.32 µM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for µ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on µ opiate receptors.

A novel µ-opioid receptor ligand with high in vitro and in vivo agonist efficacy.

The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the �- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/µ= 269 and δ/µ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).

Synthesis of morphine alkaloids and derivatives.

This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the publication of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one published by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for their preparation.

Recent advances in the synthesis of morphine and related alkaloids.

Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative.

Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (+/-)-codeine proceeds via the previously unknown alpha-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.

Novel cholesterol-based cationic lipids for gene delivery.

Gene therapy based on gene delivery is a promising strategy for the treatment of human disease. Here we present data on structure/biological activity of new biodegradable cholesterol-based cationic lipids with various heterocyclic cationic head groups and linker types. Enhanced accumulation of nucleic acids in the cells mediated by the lipids was demonstrated by fluorescent microscopy and flow cytometry. Light scattering and atomic force microscopy were used to find structure/transfection activity correlations for the lipids. We found that the ability of the lipids to stimulate intracellular accumulation of the oligodeoxyribonucleotides and plasmid DNA correlates well with their ability to form in solution lipid/NA complexes of sizes that do not exceed 100 nm. Screening of the lipids revealed the most promising transfection agents both in terms of low toxicity and efficient delivery: cholesterol-based lipids with positively charged pyridine and methyl imidazole head groups and either the ester or carbamate linker.

Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system.

Total syntheses of the morphine alkaloids are described that use a direct stereoselective formation of the phenanthrofuran system via an intramolecular 4 + 2 cycloaddition of a diene tethered to the 4-position of a 7-methoxybenzofuran-3-carboxylic acid ester.

Stability of codeine phosphate in an extemporaneously compounded syrup.

PURPOSE: The stability of codeine phosphate in an extemporaneously compounded syrup is described. METHODS: Codeine phosphate 3-mg/mL syrup was prepared using commercially available Codeine Phosphate, USP, Sterile Water for Irrigation, USP, and Ora-Sweet syrup vehicle. Samples were stored in amber polyethylene terephthalate bottles with child-resistant caps. A second batch of codeine phosphate 3-mg/mL syrup was prepared and drawn into amber polyethylene oral syringes with silicon elastomer tips. All samples were stored at room temperature and in the dark. Samples were analyzed immediately and at 7, 14, 28, 42, 56, 70, and 98 days. Codeine phosphate concentrations were measured using a modified stability-indicating high-performance liquid chromatographic method. At each test interval, the density of the syrup was determined gravimetrically using a 10-mL amber oral syringe. Excessive degradation was defined as a greater than 7% loss of the initial concentration. RESULTS: The stock internal standard was stable for at least 98 days at room temperature. The compounded syrup retained more than 93% of the initial codeine phosphate concentration for at least 98 days at 22-25 degrees C. No changes in color, clarity, or odor and no visible solids or microbial growth were observed in any sample. The pH of the syrup was initially 4.2 and remained unchanged throughout the study. CONCLUSION: Codeine phosphate 3 mg/mL in Ora-Sweet syrup vehicle was stable in both amber polyethylene terephthalate bottles and amber polyethylene oral syringes for at least 98 days when stored at 22-25 degrees C and protected from light.