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The hydroxide-catalyzed non-enzymatic, simultaneous and consecutive hydrolyses of diacetylmorphine (DAM, heroin) are quantified in terms of 10 site- and species-specific rate constants in connection with also 10 site- and species-specific acid-base equilibrium constants, comprising all the 12 coexisting species in solution. This characterization involves the major and minor decomposition pathways via 6-acetylmorphine and 3-acetylmorphine, respectively, and morphine, the final product. Hydrolysis has been found to be 18-120 times faster at site 3 than at site 6, depending on the status of the amino group and the rest of the molecule. Nitrogen protonation accelerates the hydrolysis 5-6 times at site 3 and slightly less at site 6. Hydrolysis rate constants are interpreted in terms of intramolecular inductive effects and the concomitant local electron densities. Hydrolysis fraction, a new physico-chemical parameter is introduced and determined to quantify the contribution of the individual microspecies to the overall hydrolysis. Hydrolysis fractions are depicted as a function of pH.

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Brief treatment of codeine (1) in chloroform with boron tribromide has consistently given morphine (2) in 90-91% yield after a simple isolation procedure. The yield and simplicity of operation in this method are vastly superior to those previously reported for this transformation.

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Morphine-6-glucuronide (M6G) is the primarily active metabolite of morphine, produced endogenously by the UGT enzyme, which displays analgesic activity. For this reason, M6G is a promising drug candidate for the treatment of severe pain. We described herein a new, efficient and scalable synthesis of M6G using dimorphinic derivatives. This preparation of M6G could be performed on multigram scale with good yield and high purity.

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Despite their widespread popularity as sport and companion animals and published and anecdotal reports of vast difference in drug disposition and pharmacokinetics between individuals, studies describing equine drug metabolism are limited. It has been theorized that similar to humans, members of the CYP2D family in horses may be polymorphic in nature leading to differences in metabolism of substrates. This study aims to build on the limited current knowledge regarding P450 mediated metabolism in horses by describing the metabolism of the polymorphic CYP2D6 probe drug codeine in vitro. Codeine, at varying substrate concentrations, was incubated with equine liver microsomes (±UDPGA) and a panel of baculovirus expressed recombinant equine P450s. Parent drug and metabolite concentrations were determined using LC-MS/MS. Incubation of codeine in equine liver microsomes generated norcodeine, morphine, codeine glucuronide and morphine 3- and 6- glucuronide. In recombinant P450 assays, the newly described CYP2D82 was responsible for catalyzing the biotransformation of codeine to morphine (Km of 247.4 μM and a Vmax of 1.6 pmol/min/pmol P450). CYP2D82 is 80% homologous to the highly polymorphic CYP2D6 enzyme, which is responsible for biotransformation of codeine to morphine in humans. CYP3A95, which shares 79% sequence homology with human CYP3A4 and CYP2D50 catalyzed the conversion of codeine to norcodeine (Km of 104.1 and 526.9 μM, Vmax of 2.8 and 2.6 pmol/min/pmol P450). In addition to describing the P450 mediated metabolism of codeine, the current study offers a candidate probe drug that could be used in vivo to study the functional implications of polymorphisms in the CYP2D gene in horses.

The invention discloses a method for synthesizing codeine and morphine. The method comprises the following steps: (I) taking 3-butyne-1-alcohol as a starting raw material to synthesize a compound 6: (shown in the description) (II) compound 6 firstly has intramolecular Michael addition reaction under the catalysis of a spirocyclic amine catalyst, and then acid is added to perform the dehydration cyclization reaction to obtain a chiral compound 7 with a hydrogenated dibenzofuran structure: (shown in the description) (III) the compound 7 has allylation, ozone oxidation, Foucault reaction, epoxidation, Wharton oxygen transfer reaction, debenzylation, Mitsunobu reaction, DMP oxidation, and the conversion by virtue of the reduction of sodium borohydride and Birch reduction to obtain the codeine(shown in the description). Under the action of boron tribromide, the methyl protecting group is removed from the codeine to obtain morphine. Compared with the existing synthesis method, the total synthesis method of the invention is simpler, and the catalytic asymmetric reaction has the advantages of high enantioselectivity, high yield and the like.

As the most popularly abused one of opioids, heroin is actually a prodrug. In the body, heroin is hydrolyzed/activated to 6-monoacetylmorphine (6-MAM) first and then to morphine to produce its toxic and physiological effects. It has been known that heroin hydrolysis to 6-MAM and morphine is accelerated by cholinesterases, including acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE). However, there has been controversy over the specific catalytic activities and functional significance of the cholinesterases, which requires for the more careful kinetic characterization under the same experimental conditions. Here we report the kinetic characterization of AChE, BChE, and a therapeutically promising cocaine hydrolase (CocH1) for heroin and 6-MAM hydrolyses under the same experimental conditions. It has been demonstrated that AChE and BChE have similar kcat values (2100 and 1840 min?1, respectively) against heroin, but with a large difference in KM (2170 and 120 μM, respectively). Both AChE and BChE can catalyze 6-MAM hydrolysis to morphine, with relatively lower catalytic efficiency compared to the heroin hydrolysis. CocH1 can also catalyze hydrolysis of heroin (kcat = 2150 min?1 and KM = 245 μM) and 6-MAM (kcat = 0.223 min?1 and KM = 292 μM), with relatively larger KM values and lower catalytic efficiency compared to BChE. Notably, the KM values of CocH1 against both heroin and 6-MAM are all much larger than previously reported maximum serum heroin and 6-MAM concentrations observed in heroin users, implying that the heroin use along with cocaine will not drastically affect the catalytic activity of CocH1 against cocaine in the CocH1-based enzyme therapy for cocaine abuse.

The present disclosure is directed to crystalline forms of morphine sulfate and pharmaceutical compositions comprising any of the crystalline forms of morphine sulfate. Also provided are processes for the preparation of crystalline forms of morphine sulfate.

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.

The present invention relates generally to the co-administration of an opioid agonist compound and an analgesic compound. In addition, the invention relates to, among other things, dosage forms for co-administration of an opioid agonist compound and an analgesic compound, methods for administering an opioid agonist compound and an analgesic compound, compositions comprising an opioid agonist compound and an analgesic compound, dosage forms comprising an opioid agonist compound and an analgesic compound, and so on.

The assumption that CYP2D1 is the corresponding rat cytochrome to human CYP2D6 has been revisited using recombinant proteins in direct enzyme assays. CYP2D1 and 2D2 were incubated with known CYP2D6 substrates, the three morphine precursors thebaine, codeine and (R)-reticuline. Mass spectrometric analysis showed that rat CYP2D2, not 2D1, catalyzed the 3-O-demethylation reaction of thebaine and codeine. In addition, CYP2D2 incubated with (R)-reticuline generated four products corytuberine, pallidine, salutaridine and isoboldine while rat CYP2D1 was completely inactive. This intramolecular phenol-coupling reaction follows the same mechanism as observed for CYP2D6. Michaelis-Menten kinetic parameters revealed high catalytic efficiencies for rat CYP2D2. These findings suggest a critical evaluation of other commonly accepted, however untested, CYP2D1 substrates.

An investigation into the influence of oxidative conditions on the efficiency of opiate N-demethylation using iron powder has been carried out under non-classical Polonovski conditions. This approach involves a two-step process of N-oxidation and subsequent treatment of the intermediate N-oxide hydrochloride with the redox catalyst. Significant improvements in rate and yield have been realized for these reactions in the presence of molecular oxygen. In this context, further rate enhancement was achieved by the judicious addition of small amounts of ferric ions, leading to a concomitant reduction in the amount of the zero-valent iron primary catalyst that is required. This has led to a generalized improved methodology for the N-demethylation of oripavine, codeine, morphine, and thebaine. This protocol can also be carried out in one-pot without the need to isolate the intermediate N-oxide.

We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNsamide moiety.

The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.

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.

The present invention refers to a combination of a Compound A, a benzyl-4,5-dihydro-1 H-imidazole derivative according to formula (I) and a Compound B, an opioid receptor ligand; especially of xylometazoline or oxymetazoline and a μ-opioid receptor agonist, most preferably of xylometazoline or oxymetazoline and morphine; a medicament comprising this combination; a pharmaceutical formulation for nasal application comprising this combination; or the use of this combination for the treatment of the symptoms of pain, or the prevention or the prophylaxis of the symptoms of pain, whereas pain particularily encompasses visceral pain, chronic pain, cancer pain, acute pain or neuropathic pain, specifically involving also breakthrough pain.

The structural design, preparative methods and chemical composition of two structural formulations of bivalent vaccines against morphine-heroin addiction (morphine-6-hemisuccinyl-EDC-TFCS-tetanus toxoid and 3-0-carboxymethylmorphine-EDC-TFCS-tetanus toxoid), are disclosed. These vaccines are suitable for human use in which they are capable of triggering the synthesis of polyclonal antibodies against morphine opiate and its structural analogue, heroin, through the repeated in vivo administration of these formulations, in active vaccination protocols, in pre-clinical studies in rodents. The active vaccination paradigm through which these immunogens trigger a humoral immune response consolidated with a long-term immunological memory, characterized by the presence of high titers of specific antibodies against these two drugs of abuse, is also disclosed. Furthermore, the present invention reveals the efficacy of these conjugate formulations for triggering a sustained immunoprotection against morphine and heroin addiction using an intravenous self-administration paradigm of these two opiate substances in the rodent. Finally, a discussion is also made on the potential future use of these immunoconjugates in active vaccination protocols for treating both morphine and heroin addiction in the humans.

The present invention is directed to methods and compositions for inducing, promoting or otherwise facilitating pain relief. More particularly the present invention discloses the combination of a nitric oxide donor and an opioid analgesic in the therapeutic management of vertebrate animals including humans, for the prevention or alleviation of pain, particularly moderate to severe pain. In particular, the nitric oxide donor is a slow-release nitric oxide donor or is formulated to provide a sustained release of a low dose of nitric oxide.

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.

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.

The present invention is directed to compositions and methods for inducing, promoting or otherwise facilitating pain relief. More particularly, the present invention relates to the use of a compound which either directly or indirectly prevents, attenuates or reverses the development of reduced opioid sensitivity, together with a compound which activates the opioid receptor that is the subject of the reduced opioid sensitivity, in methods and compositions for the prevention or alleviation of pain, especially in neuropathic conditions and even more especially in peripheral neuropathic conditions such as painful diabetic neuropathy (PDN).

A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.

The preparation of the diastereomerically pure β-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1. Copyright

Controlled-release dosage forms containing an opioid agonist; an opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.

PCT No. PCT/EP97/00711 Sec. 371 Date Oct. 28, 1999 Sec. 102(e) Date Oct. 28, 1999 PCT Filed Feb. 15, 1997 PCT Pub. No. WO97/31918 PCT Pub. Date Sep. 4, 1997The present invention relates to morphine and diamorphine salts of anionic non-narcotic analgesics belonging to the type of substituted carboxylic acids, preferably the morphine and diamorphine salts of diclofenac (Formula 1); to processes for their production, the use of these salts in the treatment of diseases, as well as to pharmaceutical preparations comprising these salts.

L-Selectride was shown to be an efficient and general O-demethylating agent for the opium alkaloids and their derivatives and also an efficient reagent for the cleavage of methyl carbamates, thus offering a convenient method for the N-demethylation of opioids. Further, it was shown that by choice of reaction conditions it is possible to achieve both N- decarbomethoxylation and O-demethylation in one pot, or only render N- decarbomethoxylation in high yield without accompanying O-demethylation.

The O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M) co-segregates with debrisoquine/sparteine genetic polymorphism in man. CD O-demethylation is catalysed by cytochrome P450 2D1 (CW2D1) in rats. In the present study, the O-deethylation of EM was examined and compared with that of CD in suspensions of freshly-isolated hepatocytes prepared by a collagenase method from Wistar rats with and without CYP2D1 inhibitors. Isolated hepatocytes were also prepared from Dark Agouti (DA) rats deficient in CYP2D1, and were incubated with EM or CD. EM, CD and their metabolites were quantified by HPLC with UV detection. EM had a similar pattern of metabolism to that of CD in suspensions of hepatocytes from Wistar rats. Both EM and CD were O-dealkylated to form M plus morphine-3-glucuronide (M3G) and N-demethylated to form norethylmorphine (NEM) or norcodeine (NCD), respectively, which were further metabolized to normorphine (NM) and finally glucuronidated to normorphine-3-glucuronide (NM3G). As compared to hepatocytes from Wistar rats, DA rats were characterized by a markedly decreased formation (70~75% reduction) of M plus M3G from both EM and CD. Quinine, quinidine, propafenone and sparteine all inhibited EM O-deethylation as well as CD O-demethylation. Quinine was the most potent inhibitor of both these O-dealkylations (K(i) = 0.2 μM for both EM and CD, respectively). Quinine as well as the other inhibitors inhibited both EM and CD O-dealkylation competitively and with small differences in K(i) versus EM and CD, respectively. The metabolism of EM to M plus M3G and that of CD to M plus M3G was highly correlated when results from the various separate cell suspensions were plotted. In conclusion all findings indicated that the enzyme responsible for O-demethylation of CD, CYP2D1 was also responsible for the O-deethylation of EM to M.

The effect of temperature on the kinetics of the deacetylation of diamorphine and 6-monoacetylmorphine was studied in human plasma. Diamorphine was rapidly and quantitatively degraded to 6-monoacetylmorphine with initial half-lives of 354, 18 and 3 min at temperatures of 4, 25 and 37°C, respectively. Further deacetylation to morphine was not detected. In aqueous solution, diamorphine was quantitatively degraded to give 6-monoacetylmorphine as the major product and morphine as a minor product, the rate of deacetylation being dependent on temperature and pH. At pH 4.0 and 5.6 diamorphine had a half-life of greater than 14 days at all temperatures but at alkaline pH diamorphine was rapidly deacetylated. The rate of deacetylation of 6-monoacetylmorphine was consistently slower than that of diamorphine under identical conditions of pH and temperature. A method is described for the rapid stabilization and subsequent assay of diamorphine in plasma which will prevent errors in estimation of the drug due to unwanted hydrolysis.

The influence of temperature and concentration on diamorphine stability during storage over 8 weeks has been investigated. Ampoules containing diamorphine hydrochloride in concentrations from 0.98-250 mg mL-1 have been stored at -20, 4, 21 and 37°C for 8 weeks. Their content of diamorphine, 6-monoacetylmorphine and morphine, on measurement by high performance liquid chromatography after 1, 2, 4, 6 and 8 weeks storage changes to slow degradation of diamorphine at all concentrations at temperatures of 4°C and above. This was accompanied by a corresponding increase in 6-monoacetylmorphine and morphine. There was an associated fall in pH and development of a strong odour characteristic of acetic acid. Precipitation and a white turbidity seen in solutions of 15.6 mg mL-1 and above, appeared after 2 weeks incubation.

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