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WO1996016063A1 - Derives de morphine et de codeine utilises en therapie - Google Patents

Derives de morphine et de codeine utilises en therapie Download PDF

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Publication number
WO1996016063A1
WO1996016063A1 PCT/GB1995/002712 GB9502712W WO9616063A1 WO 1996016063 A1 WO1996016063 A1 WO 1996016063A1 GB 9502712 W GB9502712 W GB 9502712W WO 9616063 A1 WO9616063 A1 WO 9616063A1
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WIPO (PCT)
Prior art keywords
moφhine
carbon atoms
alkyl
group
pharmaceutically acceptable
Prior art date
Application number
PCT/GB1995/002712
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English (en)
Inventor
Brian Arthur Marples
John Richard Traynor
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British Technology Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by British Technology Group Limited filed Critical British Technology Group Limited
Priority to CA 2201886 priority Critical patent/CA2201886A1/fr
Priority to EP95937952A priority patent/EP0793664A1/fr
Priority to AU38771/95A priority patent/AU3877195A/en
Priority to JP8516670A priority patent/JPH10509167A/ja
Publication of WO1996016063A1 publication Critical patent/WO1996016063A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • This invention is in the field of novel mo ⁇ hine-6-glucuronate and codeine-6-glucuronate analogues and their use in therapy as opioid analgesic agents.
  • mo ⁇ hine-6-glucuronide M6G
  • M6G mo ⁇ hine-6-glucuronide
  • mo ⁇ hine-6-glucuronide is a more potent antinociceptive agent than mo ⁇ hine, the exact relationship depending on the test model and route of administration, but always being more potent when administered by the intrathecal route.
  • the physicochemical characteristics of mo ⁇ hine-6-glucuronide restricts any potential oral administration and hence reduces its clinical usefulness. It is thus desirable to identify other derivatives of mo ⁇ hine which preserve the pharmokinetic advantages of mo ⁇ hine-6- glucuronide but with improved oral bioavailability for their properties as analgesic agents. Summary of the invention
  • the inventors have identified and synthesised 6-substituted derivatives of mo ⁇ hine and codeine, another opioid analgesic compound.
  • R ⁇ H (mo ⁇ hine analogue), CH3 (codeine analogue)
  • R > H, alkyl group of 1 to 4 carbon atoms, allyl, cyclopropylmethyl
  • R3 a group -O-C-R4 -O-CH2-R4 (ether)
  • X ⁇ , X2, X3, X4 and X5 which may be the same or different are separately selected from H, an alkyl group of 1 to 4 carbon atoms, NH2, NO2, alkoxy group of 1 to 4 carbon atoms, hydroxy, halogen, N-alkyl group of 1 to 4 carbon atoms, mo ⁇ holine, a group COR5 wherein R5 is H, OH, O-alkyl where alkyl is from 1 to 4 carbon atoms, or one of Xj and X , X2 and X3, X3 and X4 or X4 and X5 together with an alkylene group optionally interrupted by O, S or N of up to 5 atoms in length complete a ring and a pharmaceutically acceptable salt thereof for use in therapy.
  • Mo ⁇ hine and other traditional opiate analgesics act through opioid ⁇ receptors to induce analgesia together with the well known side effects of addiction, respiratory depression etc., whilst opioid K receptors may mediate psychomimetic and other effects. It is known that the opioid receptor profile of mo ⁇ hine and mo ⁇ hine-6-glucuronide differ. The compounds of the present invention exaggerate this difference resulting in compounds which have an equivalent ⁇ -affinity, a higher 6 -affinity and a lower K-affinity. Hence the compounds of the invention are more beneficial than M6G, by being as well as more bio- available, having reduced ⁇ -mediated side effects.
  • R j H
  • R3 is preferably a grouping
  • R4 is preferably a group
  • Xi , X 2 , X3, X4 and X 5 are H, NH 2 , NO 2 , OH, halogen or COR5 where R 5 is OH.
  • R 5 is OH.
  • X , X2, X3, X4 and X5 are H.
  • the substituents may be in the ortho, meta or para positions but where there is only one substituent preferably this is in the ortho position, more preferably in the para position and where there is more than one substituent, one is in the para position.
  • an alkylene ring formed by two of X ⁇ , X2, X3, X4 and X5 preferably this is between X2 and X3 or X3 and X4. It may be, for example a group -O-CH 2 -O.
  • the preferred compounds are mo ⁇ hine or codeine-6-nitrobenzoate, mo ⁇ hine or codeine-6-hydroxybenzoate and mo ⁇ hine or codeine-6-phthalate.
  • the mo ⁇ hine-6-glucuronide analogues and codeine-6-glucuronide analogues are believed to function as analgesic agents.
  • the invention further provides a pharmaceutical composition which comprises a compound of Formula I together with a pharmaceutically-acceptable diluent or carrier, preferably one which is sterile and pyrogen free.
  • the compounds may be formulated as salts formed with physiologically acceptable inorganic or organic acids and when so formulated it is preferred to use methane sulphonic acid, isethionic acid, tartaric acid or another solubilising acid.
  • the compounds of Formula I may be formulated singly or as a mixture of two or more compounds for use as pharmaceuticals by a variety of methods.
  • the composition may be in a form suitable for oral administration as a tablet or capsule or liquid medicine, a suppository or in a form suitable for parenteral administration by for example injection or infusion, as a sterile solution or infusion.
  • the compounds may be formulated for controlled delayed release, e.g. in tablets and suppositories.
  • compositions containing compounds of Formula I may be formulated in unit dosage form, i.e. in the form of discrete portions, each containing a unit dose or a multiple or sub-multiple of a unit dose.
  • the compound of Formula I will normally be administered to a warm-blooded animal at a dose within the range for example in man of 1-100 mg orally more preferably 5-50 mg orally or by intramuscular or subcutaneous injection up to 6 times daily.
  • the dosage used will be equivalent to or slightly less than dosages of mo ⁇ hine or codeine which are well characterised and known to a person skilled in the art. It will be appreciated however that the specific dosage for a patient will depend on how much pain that patient is experiencing and actual dosages in this case will be determined by the attending medical staff.
  • R j H (mo ⁇ hine analogue), CH3 (codeine analogue)
  • R2 H, alkyl group of 1 to 4 carbon atoms, allyl, cyclopropylmethyl
  • X ⁇ , X2, X3, X4 and X5 which may be the same or different are separately selected from H, an alkyl group of 1 to 4 carbon atoms, NH2, NO2, alkoxy group of 1 to 4 carbon atoms, hydroxy, halogen, N-alkyl group of 1 to 4 carbon atoms, mo ⁇ holine, a group COR5 wherein R5 is H, OH, O-alkyl where alkyl is from 1 to 4 carbon atoms, or one of X ⁇ and X2, X2 and X3, X3 and X4 or X4 and X5 together with an alkylene group optionally interrupted by O, S or N of up to 5 atoms in length complete a ring with the proviso that not all Xi, X2, X3, X4 and X5 are hydrogen and pharmaceutically acceptable salts thereof.
  • novel mo ⁇ hine-6-glucuronide analogues and codeine-6-glucuronide analogues of the invention may be prepared by any process known to be applicable to the preparation of chemically related compounds. Accordingly, such processes form a further feature of the invention.
  • codeine-6-benzoate derivatives for example may be synthesised from codeine by reaction with the appropriate acid anhydride or acid chloride in the presence of dimethylammino pyridine (DMAP). Protection of the 3-hydroxy functions of mo ⁇ hine as the 3-t-butyldimethylsilyl (3-t-BDMS) ether allows synthesis of the corresponding mo ⁇ hine analogues after deprotection of the 3-t-BDMS-6-esters with tetrabutylammonium fluoride (TBAF).
  • DMAP dimethylammino pyridine
  • mo ⁇ hine and codeine-6-ethers may be prepared by the reaction of codeine or similarly protected mo ⁇ hine with the appropriate alkyl chloride in the presence of sodium hydride in THF.
  • a method of alleviating pain in an individual in need of such treatment which comprises administering to said individual a therapeutically effective amount of a compound of Formula I or II as defined hereinbefore.
  • the invention also provides the use of a compound of Formula I or II as defined hereinbefore in the manufacture of a novel medicament for use in alleviating pain.
  • Tris buffer was prepared as 50mM in distilled water and the pH adjusted to 7.4 with HC1(4N). Tris-NaCl buffer contained 1 OOmM NaCl.
  • NaCl (6.92g/l), KC1 (0.35g/l), KH 2 PO 4 (0.16g/l), CaCl 2 .2H 2 O (0.375g/l for MPLM and 0.188g/l for RVD), NaHCO 3 (2.1g/l), MgSO 4 .7H 2 O (0.29g/l) and glucose (2g/l).
  • the buffer was gassed with 95% O 2 , 5% CO 2 .
  • Krebs solution for the mouse vas deferens (MVD) preparation was as above, but with the omission of MgSO4.7H 2 O (Ward et al, 1986, J. Pharmacol. Exp. Ther., ___., 625- 634).
  • Krebs/HEPES buffer was made up as Krebs buffer (above) with HEPES at a concentration of 25mM adjusted to pH 7.4 with 0.88M ammonia solution. __
  • tubes were set up containing 20 ⁇ l of tritiated ligand and 960 ⁇ l of brain homogenate in a total volume of 1ml. 20 ⁇ l of naloxone (lO ⁇ M) was added to each tube to determine the non-specific binding.
  • tubes contained labelled ligand (usually l.OnM final concentration) plus increasing concentrations of competing cold ligand, or 20 ⁇ l of water or 20 ⁇ l of naloxone (lO ⁇ M), which represented the total bound ligand and non-specifically bound ligand values respectively.
  • Assay tubes were incubated at 25 °C for 40 mins, unless stated otherwise.
  • the tube contents were filtered through glass filter papers (Whatman GFB) which were presoaked in either Tris buffer pH 7.4 or Tris-buffer pH 7.4 containing polyethyleneimine (0.1%) to reduce non-specific binding to filters.
  • the tubes were washed three times with 3ml of ice cold Tris buffer and the washings were also filtered.
  • the filters were placed in scintillation vials, ecoscint scintillant fluid added, and the filters soaked for 8 hours. The radioactivity remaining on the filters was counted in a Minaxi Tricarb 4000 Series Liquid Scintillation Counter at an efficiency of 58%.
  • Binding parameters Kp and B ⁇ were obtained using the LIGAND programme, following Scatchard analysis using the EBDA programme (McPherson, 1985, J. Pharmacol. Meth., 14, 213-228). IC50 values for competing ligands were determined using a logistic curve fitting programme developed by Barlow (1991, Ash Lea Cottage, Ravenstonedale, Kirkby Stephen, Cumbria. Foundations of pharmacology-computer curve fitting programme, publisher, Barton 1991). Isolated tissue studies Tissue preparation a) Guinea-pi? mventeric plexus-longitudinal muscle (MPLM ⁇ bioassav
  • mice Male CSI mice (930-50g), were killed by cervical dislocation. The vasa deferentia were removed immediately, and mounted under a tension of 0.5g in 1.8ml organ baths, previously coated with silicon to reduce adso ⁇ tion losses of peptides. Tissues were bathed in Krebs without MgSO4 at 37°C, aerated with 5% CO2 in 95% O . After allowing a recovery period of 1 h, each vas deferens was stimulated through platinum ring electrodes using a train of 3 square wave pulses of 1ms duration and 250ms delay at supramaximal voltage at a frequency of 0.1 Hz. Experimental
  • Antagonist affinities were added to the organ baths in a cumulative way such that when the response to any one dose reached a maximum the next dose was administered, until approximately 80% inhibition of twitch height was attained after about four cumulative doses.
  • the tissues were washed by overflow with Krebs solution until the original twitch height was restored.
  • the potency of agonists was assessed by measurement of IC5Q'S, the concentration of agonist causing 50% inhibition of the electrically evoked twitch.
  • Antagonist affinities were assessed by measurement of IC5Q'S, the concentration of agonist causing 50% inhibition of the electrically evoked twitch.
  • Antagonists were preincubated with the appropriate tissue for 15 mins, prior to the addition of an agonist. Dose-response curves for agonists were obtained before the addition of an antagonist and then repeated in the presence of varying concentrations of the antagonist (normally 10, 30, 100nM)> Dose-ratios were calculated at 50% inhibition and Schild plots constructed. Antagonists were removed from the tissue by continuous washing until the response to the added agonist was fully recovered. In some experiments antagonist Ke values were calculated using a single-dose method.
  • the antagonist equilibrium dissociation constant (Ke) is a measure of affinity and was determined for a partial agonist in the rat vas deferens by pre-incubating the test compound for 15 mins and observing the effect on the dose-response curve for the full ⁇ agonist DAMGO.
  • Antagonist equilibrium dissociation constants (Ke) were obtained by analysing the results according to Kosterlitz and Watt (1968, Br. J. Pharmacol. Chemother., 21, 266-276). Results
  • the pu ⁇ ose of this experiment was to test analogues of mo ⁇ hine-6-glucuronide for their selectivity for different opioid binding sites.
  • Ligands which have relative selectivity for different opioid binding sites are well known.
  • Table 1 Affinities of opiates and specific ligands at mu, delta and kappa binding sites in mouse brain homogenates.
  • mo ⁇ hine and M6G demonstrate the highest affinity for, and are approximately equipotent at, the ⁇ -site (Table 1).
  • the profile of mo ⁇ hine and M6G affinities differ, however, at the ⁇ - and K- sites, M6G being approximately 3 -fold more potent at -sites and 10-fold less potent at K- sites than mo ⁇ hine.
  • mo ⁇ hine and M6G The actions of mo ⁇ hine and M6G on 2 isolated tissue preparations, namely the guinea-pig myenteric plexus-longitudinal muscle (MPLM) and the mouse vas deferens (MVD) are shown in Table 2.
  • M6G is slightly more potent than mo ⁇ hine (approximately 2-fold) in both preparations.
  • Analogues were tested and selected to at least retain and preferably exaggerate the relative binding profiles of M6G compared to mo ⁇ hine, i.e. equivalent, high affinity at ⁇ - sites. and decreased affinity at ⁇ -sites.
  • 6-substituted codeine derivatives i.e. with a 3-OMe function
  • Mo ⁇ hine-6-phthalate (BTG 2403), mo ⁇ hine-6-(p-nitrobenzoate) (BTG 2404) and mo ⁇ hine-6-(p-hydroxybenzoate) (BTG 2408) therefore, all extend the differences in binding profile seen in M6G compared to mo ⁇ hine; all 5 compounds having ⁇ -affinity in the l-30nM range, with ⁇ -affinities, ranging from mo ⁇ hine of 218nM to BTG 2403 of 14.2nM, and -affmity, ranging from mo ⁇ hine of 84.7nM to BTG 2404 of >10,000nM.
  • Table 3 Affinity of 3,6-substituted morphine derivatives at mu, delta and kappa binding sites in mouse brain homogenates.
  • Table 4 Affinity of 6-substituted morphine derivatives at mu, delta and kappa binding sites in mouse brain homogenates.
  • M6G has a slightly higher affinity in brain homogenate preparations for ⁇ -binding sites compared to mo ⁇ hine (approximately 3-fold increase), on a relevant isolated tissue preparation, the mouse vas deferens (MVD), the potency difference is small (approximately 1.7-fold).
  • M6G like mo ⁇ hine, is still acting yja. ⁇ - and not ⁇ - receptors in this tissue. It was of interest, therefore, to investigate whether representative examples of the
  • 6-substituted analogues with high ⁇ -binding affinity in mouse brain homogenates were exerting their agonist effects on the MVD through ⁇ - or ⁇ -receptors in this isolated tissue.
  • IC50S of these compounds on the MVD were 41nM, 1166nM and 230nM. As shown in
  • Ke's for antagonism by naloxone of BTG 2382, BTG 2404 and BTG 2408 were similar and in the range 14.9 - 20.2 nM.
  • naloxone antagonism of all 5 compounds showed similar Ke's (range 3.0 - 4.1 nM) indicating their action on this tissue is via ⁇ -receptors.
  • Table 6 Antagonism by naloxone of morphine and derivatives on the MPLM and MVD isolated tissue preparations.
  • EXAMPLE 4 GENERAL METHOD FOR ASSESSING THE ANTTN CICEPTTVF
  • ED50 2.2 gl/kg and 1.9 mg/kg respectively, see Table 5 below.
  • mice 25.30 g (University of Nottingham Medical School) were used in these experiments. Animals were housed in groups of twelve in a room with a temperature controlled at 20°C on a 12 hour light-dark cycle and with free access to food and water.
  • Drugs were administered s.c. in saline containing 0.25% carboxylmethylcellulose and tail-flick latencies were measured at 50°C, 60 minutes later. There were six animals in each group *P ⁇ 0.05 (Wilcoxon signed rank test).
  • Table 8 Time course of the antinociceptive activity of morphine-6-j ⁇ -nitrobenzoate (10 mg kg s.c.) and morphine-6-phthalate (10 mg/kg s.c.) in the mouse warm-water tail-flick test
  • Tail-flick latency (s)
  • Drugs were administered s.c. in saline containing 0.25% carboxymethylcellulose and tail-flick latencies determined at 50°C at the stated times. There were 6 mice in each group. *P ⁇ 0.05 (Wilcoxon signed rank test).
  • Tables 7 and 8 show dose-related antinociceptive activities of the mo ⁇ hine-6- phthalate (BTG 2403) and mo ⁇ hine-6-D-nitrobenzoate (BTG 2404) on subcutaneous administration in the mouse tail-flick assay.
  • BTG 2403 was slightly more potent than BTG 2404, IC50S being 2.6 mg/kg and 16.2 mg/kg respectively.
  • Table 9 Time Course Experiment of the antinociceptive activity of morphine, 5mg/kg s.c. and morphine-6-glucuronide (M6G) 5mg/kg s.c. in the mouse warm water flick tail test
  • Drug was administered s.c. (sub-cutaneously) in saline and tail flick latencies (50° water) determined at the stated times. A cut-off time of 10 seconds was used. There were six mice in each group * P ⁇ 0.05 (Wilcoxon signed rank test).
  • Drug was administered in saline, subcutaneously, using 6 mice for each concentration. Tail flick latencies were determined 60 minutes after injection using 50 ⁇ C water. A cut-off time of 10 seconds was used. * Represents P ⁇ 0.05 (Wilcoxon signed rank test)
  • BTG 2403 would appear to exert antinociceptive effects via ⁇ -opioid receptors.
  • Table 11 Effect of naltrindole (1 mg/kg) on the antinociceptive activity of morphine (5 mg/kg) and morphine-6-phthalate (30 mg/kg) in the mouse warm-water tail-flick test
  • Drugs were administered subcutaneously in saline containing 0.25% carboxymethylcellulose and tail-flick latencies were determined at 50°C 90 minutes (mo ⁇ hine) or 120 minutes (mo ⁇ hine-6-phthalate) later. Naltrindole was administered 15 minutes prior to the agonists. *P ⁇ 0.05 (Wilcoxon signed rank test).
  • EXAMPLE 5 ANTINOCICEPTIVE EFFECTS OF MORPHINE AND DERIVATIVES ORAL ANALGESIC STUDY:- PAW LICKING TEST IN MICE
  • the vehicle was 0.25% carboxymethylcellulose in 0.9% saline and solutions were sonicated and shaken prior to administration; this was especially necessary for the high concentrations of the two test compounds (mo ⁇ hine-6-phthalate and mo ⁇ hine-6-p.- nitrobenzoate). All experiments were performed between 1400-1700h and in any one experiment at least one control animal and three of the compounds were studied.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pain & Pain Management (AREA)
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  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne un composé de la formule (I). Dans cette formule, R1 = H (analogue de morphine), CH3 (analogue de codéïne), R2 = H, un groupe alkyle ayant de 1 à 4 atomes de de carbone, allyle, cyclopropylméthyle, R3 = un groupe (A), -O-CH2-R4 (éther) ou -O-COCH=CHR4 (cinnamate) et R4 a la formule (B). Dans la formule (II), X1, X2, X3, X4 et X5 peuvent être identiques ou différents et ils sont sélectionnés séparément parmi H, alkyle ayant 1 à 4 atomes de carbone, NH2, NO2, un groupe alcoxy ayant de 1 à 4 atomes de carbone, hydroxy, halogène, N-alkyle, un groupe ayant de 1 à 4 atomes de carbone, morpholine, ou un groupe COR5 dans lequel R5 représente OH, O-alkyle où alkyle contient 1 à 4 atomes de carbone ou une des paires X1 et X2, X2 et X3, X3 et X4 ou X4 et X5 avec un groupe alkylène éventuellement interrompu par O, S ou N, ayant jusqu'à une longueur de 5 atomes et constituent un cycle. L'invention concerne également l'utilisation en thérapie de ces composés ou d'un sel de ceux-ci acceptable sur le plan pharmaceutique.
PCT/GB1995/002712 1994-11-22 1995-11-20 Derives de morphine et de codeine utilises en therapie WO1996016063A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA 2201886 CA2201886A1 (fr) 1994-11-22 1995-11-20 Derives de morphine et de codeine utilises en therapie
EP95937952A EP0793664A1 (fr) 1994-11-22 1995-11-20 Derives de morphine et de codeine utilises en therapie
AU38771/95A AU3877195A (en) 1994-11-22 1995-11-20 Morphine and codeine derivatives for use in therapy
JP8516670A JPH10509167A (ja) 1994-11-22 1995-11-20 療法に用いるためのモルフィンおよびコデインの誘導体

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GB9423542A GB9423542D0 (en) 1994-11-22 1994-11-22 Pharmaceutical compounds
GB9423542.1 1994-11-22

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WO1996016063A1 true WO1996016063A1 (fr) 1996-05-30

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EP (1) EP0793664A1 (fr)
JP (1) JPH10509167A (fr)
AU (1) AU3877195A (fr)
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WO (1) WO1996016063A1 (fr)
ZA (1) ZA959921B (fr)

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WO1997022606A1 (fr) * 1995-12-20 1997-06-26 Nycomed Imaging As Derives de morphine a activite analgesique
EP1422230A1 (fr) * 2002-11-25 2004-05-26 Chi Mei Foundation Medical Center Dérivés estérifiés de buprenorphine, procédé pour leur préparation, et médicaments analgésiques à action prolongée
KR100704085B1 (ko) * 2002-12-02 2007-04-05 치 메이 파운데이션 메디칼 센터 신규한 부프레노핀 에스테르 유도체, 그의 제조 방법 및지속성 진통제 약학 조성물
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US8182837B2 (en) 2003-09-10 2012-05-22 Qrxpharma Limited Methods and compositions for reducing the risk associated with the administration of opioid analgesics in patients with diagnosed or undiagnosed respiratory illness
US8877753B2 (en) 2008-04-25 2014-11-04 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
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US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789117B2 (en) 2011-05-18 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in diabetes type-2 associated pain
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
US9850252B2 (en) 2014-11-25 2017-12-26 Kempharm, Inc. Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxycodone, prodrugs, methods of making and use thereof
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
US10357464B2 (en) 2006-09-20 2019-07-23 The Board Of Regents Of The University Of Texas System Methods for delivering volatile anesthetics for regional anesthesia and/or pain relief
US10799496B2 (en) 2018-07-13 2020-10-13 Alkermes Pharma Ireland Limited Naphthylenyl compounds for long-acting injectable compositions and related methods
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US10849981B2 (en) 2009-07-02 2020-12-01 KemPham, Inc. Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof
US10975099B2 (en) 2018-11-05 2021-04-13 Alkermes Pharma Ireland Limited Thiophene compounds for long-acting injectable compositions and related methods
WO2023164889A1 (fr) * 2022-03-03 2023-09-07 暨南大学 Procédé de préparation de codéine et d'un dérivé et d'un intermédiaire associés

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GB2295390B (en) 1997-06-18
GB9523722D0 (en) 1996-01-24
EP0793664A1 (fr) 1997-09-10
GB2295390A (en) 1996-05-29

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