WO2008096046A1

WO2008096046A1 - Noroxymorphone for use as a medicament

Info

Publication number: WO2008096046A1
Application number: PCT/FI2008/050051
Authority: WO
Inventors: Kim Lemberg; Vesa Kontinen; Eija Kalso; Antti Siiskonen; Jari Yli-Kauhaluoma
Original assignee: Licentia Oy
Current assignee: Licentia Oy
Priority date: 2007-02-09
Filing date: 2008-02-08
Publication date: 2008-08-14
Anticipated expiration: 2009-08-09
Also published as: FI20075091A0

Abstract

The present invention concerns noroxymorphone and its use in the manufacture of an intrathecally or systemically applicable medicament for the treatment of pain and inflammation. The invention also concerns a composition comprising noroxymorphone. The present invention also relates to a novel method for producing a medicament comprising noroxymorphone. The invention also relates to a method of treating pain in a subject by administering the subject with an analgesically effective amount of noroxymorphone.

Description

NOROXYMORPHONE FOR USE AS A MEDICAMENT

FIELD OF THE INVENTION

The present invention relates to noroxymorphone for use as a medicament and especially to use of noroxymorphone in the manufacture of an intrathecally or systemically applicable medicament for the treatment of pain. The present invention further concerns a composition comprising noroxymorphone. The present invention also relates to a method for producing a medicament comprising noroxymorphone. The invention further concerns a method of treating pain in a subject with an analgesically effective amount of noroxymorphone.

BACKGROUND OF THE INVENTION

Opioids are substances that have a morphine-like action in the body. The main use is for pain relief. Opioids bind to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. There are four broad classes of opioids: endogenous opioid peptides (opioids produced naturally in the body); opium alkaloids, such as morphine (the first alkaloid isolated from opium) and codeine; semi-synthetic opioids, such as heroin and oxycodone; and fully synthetic opioids, such as pethidine and methadone. Opioid receptors are located in the part of a spinal cord which controls pain, so called substantia gelatinosa. This enables an effective spinal alleviation of pain without or minor injurious effects propagated through the brain. Opioid receptor agonists are disclosed for example in US patent 5,352,680.

Oxycodone (14-dihydrohydroxycodeinone) is a semisynthetic opioid and a derivative of thebaine. The pharmacokinetics of oxycodone are still poorly known even though it has been widely used in the management of acute and chronic pain for more than 80 years. The role of its several metabolites in its analgesic activity is still not fully understood. Oxycodone is extensively metabolized in humans mainly by hepatic cytochrome P450 (CYP) isoenzymes, including O-demethylation (mainly catalyzed by CYP2D6) to oxymorphone and N-demethylation (mainly catalyzed by CYP3A4) to noroxycodone, conjugation to α-D-glucuronic acid and conversion to 6-oxycodol (Ishida et al. 1979; Weinstein and Gaylord 1979; Ishida et al. 1982; Cone et al. 1983; Otton et al. 1993; Lalovic et al. 2004). Only 10% of oxycodone is excreted in unchanged form in urine (Poyhia et al. 1991; Kirvela et al. 1996).

Noroxymorphone is found at relatively high circulating concentrations in humans after orally administered oxycodone (Lalovic et al. 2006). Noroxymorphone is a secondary metabolite of oxycodone, and it is formed mainly after O-demethylation of noroxycodone (mainly catalyzed by CYP2D6) and also at a lower rate after N-demethylation of oxymorphone (mainly catalyzed by CYP3A4) (Lalovic et al. 2004). The metabolic formation of noroxymorphone is represented in Fig. 1.

The narcotic and anesthetic effects of noroxymorphone are known (Noroxymorphone. Material Safety Data Sheet, Mallinckrodt Inc.). While oxycodone is commonly used in the treatment of acute and chronic pain, noroxymorphone has not been studied in vivo. WO 2006/024881 describes pharmaceutical compositions, wherein the active agent is an opioid such as noroxymorphone. Kosterlitz et al. disclose the effects of certain opioids by assaying relative agonist potencies of morphine derivatives including noroxymorphone. The assay was carried out in the isolated preparations of guinea-pig ileum. The study shows that noroxymorphone is an opioid agonist, but no long term effects are disclosed (Kosterlitz et al. 1976). Yaksh and Harty have studied the effects of intrathecally administered high doses of morphine and other opioids in the hotplate and tail flick tests in the single time-point study in rats (Yaksh and Harty 1988). EP patent application 377272 relates to the methods of treating arthritic diseases and associated inflammatory diseases with nalmefene and naltrexone. Naltrexone is an opioid antagonist whereas nalmefene has both agonistic and antagonistic effects. Martindale et al. disclose the use of opioid analgesics in the treatment of postoperative pain. US patent application 2006/0205753 describes the use of quaternary derivatives of noroxymorphone for treating post-surgical gastrointestinal dysfunctions based on opioid antagonistic effects and nonpermeability through the blood-brain barrier (BBB).

Noroxymorphone has previously been synthesized from other opiates, such as morphine (Ninan and Sainsbury 1992), codeine (Schwartz and Wallace 1981), or thebaine ( US Patent 3,332,950) in moderate to good overall yields. However, several synthetic steps are required and, as previously stated by Iijima et al. (Iijima et al. 1978), noroxymorphone is difficult to purify. Commercially available naloxone is manufactured by N-allylating noroxymorphone. A rhodium-catalyzed method for purifying noroxymorphone is described in WO 2006/084389. The disclosed method is, however, not a method for producing noroxymorphone.

The effective relief of pain is of paramount importance to anyone treating subjects undergoing surgery. Not only does effective pain relief mean a smoother postoperative course with earlier discharge from hospital, but it may also reduce the onset of chronic pain syndromes.

The current practiced drug treatments for pain and inflammatory pain have drawbacks, such as that intrathecally administered opioids provide only short duration of effect after single administration (e.g. while injecting together with local anesthetics for perioperative analgesia). Consequently, for longer duration of effect, intrathecal catheters have been used. These are, however, contraindicated in many patients because of the increasingly aggressive perioperative antithrombotic treatment. Inflmmatory pain, e.g. osteoarthritis pain, is common in the elderly. These patients have an increased risk for the adverse effects caused by non-steroidal anti-inflmmatory (NSAID) type drugs. Paracetamol (acetaminophen) is often effective enough. Opioids can cause sedation and respiratory depression and other adverse effects mediated through the central nervous system. The need exists for opioids that do not cross the BBB but that would be effective through the peripheral opioid receptors that are upregulated in inflammation for treating e.g. inflammatory pain in the eldery and other patients who do not tolerate NSAIDs.

Because of the relatively invasive nature of spinal administration of opioids in patients, an ideal molecule for spinal analgesia should have strong potency and efficacy and a long duration of the analgesic effect, and it should not be neurotoxic. A spinal analgesic should also be water-soluble. Morphine is so far the only intrathecally administered water-soluble opioid. Fentanyl has also been used, but since it is fat-soluble, the duration of the analgesic effect is short. The need exists for an efficient medicament with long duration of the analgesic effect.

BRIEF DESCRIPTION OF THE INVENTION

The present invention seeks to overcome or at least significantly reduce the above mentioned problems. Especially there is a need for a new effective and long-term spinal analgesic, which would have strong potency and efficacy and a long duration of the analgesic effect, and it should not be neurotoxic. A spinal analgesic should also be water- soluble.

The objects of the invention are achieved by a compound, compositions, a method and use, which are characterized by what is stated in the independent claims.

The invention relates to use of noroxymorphone in the manufacture of an inthrathecally or systemically applicable medicament for treatment of pain.

The invention relates to noroxymorphone for the treatment of perioperative, postoperative pain, severe cancer pain necessitating spinal administration of opioids or long term pain or inflammatory pain.

The invention also relates to a composition comprising an analgesically effective amount of noroxymorphone together with a pharmaceutically acceptable carrier, excipient, or diluent.

The invention also relates to a method for producing a medicament comprising noroxymorphone, characterized in that naloxone is transformed to noroxymorphone by N- deallylation of naloxone by heating in the presence of a rhodium catalyst.

The invention also relates to a method of treating pain in a subject wherein the method comprises administering the subject with an analgesically effective amount of noroxymorphone.

The preferred embodiments of the present invention are presented in the dependent claims. According to an embodiment of the invention the medicament is for the treatment of perioperative, postoperative or long term pain.

According to an embodiment of the invention the inthrathecally applicable medicament has a long duration of analgesic effect. According to another embdiment of the invention the systemically applicable medicament is for treatment of inflammatory pain.

In an embodiment of the method of the present invention for producing a medicament comprising noroxymorphone, naloxone is transformed to noroxymorphone by N- deallylation of naloxone by heating in the presence of a rhodium catalyst. Preferably, naloxone is dissolved in an aqueous solution. The rhodium catalyst has preferably a triphenylphosphine ligand. In another embodiment of the invention the catalyst and triphenylphosphine oxide formed, are removed before recovering noroxymorphone.

In an embodiment of the present method of treating pain in a subject, intrathecally or systemically administrable noroxymorphone is used for perioperative, postoperative or long term spinal analgesia.

Intrathecally administered noroxymorphone was shown to be an efficient and potent analgesic with a significantly long duration of the analgesic effect. Especially it was found out that noroxymorphone is a useful new spinal analgesic for both perioperative and long term spinal analgesia. Noroxymorphone is more water-soluble μ-opioid receptor agonist than morphine.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the invention will be described in greater detail by means of embodiments with reference to the attached figures.

Figure 1 illustrates a schematic diagram of the formation of noroxymorphone, modified from Lalovic et al. 2006. Abbreviation: CYP, cytochrome P450.

Figures 2a, 2b and 2c depict effects of subcutaneous administration of the drugs studied in the models of nociception. Time-courses of the antinociceptive effect of oxycodone (2.5 mg/kg) and noroxymorphone (5, 10 and 25 mg/kg) after subcutaneous administration in the (2a) tail flick test, (2b) hotplate test and (2c) in the paw pressure test. All drugs were given 30 min before testing. Results are given as means of the maximum possible effects (MPE%) ±SEM plotted over time (min). The asterisks (*) indicate statistically significant differences (p<0.05) as compared with the saline control. Figure 3 depicts effects of subcutaneous administration of the drugs studied in the carrageenan inflammation model. Antiallodynic effects of saline, oxycodone (2.5 mg/kg) and noroxymorphone (25 mg/kg) after subcutaneous administration. All drugs were given 30 min before the testing (black bars). Results are given as the means of the forces (g) inducing an allodynic behavior (±SEM). The asterisks (*) indicate statistically significant differences (p<0.05) as compared with the predrug (white bars) thresholds.

Figure 4 depicts effects of subcutaneous administration of the drugs studied on the performance in the rotarod test. Effects of subcutaneous oxycodone (2.5 and 5 mg/kg) and noroxymorphone (5, 10 and 25 mg/kg) on the latencies on the rotating rod. Results are given as percentages of the predrug latencies (%). All drugs were given 30 min before the testing. The asterisks (*) indicate statistically significant differences (p<0.05) as compared with the saline control.

Figures 5a and 5b depict effects of intrathecal administration of noroxymorphone and morphine in the tail flick test. Time-course of the antinociceptive effect of (5a) noroxymorphone (1, 5 μg/10 μl) and (5b) morphine (1 and 5 μg/10 μl) and saline after intrathecal (i.t.) administration in the tail flick test. Drugs were given 15 min prior to the testing. Results are given as means of the maximum possible effect (MPE%) ±SEM plotted over time (min). The asterisks (#) indicate statistically significant differences (p<0.05) between the study drugs.

Figure 6 depicts effect of subcutaneous naloxone (1 mg/kg) on the antinociceptive effect of intrathecally administerated noroxymorphone and morphine in the tail flick test. Effect of pretreatment of subcutaneous naloxone (1 mg/kg) on the antinociceptive effect of morphine (intrathecal administration 5 μg/10 μl) and noroxymorphone (intrathecal administration 5 μg/10 μl ) studied in the tail flick test. Results are given as means of the maximum possible effect (MPE%) ±SEM. The asterisks (#) indicate statistically significant differences (p<0.05) with the study drugs when compared with the saline control. The asterisks (*) indicate statistically significant differences ((p<0.05) with the naloxone pretreatment group when compared with the saline pretreatment group. Naloxone or saline were given 15 min prior to the intrathecal administration of the study drugs. Tail flick latencies (MPE%) are given 15 min after intrathecal administration of noroxymorphone and 30 min after intrathecal administration of morphine.

Figures 7a and 7b depict effect of subcutaneous administration of naloxone (1 mg/kg) on the antinociceptive effect of intrathecally administerated noroxymorphone and morphine in the tail flick test. Time-course of the antinociceptive effect of with pretreatment with subcutaneous naloxone (1 mg/kg) on the antinociceptive effect of (7a) intrathecal (i.t.) noroxymorphone (5 μg/10 μl) and (7b) intrathecal (i.t.) morphine (5 μg/10 μl) in the tail flick test. Results are given as means of the maximum possible effects (MPE%) ±SEM plotted over time (min). The asterisks (#) indicate statistically significant differences (p<0.05) between the study drugs. Naloxone or saline were given 15 min before intrathecal administration of the study drugs. Tail flick latencies (MPE%) are given 15 min after intrathecal administration of noroxymorphone and 30 min after intrathecal administration of morphine.

Figure 8 depicts effects of intrathecal administration of oxycodone in the tail flick test. Time-course of the antinociceptive effect of intrathecal (i.t.) oxycodone (200 μg/10 μl) and intrathecal (i.t.) noroxymorphone (5 μg/10 μl) in the tail flick test. All drugs were given 15 min before testing. Results are given as means of the maximum possible effect (MPE%) ±SEM plotted over time (min). The asterisks (#) indicate statistically significant differences (p<0.05) between the study drugs.

Figure 9 depicts ¹³C NMR spectrum of noroxymorphone (75 MHz, dβ -DMSO).

Figure 10 depicts ¹H NMR spectrum of noroxymorphone (300 MHz, dβ-DMSO).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the surprising finding that that noroxymorphone was shown to be an efficient and potent analgesic with a significantly long duration of the analgesic effect. Especially intrathecally administered noroxymorphone is a useful new spinal analgesic for both perioperative and long term spinal analgesia providing especially long duration of the analgesic effect. The duration of analgesic effect of noroxymorphone is notably longer than with other opioids. Unless otherwise specified, the terms, which are used in the specification and claims, have the meanings commonly used in the pharmacology, medicinal and pharmaceutical chemistry, anesthesiology and medicine.

The term "intrathecal" or "intrathecal administration" means administration of medicament, such as pain medicament, into the cerebrospinal fluid (intrathecal space surrounding the spinal cord). Using intrathecal administration the blood-brain barrier can be avoided. If the drug were given via other routes of administration where it would enter the blood stream it would be unable to reach the brain. Drugs given intrathecally cannot contain any preservative or other potentially harmful inactive ingredients that are sometimes found in standard injectable drug preparations.

The term "perioperative" means the time period surrounding a subject's surgical procedure. The perioperative period commonly includes ward admission, anesthesia, surgery and recovery. Perioperative, generally refers to the three phases of surgery, namely preoperative, intraoperative and postoperative. The goal of perioperative care is to provide better condition for subjects before operation, during operation and after operation

The term "postoperative" means the time period after surgery or relating to, or occurring in the period following a surgical operation

The term "analgesic" means a member of the diverse group of drugs used to relieve pain. In other words analgesic is painkiller or pain medicament. Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others. Some other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants.

The term "analgesic effect" means the pain relievieng effect. In other words to achieve analgesia. The term "long duration of analgesic effect" means that the effect of pain medicament or analgesic affects longer period of time. In the present invention intrathecal noroxymorphone induced a significantly longer lasting antinociceptive effect compared with oxycodone and morphine.

The term "nociceptive" means caused by or in response to pain. In other words it means the process of pain transmission, usually relating to a receptive neuron for painful sensations. "Nociceptive pain" includes for example sprains, bone fractures, burns, bumps, bruises, inflammation (from an infection or arthritic disorder), obstructions, and myofascial pain (which may indicate abnormal muscle stresses). The pain is typically well localized, constant, and often with an aching or throbbing quality. Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves. Arthritis is a notable exception in that it is not time limited. Another characteristic of nociceptive pain is that it tends to respond well to treatment with opioids.

The term "antinociceptive" means reducing sensitivity to painful stimuli.

The term "inflammatory pain" means pain related to inflammation, which is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. In the present invention medicament to inflammatory pain is applied systemically providing peripherical analgesia. Inflammatory pain includes for example but is not restricted to rheumatoid arthritis and osteoarthritis.

The term "peripheral" means that the compound or medicament acts primarily on physiological systems and components outside the central nervous system. In other words the compound does not cross the blood-brain barrier (BBB). According to the present invention noroxymorphone has peripherical analgesic properties. Systemically administered noroxymorphone remains in the peripheria.

The term "allodynia" means an exaggerated response to otherwise non-noxious stimuli and can be either static or mechanical. Allodynia is different from hyperalgesia, even though both conditions are characterized by intense pain. There are different kinds or types of allodynia: mechanical allodynia (tactile allodynia) and thermal (hot or cold) allodynia. The term "hyperalgesia" means an increased sensitivity to pain, which in one form is caused by damage to nociceptors in the body's soft tissues. Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. The focal form is typically associated with injury, and is divided into primary hyperalgesia, which describes pain sensitivity that occurs directly in the damaged tissues, and secondary hyperalgesia describing pain sensitivity that occurs in surrounding undamaged tissues.

The term "pharmaceutically acceptable carrier, excipient, or diluent" means pharmaceutically acceptable carriers, vehicles, excipients, diluents and processing aids helpful for forming the desired dosing form. The compound (including its salts) can be formulated into pharmaceutical compositions suitable for parenteral, e. g. intrathecal injection administration. In such compositions, noroxymorphone or its salt is usually a minor component (0.1 to say 50% by weight) with the remainder being various pharmaceutically acceptable carriers, vehicles, excipients, diluents and processing aids helpful for forming the desired dosing form. A liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending dispensing agents, colorants, antioxidants, and other ingredients typically used in this field of technology may be used. In the case of injectable compositions, they are commonly based on injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.

The usual intrathecally administered dose of morphine to opioid naϊve subject is 0.2 mg during surgery, the effective time being about 12 hours. Intravenous dose is 4 to 5 mg and the effective time is from 0.5 to 1 hour. When morphine is given orally the single dose is 10-20 mg. Cancer patients with long time usage of opioids might need doses from 1 to 4 g, (normal dose being 200-400 mg/day). It can be said that the dose of intrathecally administered morphine is 1/100 of the oral dose.

The present invention relates to noroxymorphone for use as a medicament. The invention relates to noroxymorphone for the treatment of perioperative, postoperative and long term pain or inflammatory pain. Especially the invention relates to use of noroxymorphone in the manufacture of an intrathecally or systemically applicable medicament for the treatment of pain. Preferably the medicament is to be applied to a patient intrathecally. Preferably the medicament is used in the treatment of perioperative, postoperative and long term pain. In another embodiment of the invention noroxymorphone is used in the manufacture of a medicament for the treatment of inflammatory pain.

The invention also relates to a method for producing a medicament comprising noroxymorphone, wherein naloxone is transformed to noroxymorphone by N-deallylation of naloxone by heating in the presence of a rhodium catalyst. Naloxone is preferably dissolved in an aqueous solution. The rhodium catalyst has preferably a triphenylphosphine ligand. The catalyst and triphenylphosphine oxide formed, are preferably removed before recovering noroxymorphone. Oxygen is preferably removed from the reaction mixture prior to commencing heating.

The invention also relates to a method of treating pain, inflammation or diarrhea in a subject, wherein the method comprises administering the subject with an analgesically effective amount of noroxymorphone. Noroxymorphone is preferably used for perioperative, postoperative and long term spinal analgesia.

The present invention is especially useful in two indication areas: in strong pain, wherein the medicament is applied intrathecally, and in inflammatory pain, wherein medicament is applied systemically providing peripherical analgesia. Strong pain includes but is not restricted to perioperative, postoperative and long term pain such as cancer pain. Inflammatory pain includes for example but is not restricted to rheumatoid arthritis, and osteoarthritis.

Intrathecally administered noroxymorphone was shown to be an efficient and potent analgesic with a significantly long duration of the analgesic effect. Especially it was found out that noroxymorphone is a useful new spinal analgesic for both perioperative and long term spinal analgesia. Noroxymorphone is more water-soluble μ-opioid receptor agonist than morphine. Strong analgesic effect was achieved with significantly smaller doses and the duration of the analgesic effect was several hours. This enables a long duration of analgesic effect of a single spinal injection instead of several uncomfortable injections or catheters. In long-term use this means that a dosing pump needs to be filled less frequently than when using morphine. This decreases the time needed for hospitalization during treatments.

Noroxymorphone for spinal analgesia

In the present invention the in vivo behavioral properties of noroxymorphone are characterized for the first time. The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats and role of noroxymorphone in oxycodone-induced antinociception was evaluated. Intrathecally administered noroxymorphone induced a significantly longer lasting antinociceptive effect compared with oxycodone and morphine. Intrathecally administered morphine induced a potent antinociceptive effect with a shorter duration. Pretreatment with subcutaneous naloxone before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine, indicating an opioid receptor mediated antinociceptive effect. In the hotplate-, paw pressure- and tail flick tests subcutaneous noroxymorphone was inactive in doses of 5, 10 and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antiallodynic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg.

The present inventors demonstrate that noroxymorphone is a potent μ-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood-brain barrier due to its low calculated logD value (log octano I/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia following systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect noroxymorphone is an interesting opioid for spinal analgesia with a minor abuse potential.

In order to test the possibility that noroxymorphone could activate peripheral μ-opioid receptors in inflammation, subcutaneous noroxymorphone was studied in the carrageenan model (Winter et al. 1962). Noroxymorphone is tested in these models at different doses in order to better characterize its efficacy in peripheral analgesia. After intrathecal administration, drugs do not need to penetrate the lipid-rich blood-brain- barrier. This enables drugs that have lower calculated logD values i.e. better distribution in aqueous phase/higher polarity to induce analgesia after spinal administration (Table 1). In the present invention noroxymorphone induced a potent and longer lasting antinociceptive effect compared with morphine and oxycodone after intrathecal administration.

Because of the relatively invasive nature of spinal administration of opioids in patients, an ideal molecule for spinal analgesia should have strong potency and efficacy and a long duration of the analgesic effect, and it should not be neurotoxic. The present inventors unexpectedly found that noroxymorphone was efficient and potent for spinal analgesia, but with a significantly longer duration of the analgesic effect than with morphine. The efficacy and safety of noroxyorphone is studied in the clinic. Noroxymorphone is a useful new spinal analgesic for both perioperative and long term spinal analgesia.

In addition, noroxymorphone is used intrathecally administered in the treatment of chronic pain due to cancer and in the treatment of certain difficult non-cancer related pains. Noroxymorphone used according to the invention in the treatment of pain is administered in the spinal fluid via catheter. One end of the catheter is connected to a subcutaneous dosing pump, which is filled when necessary with the injection through the skin.

Noroxymorphone hydrochloride was synthesized from naloxone hydrochloride by a microwave-assisted rhodium-catalyzed N-deallylation in water. The N-deallylation was accomplished by rhodium-catalyzed (Wilkinson's catalyst) isomerization of N-allyl to enamine, followed by hydrolysis of the enamine under the reaction conditions. The present method for preparing noroxymorphone is facile and robust. The present method is more effective and environmentally friendlier than the present methods for synthesizing noroxymorphone. The synthesis is carried out in water, which is an environmentally friendly solvent. The reaction produces noroxymorphone quantitatively (-100% calculated from the starting material) and in pure form. NMR spectra of noroxymorphone are presented in Fig. 9 and 10. The invention has been described mainly by referring to noroxymorphone for use as spinal analgesic. However, the same principles apply also to a compound of formula (I) representing pro drug -type ester and carbamate derivatives of noroxymorphone

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of H, COR⁴, wherein R⁴ is H, C₁-C₁₈ alkyl (straight chain or branched or cyclic), alkenyl or alkynyl, aryl, alkyl aryl, heteroaryl or alkyl heteroaryl; and CO₂R⁴, wherein R⁴ is H, C₁-C₁₈ alkyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl;

R² is selected from the group consisting of H, COR⁴, wherein R⁴ is H, Ci-Ci₈ alkyl, alkenyl or alkynyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl; and CO₂R⁴, wherein R⁴ is H, C₁-C₁₈ alkyl, alkenyl or alkynyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl;

R³ is selected from the group consisting of H, COR⁴, wherein R⁴ is H, C₁-C₁₈ alkyl, alkenyl or alkynyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl; and CO₂R⁴, wherein R⁴ is H, C₁-C₁₈ alkyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl; and

R⁵ is selected from the group consisting of O, S, N-OR⁶, wherein R⁶ is H, C₁-C₁₈ alkyl, alkenyl or alkynyl (straight chain or branched or cyclic), aryl, alkyl aryl, heteroaryl or alkyl heteroaryl.

The term "alkyl" as used herein, represents straight or branched or cyclic alkyl. Lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, 3-pentyl, 2-methylbutyl, 1-methylbutyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3- hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 1-nonyl, 2- nonyl, 3-nonyl, 4-nonyl, 5-nonyl or the branched or cyclic isomers thereof.

Higher alkyl is 1-decyl, 1-undecyl, 1-dodecyl, 1-tridecyl, 1-tetradecyl, 1-pentadecyl, 1- octadecyl, 1-nonadecyl, 1-eicosanyl, 1-heneicosanyl or the branched or cyclic isomers thereof

"Alkenyl" is for example, vinyl or allyl. "Alkynyl" is for example, propargyl.

"Aryl" is for example, phenyl, naphthyl, phentanhryl, anthracenyl, o-tolyl, m-tolyl, p-tolyl or xylyl.

"Alkyl aryl" is for example, benzyl, α-methylbenzyl, 4-methylbenzyl, 3-methylbenzyl, 2- methylbenzyl, 4-methoxybenzyl, 3-methoxybenzyl. 2-methoxybenzyl, 4-ethylbenzyl, 3- ethylbenzyl, 2-ethylbenzyl, 4-isopropylbenzyl, 3-isopropylbenzyl, 2-isopropylbenzyl, 2,6- dimethylbenzyl, 2,3-dimethylbenzyl, 2,4-dimethylbenzyl, 2,3-dimethoxybenzyl, 2,4- dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-ethoxybenzyl, 3-ethoxybenzyl or 2- ethoxybenzyl.

"Heteroaryl" is for example, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, imidazopyridinyl, benzofurazan, quinoxalinyl, pyrazolopyridine, quinolinyl, isoquinolinyl, benzothiazinyl, dibenzothienyl, furyl, thiophenyl (also known as thienyl), pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3- triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or thiazolyl.

"Alkyl heteroaryl" is for example, pyridinylmethyl or pyrimidinylmethyl.

Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention EXAMPLES

EXAMPLE 1 Materials and methods

Synthesis of noroxymorphone hydrochloride

Naloxone hydrochloride dihydrate (56 mg, 0.14 mmol) was dissolved in ion-exchanged water (2 mL) in a microwave reactor vial. Wilkinson's catalyst (RhCl(PPh₃ )₃) (10 mol-%) was added and the vial was sealed. Argon was bubbled through the heterogeneous mixture for 30 min to remove any dissolved oxygen. The mixture was heated to 200 ⁰C for 60 min, cooled to room temperature and filtered through Cl 8 column to remove the catalyst and a small amount of triphenylphosphine oxide formed in the reaction. The column was further eluted with water (10 mL). The water was evaporated in vacuo to afford pure noroxymorphone hydrochloride.

Animals

The research was carried out according to the guidelines of local authorities and the International Association for the Study of Pain (Zimmermann 1983). The institutional animal investigation committee and the provincial government of Southern Finland approved the protocol of the study (Uudenmaan laaninhallitus, Helsinki, Finland). Opioid- naϊve male SpragueDawley rats (Harlan, Netherlands) weighing 200-250 g were used (n=6-8). The animals were housed in clear plastic cages with a 12 h/12 h artificial light- dark cycle. Water and lab chow were available ad libitum. Before the tests the animals were habituated to the testing environment for 30 min/day for 3 days. After the tests the animals were killed by decapitation under CO₂ anesthesia.

Drugs

Oxycodone hydrochloride and morphine hydrochloride were purchased from the University Pharmacy, Helsinki, Finland and naloxone hydrochloride from RBI (Natick, MA, USA). Noroxymorphone hydrochloride was synthesized from naloxone hydrochloride dehydrate obtained from Sigma- Aldrich Finland Oy (Helsinki, Finland). All drugs were dissolved in saline and administered subcutaneously or intrathecally. Saline served as control. The volume of the intrathecally administered drug solutions was 10 μl followed by a 10 μl flush of saline. Naloxone (or saline as a control) was administered subcutaneously 15 min before the intrathecal administration of the study drugs.

Nociceptive tests

For the paw pressure test, performed with a paw pressure apparatus (Ugo Basile, Milan, Italy), the rats were gently wrapped in a towel. The left hindpaw of the rat was placed under the weight of the apparatus, and the test was started. A brisk foot withdrawal of the hindlimb after constantly increasing pressure terminated the measurement, and the pressure was recorded. To avoid tissue damage, 45 g was set as the cut-off.

Hotplate latencies were tested with a Harvard Apparatus Ltd. hotplate (Edenbridge, Kent, U.K.). In the test, the rats were kept inside a transparent plastic cage on a hotplate (52 ± 0.3 ⁰C). Licking or shaking the hindpaw or jumping was considered as signs of thermal nociception. To avoid tissue damage, 60 s was set as the cut-off time.

Tail flick latencies were tested with Ugo Basile (Comerio, Italy) apparatus. In the test, the rats were placed in transparent hard plastic tubes. The tests were repeated three times (with a 15 s-interval) at every time point. The intensity of the light beam was adjusted to produce a baseline latency of 3 s and the cut-off was set at 8 seconds to avoid tissue damage.

The results of the nociceptive tests where a cut-off value was used (paw pressure, hotplate and tail flick tests) are reported as mean of the maximum percentage effect (MPE%), calculated as: [(postvalue - prevalue)/(cut off- prevalue)] * 100%.

Carrageenan inflammation

Enflurane (Abbot Scandinavia AB., Solna, Sweden) was used to anesthetize the rats, and 0.2 mg λ-carrageenan (Sigma, St. Louis, MO, USA) in 0.1 ml of saline was injected subcutaneously into the left hindpaw. The studied drugs were administered subcutaneously 90 min after carrageenan injection and the test for mechanical allodynia was started 30 min after the injection of the study drugs. Saline served as a control. Predrug testing was performed 30 min before the carrageenan injection. Thresholds for mechanical allodynia were tested with a digital force gauge (Imada DPS-I, Imada Co., Northbrook, Illinois, USA) with a custom made metal tip (0=0.5 mm). Both ipsi- and contralateral paws were tested. The rats were kept on a metal mesh covered with a transparent plastic cover. The ventral surface of the inflamed paw was touched with a tip of the gauge until a paw withdrawal (a brisk foot withdrawal, shaking or licking of the paw) was observed and the force was recorded. A force of 90 g was able to lift a noninflamed paw and it was considered as a cut-off value.

Rotarod test

To study possible changes in motor function or sedative effects of the drugs the rats were tested with a rotarod test apparatus (Palmer electric recording drum, UK; diameter 80 mm, speed 10 RPM) with a protocol modified from Vaananen et al. (Vaananen et al. 2004). Rats were placed on the rotating rod and the time the rat stayed on the rotating rod was calculated. Animals that stayed at least 120 s on the rotating rod before drug administration (pre value) were included to the test and 120 s was set as the cut-off time in the actual test.

Intrathecal Cannulation

Intrathecal cannulation was performed during anesthesia with subcutaneous injection of midazolam 5.0 mg/kg (Midazolam Alpharma^®, Alpharma, Oslo, Norway) and Hypnorm^® 1.0 ml/kg (fentanyl 0.2 mg/ml and fluanisone 10 mg/ml, Janssen Pharmaceutica, Beerse, Belgium). A thin polyethene cannula (Portex Ltd, Hythe, Kent, UK) (original ID = 0.28 mm and OD = 0.61 mm, stretched to double its original length in hot water according to Yaksh and Rudy (Yaksh and Rudy, 1976) was inserted through the cisterna magna to the lumbar subarachnoid space with the tip of the cannula at 8 cm from the insertion. The cannula was fixed with a suture to the paravertebral muscles (Yaksh and Rudy 1976). The condition of the animals was checked after surgery and the animals were housed individually in clear plastic cages. Animals with any neurologic disturbances were immediately sacrificed. Proper placement of the polyethene cannula was verified with an intrathecal injection of 10 μl of 10 mg/ml lidocaine (Lidocain^®, Orion, Espoo, Finland) 5 days after cannulation. Only rats with reversible symmetrical paralysis of both hindlimbs after injection were used in the experiments, which started 10 days after the cannulation.

Statistical Analysis

Paired non-parametric analyses of variance with Bonferroni and Tukey tests implemented in Prism 4.0 (GraphPad Software Inc., San Diego, CA, USA), were used for the statistical analysis. EXAMPLE 2

Subcutaneous administration of noroxymorphone

Subcutaneously administered noroxymorphone failed to induce antinociception in the models of thermal (Figs. 2a and b) and mechanical nociception (Fig. 2c) with the doses used (5, 10 and 25 mg/kg). A 100% MPE in the tail flick test, an 80.4% MPE in the hotplate test and an 84.3% MPE in the paw pressure test were achieved with oxycodone 2.5 mg/kg 30 min after drug administration (significantly different from the saline group). In the carrageenan inflammation model (Fig. 3), no signs of allodynia were observed before the carrageenan injection. In the control group, subcutaneous administration of saline 30 min before the testing had no antiallodynic effects and a statistically significant decrease (from 79 g to 32 g) in the thresholds compared with the pretreatment thresholds was observed in the inflamed paws. There were no changes in the thresholds in the contralateral paws (data not shown). Subcutaneous administration of 25 mg/kg of noroxymorphone 30 min before testing had no antiallodynic effects in this test. Subcutaneous administration of oxycodone 2.5 mg/kg abolished all allodynic behavior and no statistically significant difference compared with the pretreatment thresholds was found.

In the rotarod test no change in motor function or sedation was observed after subcutaneous administration of noroxymorphone with the studied doses (5, 10 and 25 mg/kg) 30 min after drug administration (Fig. 4). A 100% latency on the rotating rod was also achieved after administration of oxycodone 2.5 mg/kg. A statistically significant decrease in the rotarod latencies (65% compared with the predrug latencies) compared with the saline group was observed after oxycodone 5 mg/kg, 30 min after drug administration.

EXAMPLE 3

Intrathecal administration of noroxymorphone

Intrathecally administered noroxymorphone induced statistically significant potent and long lasting antinociception (Fig. 5a). With 5 μg/10 μl of noroxymorphone, an MPE of 96% was achieved 15 min after the drug was administered and an MPE of 81% was still observed 12 h after the administration. A MPE of 17% was observed 24 h after the drug administration. Intrathecally administered morphine induced a potent antinociceptive effect with a shorter duration. A peak antinociceptive effect (MPE 95%) was reached 30 min after the intrathecal morphine administration (5 μg/10 μl) and an MPE of 13% was observed 4 h after morphine administration (Fig. 5b). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal opioid administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine compared with the saline pretreatment group (Fig. 6). A relatively short effect of subcutaneously administered naloxone was observed with the dose of 1 mg/kg used. An antinociceptive effect of intrathecal morphine and noroxymorphone could be observed after the antagonist effect of naloxone had worn off (Fig. 7a and 7b). Intrathecal oxycodone showed weak antinociceptive potency (Fig. 8). An MPE of 100% was achieved 15 min after the administration of a high dose of oxycodone 200 μg/10 μl. The effect was short, and an MPE of 55% was observed 90 min after the drug administration. Intrathecally administered noroxymorphone 20 μg/10 μl induced spontaneous agitation in two rats tested. Such behavior was not observed with the lower doses or other study drugs. Saline had no effects to the tail flick latency in this test.

Discussion

The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats and role of noroxymorphone in oxycodone- induced antinociception was evaluated. Intrathecal noroxymorphone induced a significantly longer lasting antinociceptive effect (Fig. 5a; Example 3) compared with oxycodone and morphine (Fig. 5b; Example 3). Pretreatment with subcutaneous naloxone 15 min before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine (Fig. 6; Example 3), indicating an opioid receptor mediated antinociceptive effect. In the hotplate-, paw pressure- and tail flick tests subcutaneous noroxymorphone was inactive in doses of 5, 10 and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antiallodynic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg.

The results of this study indicate that noroxymorphone is a potent μ-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood-brain barrier due to its low calculated logD value (log octano I/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia following systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect noroxymorphone is an interesting opioid for spinal analgesia with a minor abuse potential.

A practical method for the N-deallylation of naloxone hydrochloride to afford noroxymorphone hydrochloride is presented. The N-deallylation was accomplished by rhodium-catalyzed (Wilkinson's catalyst) isomerization of N-allyl to enamine, followed by hydrolysis of the enamine under the reaction conditions. The catalyst is not soluble in water under normal conditions and therefore such deallylations are typically done in a mixture of water and an organic solvent such as acetonitrile. However, the catalyst seems to be soluble in water, to some extent, at very high temperatures because when a heterogeneous mixture of naloxone in water and 5 to 10 mole per cent of the catalyst was stirred at 200 ⁰C for 30-60 min, a complete N-deallylation was observed (as determined by ¹H NMR). When the reaction was performed at 150 ⁰C or without the catalyst, no N- deallylation was observed at all. The developed microwave-assisted and rhodium-catalyzed N-deallylation method for preparing noroxymorphone is facile and robust.

This is the first study characterizing the in vivo behavioral properties of noroxymorphone. Subcutaneous administration of noroxymorphone was found inactive in all studied models of nociception (Figs. 2a, b and c) and inflammation (Fig. 3), whereas a potent antinociceptive effect was observed after subcutaneous administration of oxycodone 2.5 mg/kg. No changes in motor function or any signs of sedative effect were seen after subcutaneous administration of noroxymorphone at the studied doses of 5, 10 and 25 mg/kg (Fig. 4). A moderate, but statistically significant, decrease in the survival on the rotating rod compared with the saline group was observed after subcutaneous administration of oxycodone 5 mg/kg, as a sign of sedation and reduced motor performance. No change in the rotarod latencies were observed with oxycodone 2.5 mg/kg (Fig. 4). Plasma concentrations of noroxymorphone have been found to be relatively high after oral administration of oxycodone in humans and after intragastric administration in rats (Lalovic et al. 2006). In the same study Lalovic et al. also found that the brain-to- plasma distribution ratio of noroxymorphone (~0,008) is extremely low due to its markedly lower calculated logD (pH 7-8) compared with that of oxycodone (~2,07). This is in agreement with the present results, as noroxymorphone was found to be inactive after subcutaneous administration. In order to test the possibility that noroxymorphone could activate peripheral μ-opioid receptors in inflammation, subcutaneous noroxymorphone was studied in the carrageenan model (Winter et al. 1962). However, no antihyperalgesic effect was seen. This may have been due to the relatively acute character of the carrageenan model. Carrageenan-induced inflammation has been reported to up-regulate levels of μ-opioid receptor protein in dorsal root ganglions (Ji et al. 1995). Marked up-regulation takes place after 1-3 days of carrageenan injection. A rapid induction of μ-opioid receptor protein in the dorsal root ganglions has also been reported after injection of complete Freud's adjuvant (Puehler et al. 2004). The early phase of hyperalgesia takes place after 1-2 h of injection and the late phase after 4 days. This indicates that different models of inflammation are able to induce different kinds of changes in gene regulation in dorsal root ganglions. In the present study, for ethical reasons, the animals were tested only after 120 min of carrageenan injection. Previously, loperamide, another μ-opioid receptor agonist that does not cross the blood- brain-barrier, has been shown to have antiallodynic effects in thermal injury (Nozaki- Taguchi and Yaksh 1999) and in arthritic rats (Cook and Nickerson 2005). Noroxymorphone is tested in these models at different doses in order to better characterize its efficacy in peripheral analgesia.

Opioids are administered intrathecally to achieve segmental spinal analgesia and to avoid adverse effects mediated by supraspinal opioid-receptor activation. After intrathecal administration, the antinociceptive potencies of opioids cannot be fully predicted by the receptor binding affinity, because the pharmacological activity is modulated by complicated pharmaokinetics. Intrathecally administered opioids can spread through various routes, which are controlled mainly by their lipophilicity. The physicochemical properties of opioids, particularly the logD, can change the relative intrathecal/systemic potencies of the drugs and, more importantly, the duration of spinal analgesia.

After intrathecal administration, drugs do not need to penetrate the lipid-rich blood-brain- barrier. This enables opioids that have lower calculated logD values (better distribution in aqueous phase/higher polarity/more water soluble) to induce analgesia after spinal administration (Table 1.). In the present study noroxymorphone (1 and 5 μg/10 μl) induced a potent and longer lasting antinociceptive effect compared with morphine (1 and 5 μg/10 μl) and oxycodone (200 μg/10 μl) after intrathecal administration in rats (Figs. 5a, 5b and 8). McQuay et al. have postulated that the antinociceptive potencies of intrathecally administered μ-opioid receptor agonists are inversely related to their lipofilicity (McQuay et al. 1989). The longer duration of the analgesic effect induced by intrathecal administration of noroxymorphone compared with oxycodone may thus be related to its lower logD value (more water soluble), because of the low vascular absorption of the high polarity drugs (like noroxymorphone) from the spinal fluid (Dickenson et al. 1990). The poor intrathecal potency of oxycodone compared with noroxymorphone and morphine can be explained with the lower μ-opioid receptor affinity of oxycodone compared with the other study drugs. The superior potency of noroxymorphone i.e. longer duration of antinociception of noroxymorphone compared with morphine seems to be related to both its chemical properties as a very hydrophilic compound with a low ClogD value (more water soluble) and relatively high affinity to the μ-opioid receptor (Lalovic et al. 2006). The physicochemical properties, liposolubility and protein-binding of oxycodone resemble those of morphine (Poyhia and Seppala 1994). Noroxymorphone was somewhat more potent compared with morphine in the doses used. Similar intrathecal doses of morphine and noroxymorphone that produced similar MPE% values were used. However, the MPE% values were close to the maximum, even with the lower dose of 1 mg/ml. When hydrophilic drugs are administered intrathecally they can spread to supraspinal parts of the central nervous system and cause sedation and respiratory depression. No respiratory depression was observed after intrathecal administration of noroxymorphone in the doses that were used in this study.

Noroxymorphone has shown relatively high affinity to the μ-opioid receptor («3 times higher than oxycodone) in transfected Chinese hamster ovary cells (CHO-cells) (Lalovic et al. 2006). In the same study, the affinity of noroxymorphone for the μ-opioid receptor compared with that of morphine was reported to be almost 1.8 times lower. In G-protein activation studies, the EC50 of noroxymorphone has been shown to be 2.1 (in CHO-cells) and 7.3 (in rat thalamic membranes) times lower than that of oxycodone with an almost similar E_max (Thompson et al. 2004; Lalovic et al. 2006). In the above mentioned studies of G-protein activation, noroxymorphone has a similar EC50 value as morphine when studied in the rat thalamic membranes (1.2 times lower E_max) and 1.7 times higher when studied in CHO-cells.

The good systemic potency of oxycodone and the low potency after spinal administration in both humans (epidural) (Backlund et al. 1997; Yanagidate and Dohi 2004) and rats (intrathecal) (Plummer et al. 1990; Poyhia and Kalso 1992) has led to the suggestion that active metabolites are important. Previously Lalovic et al. postulated that the analgesic activity of oxycodone can be explained by activity of its own (Lalovic et al. 2006). According to the results of the present study noroxymorphone cannot explain the pharmacokinetic/pharmacodynamic discrepancy between the good systemic effectiveness of oxycodone compared with its relatively low binding affinity to the μ-opioid receptor in vitro (Chen et al. 1991; Monory et al. 1999; Lalovic et al. 2006), because it is not pharmacologically active after subcutaneous administration in doses that are relevant to the analgesic activity of oxycodone.

Mechanisms that may influence the pharmacokinetics of intrathecally administered opioids include cell membrane bound proteins that may act as influx or efflux transporters for opioids. A recent study by Bostrόm et al. found that oxycodone has a 3 times higher unbound concentration in the brain than in the blood, indicating an active influx across the blood-brain-barrier with an unidentified carrier protein (Bostrom et al. 2006). The findings of high concentrations of free oxycodone in the central nervous system followed by systemic administration may explain the mechanisms for the high potency of systemic oxycodone.

In rats and mice, intrathecally administered large doses of morphine may cause hyperalgesia, allodynia and agitation (Yaksh and Harty 1988; Sakurada et al; 1996). This behavior is not reversed by opioid receptor antagonists (Yaksh and Harty 1988; Sakurada et al; 1996), whereas it is abolished by neurokinin 1 and N-methyl-D-aspartate antagonists (Sakurada et al; 2002), indicating involvement of non-opioid neuronal mechanisms. Like morphine, large doses of noroxymorphone have been reported to induce spontaneous and touch-evoked agitation in rats (Yaksh and Harty 1988). In that study, the ED50 of noroxymorphone to produce spontaneous or touch-evoked agitation was 161 and 92 μg, respectively. In the present study, no such behavior was observed with the doses studied (1 and 5 μg). Table 1

The calculated log octanol/water partition coefficients (ClogD) of opioids at 25 ⁰C. ClogD accounts for the charge of the compound at specific pH values. The lipophilicity of ionizable molecules depends on their charge at the specific pH of the aqueous solution.*

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Claims

1. Use of noroxymorphone in the manufacture of an intrathecally or systemically applicable medicament for the treatment of pain.

2. Use according to claim 1, wherein the medicament for treatment of pain is intrathecally applicable.

3. Use according to claim 1 or 2 for the treatment of perioperative, postoperative or long term pain.

4. Use according to claim 2 or 3, wherein the intrathecally applicable medicament has a long duration of analgesic effect.

5. Use according to claim 1, wherein the systemically applicable medicament is for treatment of inflammatory pain.

6. Noroxymorphone for the treatment of perioperative, postoperative or long term pain or inflammatory pain.

7. A composition, characterized in that it comprises an analgesically effective amount of noroxymorphone together with a pharmaceutically acceptable carrier, excipient, or diluent.

8. A method for producing a medicament comprising noroxymorphone, characterized in that naloxone is transformed to noroxymorphone by N- deallylation of naloxone by heating in the presence of a rhodium catalyst.

9. The method according to claim 8, characterized in that naloxone is dissolved in an aqueous solution.

10. The method according to claim 8, characterized in that the rhodium catalyst has triphenylphosphine ligand.

11. The method according to claim 10, characterized in that the catalyst and triphenylphosphine oxide formed, are removed before recovering noroxymorphone.

12. The method according to claim 8, characterized in that oxygen is removed from the reaction mixture prior to commencing heating.

13. A method of treating pain in a subject characterized in that the method comprises administering the subject with an analgesically effective amount of noroxymorphone.

14. The method according to claim 13, characterized in that intrathecally or systemically administrable noroxymorphone is used for perioperative, postoperative or long term spinal analgesia to obtain long duration of analgesic effect.