WO2009138734A2 - Utilisation de composés opiacés pour les douleurs périphériques, la cicatrisation des plaies et la formation de cicatrices - Google Patents

Utilisation de composés opiacés pour les douleurs périphériques, la cicatrisation des plaies et la formation de cicatrices Download PDF

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Publication number
WO2009138734A2
WO2009138734A2 PCT/GB2009/001184 GB2009001184W WO2009138734A2 WO 2009138734 A2 WO2009138734 A2 WO 2009138734A2 GB 2009001184 W GB2009001184 W GB 2009001184W WO 2009138734 A2 WO2009138734 A2 WO 2009138734A2
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WO
WIPO (PCT)
Prior art keywords
compound according
pain
wound
compound
chronic
Prior art date
Application number
PCT/GB2009/001184
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English (en)
Other versions
WO2009138734A3 (fr
Inventor
Andrew Douglas Baxter
Alan Rothaul
Original Assignee
Serentis 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
Priority claimed from GB0808753A external-priority patent/GB0808753D0/en
Priority claimed from GB0808755A external-priority patent/GB0808755D0/en
Priority claimed from GB0808754A external-priority patent/GB0808754D0/en
Application filed by Serentis Limited filed Critical Serentis Limited
Publication of WO2009138734A2 publication Critical patent/WO2009138734A2/fr
Publication of WO2009138734A3 publication Critical patent/WO2009138734A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • This invention relates to non-CNS-penetrant opioid compounds and to their use for the treatment of peripheral pain and, wound care, and to modify scar formation.
  • opioids act solely on the central nervous system, producing analgesia by interaction with cerebral and spinal opioid receptors. It is now understood that the number of opioid receptors in peripheral tissue is normally low but rapidly increases during inflammation (Hassan et a/., 1993; Schafer et al., 1995; Stein et al., 1996).
  • Immune cells are a major source of endogenous opioid peptides and it appears, by binding peripheral opioid receptors, they may constitute a mechanism of peripheral pain control (Stein et a/., 2003).
  • the present invention is based on the discovery that peripherally-acting analogues of opioids are capable of treating peripheral pain without CNS- mediated effects.
  • the peripherally-acting analogues can be used to boost analgesia when pain is associated with inflammation.
  • a partial agonist pharmacological profile confers both analgesic and antiinflammatory activity.
  • such compounds can be used, inter alia, in the treatment of pain conditions such as acute and chronic pain (as well as, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, trauma, musculoskeletal injury, such as osteoarthritis, back pain or repetitive strain injury or disease, visceral diseases) and migraine headache.
  • painful conditions to be treated can be neuropathic (post-herpetic neuralgia, diabetic neuropathy, drug induced neuropathy, HIV-mediated neuropathy, sympathetic reflex dystrophy or causalgia, fibromyalgia, myofacial pain, entrapment neuropathy, phantom limb pain, trigeminal neuralgia).
  • Neuropathic conditions include pain related to stroke, multiple sclerosis, spinal cord injury, arachnoiditis, neoplasms, syringomyelia, Parkinson's and epilepsia.
  • peripherally-acting analogues of opioids are capable accelerating the healing of both chronic and acute wounds.
  • These compounds are also capable of accelerating collagen deposition during scar formation and are therefore capable of increasing scar strength in acute wounds, surgical incisions and similar events and by doing so reducing scar formation.
  • they can be used to boost analgesia when such wounds are associated with pain.
  • Wounds typically associated with pain include chronic dermal wounds, diabetic ulcers, pressure wounds, ophthalmic injury, skin grafts at the graft and donor sites, abrasive wounds and burns.
  • opioids applied locally provide some pain relief, they are still susceptible to causing unwanted systemic and CNS side-effects. These side- effects can be managed by the peripherally-acting analogues of the invention as they do not penetrate the CNS.
  • a quaternary ammonium derivative of an opioid is used for wound healing, to modify scar formation or to treat peripheral pain or pain associated with an inflammatory condition, e.g. as described above.
  • a compound of or for use in the invention is an opioid which normally comprises a tertiary amine and which has been modified by introducing an alkyl group on that nitrogen atom.
  • opioids such as (but not limited to) fentanyl (1), tramadol (2), buprenorphine (3), methadone (4), morphine (5), oxycodone, hydrocodone, dihydrocodone, hydromorphone, oxymorphone, alfentanil, sufentanil, remifentanyl, dextropropxyphene, bezitramide, piritramide, pentazocine, phenazocine, nalbufine, levorphanol, loperamide and diphenoxylate, i.e. including compounds of the formulae
  • R1 is C 1 -C 4 alkyl
  • X is counterion of any pharmaceutically acceptable acid, including halide, sulphate, methosulphate, phosphate or of an organic acid such as citrate, succinate, tartarate, fumarate, maleate, acetate or methanesulphonate.
  • Analogues of opiates that act as partial agonists at ⁇ and K opioid receptors while demonstrating antagonist activity at ⁇ receptors may be preferred.
  • Compounds of the invention may have one or more chiral centres. Any reference herein to these compounds should be understood as a reference to any diastereomer, enantiomer or mixture thereof. Any enantiomer may be substantially free of others, e.g. in an enantiomeric excess of at least 80%, preferably at least 90% and more preferably at least 95%. Similarly, any mixture of diastereomers may be substantially free of the other. The form of each of formulae 1 to 5 drawn above is preferred.
  • the active agent may be administered by various routes, including parenteral, oral, intraoral, rectal, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, vaginal, rectal, intradural, intraocular, intrarespiratory, or nasal inhalation and like forms.
  • the amount of active ingredient that is used can be chosen by the skilled person having regard to the usual factors.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • the composition may be in immediate or controlled release form.
  • the topical route may be preferred for compounds of formulae (1), (2) or
  • the active agent is typically formulated, e.g. with conventional diluents or carriers, or as a dressing or a patch, as a medicament adapted to be delivered by the chosen route.
  • Such formulations may be designed to retard the passage of the compound into the systemic circulation and are chosen according to such considerations as the potency of the drug, the severity of the condition and the route of administration.
  • the active agent may be administered into the incision/traumatic site in a suitable dermal or topical formulation.
  • the amount of active ingredient that is used can be chosen by the skilled person having regard to the usual factors.
  • the suture or incision closing device is impregnated with a compound of the invention.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trials, as is required in the pharmaceutical art. In general, the daily dose range will lie within the range of from about 0.1 ⁇ g to 1000 mg per kg body weight of a mammal, often 0.01 mg to about 100 mg per kg, for example 0.1 ⁇ g to 10 mg per kg, in single or divided doses. It may be necessary to use dosages outside these limits in some cases.
  • a compound of the invention is preferably administered via the oral, parenteral, intranasal, inhaled, sub-lingual, buccal, topical or transdermal route.
  • a typical daily dose is less than 1000 mg, e.g. 0.1 to 100 mg.
  • Quaternary ammonium derivatives of opioids can be prepared by treatment of the opioid with R1-X.
  • the following reaction may be used:
  • Peripherally active compounds of formula (5) can be prepared according to the general scheme below.
  • X is typically a reactive halide such as chloride, bromide or iodide, or methosulphate.
  • X is typically a reactive halide such as chloride, bromide or iodide, or methosulphate.
  • the transformation may be carried out using methods known to those skilled in the art.
  • Such another drug may be a local anaesthetic, anti-septic or antibiotic.
  • another drug may be a local anaesthetic, anti-septic or antibiotic.
  • Other combinations include those with an anti-convulsant, such as phenytoin, or a compound used to enhance vascular permeability, including peripheral vasodilators such as adenosine agonists or re-uptake inhibitors (e.g. dipyridamole), anti-platelets agents (e.g. ketanserin) and pentoxyfylline, and vasopeptidase inhibitors such as neutral endopeptidase (NEP) inhibitors or combined ACE/NEP inhibitors.
  • an anti-convulsant such as phenytoin
  • a compound used to enhance vascular permeability including peripheral vasodilators such as adenosine agonists or re-uptake inhibitors (e.g. dipyridamole), anti-platelets agents (e.g
  • Such another drug may be selected from corticosteroids (examples including Cortisol, cortisone, hydrocortisone, dihydrocortisone, fludrocortisone, prednisone, prednisolone, deflazacort, flunisolide, beconase, methylprednisolone, triamcinolone, betamethasone, and dexamethasone), disease modifying anti-rheumatic drugs (DMARDs) (examples including azulfidine, aurothiomalate, bucillamine, chlorambucil, cyclophosphamide, leflunomide, methotrexate, mizoribine, penicillamine and sulphasalazine), immunosuppressants (examples including azathioprine, cyclosporine and mycophenolate), COX inhibitors (examples including Cortisol, cortisone, hydrocortisone, dihydro
  • lodomethane (2 mL, 32.3 mmol) was added to a solution of methadone (0.20 g, 0.65 mmol) in ethyl acetate (10 mL). The mixture was stirred at room temperature for 4 h. The resulting precipitate was filtered and washed with a small amount of ethyl acetate. After drying under vacuum the product was obtained as white powder (0.19 g, 66%).
  • lodomethane (5 ml_, 80.2 mmol) was added to a solution of fentanyl (0.50 g, 1.49 mmol) in ethyl acetate (50 ml_). The resulting slurry was stirred at room temperature overnight an then filtered. The crude product was washed with hot ethyl acetate twice and dried under vacuum to obtain product as white powder (0.29 g, 41%).
  • lodomethane (3.5 ml_, 56.1 mmol) was added to slurry of morphine (0.32 g, 1.1 mmol) in acetonitrile (16 mL). The mixture was stirred at room temperature overnight and filtered. The crude product was purified by trituration with acetonitrile followed by trituration with ethyl acetate. After drying under vacuum the product was obtained as white powder (0.20 g, 42%).
  • Buprenorphine (5 g, 10.7 mmol) and MeI (34.2 g, 15 ml, 240 mmol) were taken up in MIBK (30 ml), halved between two sealed tubes and heated at 70 0 C for six days.
  • Buprenorphine and buprenorphine methiodide were assayed for binding to the human opiate receptors in radiolabel binding studies. The results are shown in Table 1. Buprenorphine methiodide showed significant inhibition in all three of the opiate receptor binding assays. Table 1 : Opiate receptor binding potency
  • nt not tested Buprenorphine methiodide also demonstrated partial agonism in an isolated organ bath experiment (guinea pig ileum twitch response, 50% of control at 10 ⁇ M).
  • buprenorphine is a partial ⁇ receptor agonist which also shows partial agonism for K receptors, but is a potent antagonist at ⁇ receptors.
  • the data demonstrate that buprenorphine methiodide has retained the opiate receptor profile of buprenorphine at ⁇ and K opiate receptors.
  • Buprenorphine methiodide and methyl-naloxone were co-administered each at 1 mg/kg i.v. via the tail vein.
  • Plasma and brains were prepared from 3 rats at each of the pre-dose and 30, 60, 120 and 180 minutes post dose. Samples were extracted by protein precipitation and analysed by HPLC-MS/MS for buprenorpine methiodide, and methyl-naloxone. Results are shown in Table 4.
  • Plasma cone ng 3 // ⁇ ml
  • Brain cone ng/mL
  • Time(Hrs) BupMel Methyl- BupMel Methyl- io NNaloxone Naloxone
  • Example 7 Activity in an inflammatory pain model
  • the analgesic effects of buprenorpine methiodide were evaluated in the Acute Inflammatory Pain Test (carrageenan) in the rat.
  • the method which detects analgesic/anti-inflammatory activity in rats with inflammatory pain, follows that described by Winter et a/ (Proc. Soc. Exp. Biol. Med., 111 , 544-547, 1962). Rats were injected with a suspension of carrageenan into the lower surface of the right hindpaw. Two hours later, rats were submitted consecutively to tactile and thermal stimulation of both hindpaws. Buprenorpine methiodide was evaluated at 3 doses, administered as an i.v.
  • buprenorpine methiodide significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé qui est un sel d'ammonium quaternaire dérivé d'un opiacé destiné à une utilisation thérapeutique.
PCT/GB2009/001184 2008-05-14 2009-05-11 Utilisation de composés opiacés pour les douleurs périphériques, la cicatrisation des plaies et la formation de cicatrices WO2009138734A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0808754.6 2008-05-14
GB0808753A GB0808753D0 (en) 2008-05-14 2008-05-14 Use of opioid compounds in wound healing and scar formation
GB0808755A GB0808755D0 (en) 2008-05-14 2008-05-14 Use of opioid compounds in peripheral pain
GB0808755.3 2008-05-14
GB0808753.8 2008-05-14
GB0808754A GB0808754D0 (en) 2008-05-14 2008-05-14 Use of opiod compounds in peripheral pain

Publications (2)

Publication Number Publication Date
WO2009138734A2 true WO2009138734A2 (fr) 2009-11-19
WO2009138734A3 WO2009138734A3 (fr) 2010-01-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013084060A1 (fr) * 2011-12-08 2013-06-13 Purdue Pharma L.P. Analogues de buprénorphine quaternisés
US20150352100A1 (en) * 2013-01-21 2015-12-10 Avant Derma Pte. Ltd. Use of selective delta-opioid receptor antagonists and specific sensory receptor ligands
WO2017070017A1 (fr) * 2015-10-23 2017-04-27 Rush University Medical Center Compositions topiques assurant un soulagement de la douleur et procédés d'utilisation de ces compositions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0897726A1 (fr) * 1996-11-25 1999-02-24 Toray Industries, Inc. Agent antiprurigineux

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0897726A1 (fr) * 1996-11-25 1999-02-24 Toray Industries, Inc. Agent antiprurigineux

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013084060A1 (fr) * 2011-12-08 2013-06-13 Purdue Pharma L.P. Analogues de buprénorphine quaternisés
JP2015502952A (ja) * 2011-12-08 2015-01-29 パーデュー、ファーマ、リミテッド、パートナーシップ 四級化ブプレノルフィン類似体
US9096606B2 (en) 2011-12-08 2015-08-04 Purdue Pharma, L.P. Quarternized buprenorphine analogs
US20150352100A1 (en) * 2013-01-21 2015-12-10 Avant Derma Pte. Ltd. Use of selective delta-opioid receptor antagonists and specific sensory receptor ligands
WO2017070017A1 (fr) * 2015-10-23 2017-04-27 Rush University Medical Center Compositions topiques assurant un soulagement de la douleur et procédés d'utilisation de ces compositions

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WO2009138734A3 (fr) 2010-01-07

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