WO2009138734A2

WO2009138734A2 - Use of opioid compounds in peripheral pain, wound healing and scar formation

Info

Publication number: WO2009138734A2
Application number: PCT/GB2009/001184
Authority: WO
Inventors: Andrew Douglas Baxter; Alan Rothaul
Original assignee: Serentis Limited
Priority date: 2008-05-14
Filing date: 2009-05-11
Publication date: 2009-11-19
Also published as: WO2009138734A3

Abstract

A compound which is a quaternary ammonium salt derivative of an opioid, for use in therapy.

Description

USE OF OPIOID COMPOUNDS IN PERIPHERAL PAIN, WOUND HEALING

AND SCAR FORMATION

Field of the Invention

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. Background of the Invention

It had long been thought that 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).

Local delivery of opioids has been employed in pain therapy to minimize the CNS side-effects traditionally associated with systemic use. Injection of opioids into knee joints after knee surgery (Stein et a/., 1991) or local delivery after dental surgery (Likar et a/., 1998) caused prolonged post-operative analgesia in humans.

Summary of the Invention

The present invention is based on the discovery that peripherally-acting analogues of opioids are capable of treating peripheral pain without CNS- mediated effects. In addition, the peripherally-acting analogues can be used to boost analgesia when pain is associated with inflammation. Surprisingly, a partial agonist pharmacological profile confers both analgesic and antiinflammatory activity. Accordingly, 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. Additionally, 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. In addition, 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. In addition, 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.

While 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.

According to the invention, 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. Such compounds are derivatives of 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

(D (2)

(3)

(4) (5)

wherein R1 is C₁-C₄ alkyl; and 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.

Most of these compounds are new. Those that are known have never been used in therapy or, more particularly, for the treatment of peripheral pain or pain associated with an inflammatory condition, wound healing or to modify scar formation.

Analogues of opiates that act as partial agonists at μ and K opioid receptors while demonstrating antagonist activity at δ receptors may be preferred.

Description of the Invention

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

(3). For use through this route of delivery 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. In another aspect of the invention, the suture or incision closing device is impregnated with a compound of the invention.

It will be understood that 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 μg to 1000 mg per kg body weight of a mammal, often 0.01 mg to about 100 mg per kg, for example 0.1 μg 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. In this context, 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. For example, the following reaction may be used:

Peripherally active compounds of formula (5) can be prepared according to the general scheme below.

wherein 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.

It will often be advantageous to use the compounds of the invention in combination with another drug used for pain, inflammation or wound care therapy. Such 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. It will also be often advantageous to use the compounds of the invention in combination with another drug used for pain or inflammation. 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 aceclofenac, acemetacin, alcofenac, alminoprofen, aloxipirin, amfenac, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacine, choline salicylate, chlometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole, etodolac, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, mefenamic acid, metamizole, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, rofecoxib, salicylamide, salsalate, suiindac, suprofen, tiaramide, tinoridine, tolfenamic acid and zomepirac), neutralising antibodies (examples including etanercept and infliximab), antibiotics (examples including doxycycline and minocycline), analgesics (opiate or non opiate such as baclofen), neuropathic pain agents (such as gabapentin or pregabalin), non steroidal anti-inflammatory drugs, NMDA antagonists, neuroleptics, anticonvulsants, anti-spasmodics, anti-depressants or muscle relaxants. The following Examples illustrate the invention.

Example 1 Methadone methiodide

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%).

¹H NMR (δ, 200MHz, d₆-DMSO): 0.41 (d, 3H, CH₃), 0.69 (t, 3H, CH₃), 2.21-2.33 (m, 4H), 3.10-3.31 (m, 1 H, CH₂), 3.0 (s, 9H, CH₃), 7.20-7.57 (m, 10H, aromatic). m/z 324=451 (M_T842) - 127 (I^"). Example 2 Fentanyl methiodide

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%).

¹H NMR (δ, 200MHz, d₆-DMSO): 0.88 (t, 3H, CH₃), 1.78-1.99 (m, 5H), 2.89 (S, 3H, CH₃), 3.33 (S, 3H, CH₃), 3.50-3.55 (bm, 6H), 4.58 (bm, 1H), 7.26-7.34 (m, 7H), 7.48-7.25 (m, 3H). m/z 351=478 (MT₈₄₂) - 127 (I^"). Example 3 Morphine methiodide

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%). 1H NMR (δ, 200MHz, d₆-DMSO): 1.78-1.85 (bd, 1 H), 2.70-2.81 (m, 2H), 3.10- 3.40 (m, 10H), 4.14 (bs, 1 H), 4.36 (bs, 1H), 4.79 (d, 1 H), 5.05 (d,1 H), 5.25 (d, 1H)₁ 5.60 (bd, 1H), 6.41-6.56 (m, 2H), 9.01 (s, 1H). m/z 300=427 (M_T842) - 127 (V). Example 4 Buprenorphine Methiodide

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 70⁰C for six days.

The tubes were allowed to cool to RT, combined and evaporated. The residue was triturated with ¹PrOAc, and the solid formed was filtered off and dried. The solid was purified by column chromatography (2%-5% MeOH in CH₂CI₂). The product obtained was triturated with MTBE and the solid formed was filtered off and dried in vacuo to give 2 g (31% yield) of the title product as a pale yellow solid.

¹H NMR (δ, 400MHz, d₄-MeOH): 0.50-0.58 (m, 1H), 0.61-0.68 (m, 1 H), 0.80-0.95 (m, 2H), 1.025 (s, 9H, 'butyl CH₃), 1.05-1.18 (m, 1H), 1.19-1.3 (m,2H), 1.40 (s, 3H, CH₃), 1.48-1.68 (m, 2H), 1.85-1.97 (bd, 2H), 2.1 (dd, 1 H), 2.45 (dd, 1 H), 2.68-2.80 (m, 2H), 3.05 (dd, 1H), 3.15 (dd, 1H), 3.30 (m, 1H), 3.50 (s, 3H, CH₃O), 3.56 (m, 1H), 3.59 (s, 3H, CH₃N), 4.08 (dd, 1H), 4.18 (d, 1H), 4.65 (s, 1 H, CH₂CHO), 6.65 (d, 1 H, aromatic), 6.74 (d, 1H, aromatic). Example 5 Opiate receptor pharmacology

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

Both compounds were assayed for opiate receptor agonism and antagonism activity using GTPγS binding assays against human cloned μ, δ and K receptors. The methiodide analogues of methadone, morphine and fentanyl were screened for agonist and antagonist activity against μ opiate receptors in a guinea pig ileum organ bath assay. The results are shown in Tables 2 & 3.

Table 2: Opiate receptor agonist activity

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 μM).

The results confirm that buprenorphine is a partial μ receptor agonist which also shows partial agonism for K receptors, but is a potent antagonist at δ receptors. The data demonstrate that buprenorphine methiodide has retained the opiate receptor profile of buprenorphine at μ and K opiate receptors.

The results confirm that Methadone methiodide, Morphine Methiodide and Fentanyl Methiodide behave as μ-receptor agonists. Example 6

Restriction to peripheral sites

To determine if the activity of buprenorphine methiodide is restricted to the periphery, a pharmacokinetic study was performed and the CNS penetration determined following i.v. dosing. Brains and plasma were sampled from rats that had been co-administered i.v. with buprenorphine methiodide and methyl- naloxone. Methyl-naloxone (Sigma-Aldrich N 129) was used as a control compound, to check for blood contamination during the brain collection process. Methyl-naloxone is a compound known not to cross the blood-brain barrier.

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.

Table 4

Plasma cone (ng ₃//πml) Brain cone (ng/mL) tat Time(Hrs) BupMel Methyl- BupMel Methyl- io NNaloxone Naloxone

1 P re BLQ BLQ BLQ BLQ

2 Pre BLQ BLQ BLQ BLQ

3 Pre BLQ BLQ BLQ BLQ

4 0.5 78.6 46.7 BLQ BLQ

5 0.5 84.4 52.7 BLQ BLQ

6 0.5 70.8 55.3 BLQ BLQ

7 1 18.7 32.3 BLQ BLQ

8 1 22.1 29.2 BLQ BLQ

9 1 27.5 32.9 BLQ BLQ

10 2 17.4 19.2 BLQ BLQ

11 2 7.13 13.3 BLQ BLQ

12 2 4.51 15.5 BLQ BLQ

13 3 3.60 13.2 BLQ BLQ

14 3 2.98 8.68 BLQ BLQ

15 3 BLQ 6.17 BLQ BLQ

BLQ= below limit of quantitation

The results show that buprenorpine methiodide was not found in brain tissue and does not penetrate the CNS. 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. bolus 15 minutes before testing, and compared with a vehicle control group and morphine (4 mg/kg i.v.) used as reference substance. In this model, buprenorpine methiodide significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose- dependent manner.

Claims

1. A compound which is a quaternary ammonium salt derivative of an opioid, for use in therapy.

2. A compound according to claim 1 , wherein the opioid is selected from fentanyl, tramadol, buprenorphine, methadone, morphine, oxycodone, hydrocodone, dihydrocodone, hydromorphone, oxymorphone, alfentanil, sufentanil, remifentanyl, dextropropxyphene, bezitramide, piritramide, pentazocine, phenazocine, nalbufine, levorphanol, loperamide and diphenoxylate.

3. A compound of formula (1)

(D wherein R1 is CrC₄ alkyl and X is the counterion of a pharmaceutically acceptable acid.

4. A compound of formula (2)

(2)

wherein R1 and X are as defined in claim 3.

5. A compound of formula (3)

(3) wherein R1 and X are as defined in claim 3.

6. A compound of formula (4)

wherein R1 and X are as defined in claim 3.

7. A compound of formula (5)

(5) wherein R1 and X are as defined in claim 3.

8. A compound according to any preceding claim, which has a counterion of the quaternary or which is sulphate, methosulphate or phosphate or of an organic acid such as citrate, succinate, tartarate, fumarate, maleate, acetate or methanesulphonate.

9. A compound according to any preceding claim, wherein the salt or X is a halide.

10. A compound according to any preceding claim e.g. as defined in claim 7, wherein the treatment is of a pain condition.

11. A compound according to claim 10, for the treatment of peripheral pain.

12. A compound according to claim 11 , wherein the pain is inflammatory pain.

13. A compound according to claim 10, for the treatment of chronic pain.

14. A compound according to claim 13, wherein the pain is back pain, malignant pain, chronic headache (including migraine and cluster headaches) or arthritic pain.

15. A compound according to claim 10, for the treatment of acute pain.

16. A compound according to claim 15, wherein the pain is post-operative pain, post-traumatic pain or acute disease-induced pain.

17. A compound according to claims 10, for the treatment of neuropathic pain.

18. A compound according to any of claims 1 to 9, for use in wound care.

19. A compound according to claim 18, for use in scar formation and increase of scar strength in a wound.

20. A compound according to claim 18, wherein the wound is a chronic dermal wound.

21. A compound according to claim 18, wherein the wound is a diabetic ulcer.

22. A compound according to claim 18, wherein the wound is caused by a skin graft.

23. A compound according to claim 18, wherein the wound is a chronic dermal wound on a graft or donor site.

24. A compound according to claim 18, wherein the wound is a burn.

25. A compound according to claim 18, wherein the wound is a chronic dermal wound or an acute or chronic abrasive injury.

26. A compound according to claim 18, wherein the wound is a surgical incision.

27. A compound according to claim 18, wherein the wound is a traumatic incision.

28. A compound according to claim 18, wherein the wound is laceration.

29. A compound according to claim 18, wherein the wound is caused by acne, chicken pox or a dermatological condition.

30. A compound according to any of claims 18 to 29, for administration via direct installation into the wound.

31. A compound according to any of claims 18 to 29, for administration via direct installation into the dermis of the skin.

32. A compound according to any of claims 18 to 29, used in combination with another agent capable of facilitating or accelerating wound healing.

33. A compound according to any of claims 18 to 29, used in combination with an anti-convulsant, a peripheral vasodilator, a vasopeptidase inhibitor or an anti-platelets agent.

34. A compound according to any of claims 18 to 29, used in combination with an antiseptic or an antibiotic agent.

35. A compound according to any preceding claim, used in combination with an analgesic, a local anesthetic or an anti-inflammatory agent.

36. A compound according to any preceding claim, for administration via a topical or percutaneous route.

37. A compound according to any of claims 1 to 35, for administration via the oral route.