WO2010103312A1 - Hydroxymorpholines et leur utilisation pour le traitement de troubles inflammatoires et de la douleur - Google Patents

Hydroxymorpholines et leur utilisation pour le traitement de troubles inflammatoires et de la douleur Download PDF

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Publication number
WO2010103312A1
WO2010103312A1 PCT/GB2010/050401 GB2010050401W WO2010103312A1 WO 2010103312 A1 WO2010103312 A1 WO 2010103312A1 GB 2010050401 W GB2010050401 W GB 2010050401W WO 2010103312 A1 WO2010103312 A1 WO 2010103312A1
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Prior art keywords
compound according
condition
pain
disease
alkyl
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PCT/GB2010/050401
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English (en)
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Robin Mark Bannister
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Biocopea Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to novel compounds which are inhibitors of cytokines and possess anti-inflammatory properties as well as utility in reducing pain in pain conditions where cytokines are involved.
  • Immune-driven inflammatory events are a significant cause of many chronic inflammatory diseases where prolonged inflammation causes tissue destruction and results in extensive damage and eventual failure of the effected organ.
  • the cause of these diseases is unknown, so are often called autoimmune, as they appear to originate from an individual's immune system turning on itself.
  • Conditions include those involving multiple organs, such as systemic lupus erythematosus (SLE) and scleroderma.
  • autoimmune disease can involve specific tissues or organs such as the musculoskeletal tissue (rheumatoid arthritis, ankylosing spondylitis), gastrointestinal tract, (Crohn's disease and ulcerative colitis), the central nervous system (Alzheimer's, multiple sclerosis, motor neurone disease, Parkinson's disease and chronic fatigue syndrome), pancreatic beta cells (insulin dependent diabetes mellitus), the adrenal gland (Addison's disease), the kidney (Goodpasture's syndrome, IgA nephropathy, interstitial nephritis), exocrine glands (Sjogren's syndrome and autoimmune pancreatitis) and skin (psoriasis and atopic dermatitis).
  • Inflammation of skin structures is a common set of conditions. These diseases are treated using a wide array of therapies, many of which have very severe side-effects.
  • compounds of formula (I) are inhibitors of cytokines and possess anti-inflammatory properties as well as utility in reducing pain in pain conditions where cytokines are involved.
  • an inflammatory condition as previously described is treated by the use of such compounds.
  • pain such as acute, chronic or neuropathic pain (including, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, painful neuropathies, trauma, musculoskeletal injury or disease, and visceral diseases) and migraine headache in mammals, can be treated by the use of compounds of the formula
  • Ri is aryl or heteroaryl optionally substituted with R 5
  • R 2 is H, alkyl, cycloalkyl or CH 2 OH (and can form a ring with R 3 );
  • R 3 is H, alkyl, cycloalkyl or CH 2 OH (and can form a ring with R 2 );
  • R 4 is H or alkyl;
  • R 5 is alkyl, CF 3 , OR 6 , OCOR 6 , CONH 2 , CN, Cl, Br, I, N(R 6 ) 2 , NO 2 , NHCHO, NHCONH 2 , NHSO 2 R 6 , CON(R 6 ) 2 , S(O) n R 6 , CH 2 OH or OCON(R 6 ) 2 ;
  • R 6 is H, alkyl or cycloalkyl; and n is 0-2; or a salt thereof.
  • aryl is typically phenyl or naphthyl
  • heteroaryl is typically aryl comprising 1 to 3 heteroatoms selected from O, NH and S
  • alkyl has 1 to 8 C atoms
  • cycloalkyl has 3 to 6 C atoms.
  • the compounds of formula (I) can be used to treat inflammatory diseases including, for example, autoimmune diseases involving multiple organs, such as systemic lupus erythematosus (SLE) and scleroderma, specific tissues or organs such as the musculoskeletal tissue (rheumatoid arthritis, ankylosing spondylitis), gastro-intestinal tract' (Crohn's disease and ulcerative colitis), the central nervous system (Alzheimers, multiple sclerosis, motor neurone disease, Parkinson's disease and chronic fatigue syndrome), pancreatic beta cells (insulin dependent diabetes mellitus), the adrenal gland (Addison's disease), the kidney (Goodpasture's syndrome, IgA nephropathy, interstitial nephritis), exocrine glands (Sjogren's syndrome and autoimmune pancreatitis) and skin (psoriasis and atopic dermatitis), chronic inflammatory diseases such as osteoarthritis, periodontal disease, diabetic
  • Dermatitis conditions include: actinic keratosis, acne rosacea, acne vulgaris, allergic contact dermatitis, angioedema, atopic dermatitis, bullous pemiphigoid, cutaneous drug reactions, erythema multiforme, lupus erythematosus, photodermatitis, psoriasis, psoriatic arthritis, scleroderma and urticaria.
  • Ophthalmic diseases include age-related macular degeneration (ARMD), dry eye, uveitis and glaucoma.
  • Compounds of formula (1) may be used according to the invention when the patient is also administered or in combination with another therapeutic agent 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, cyclosporin, mycophenolate), COX inhibitors (example
  • the activity of these compounds may be determined by the use of the appropriate in vivo assay.
  • This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from chronic, acute or neuropathic pain; and more specifically, a method of treatment involving the administration of the analgesic of formula (I) as the active constituent.
  • the compounds of formula (I) can be used among other things 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, musculo-skeletal injury or disease, visceral diseases, painful bladder syndrome) and migraine headache.
  • the painful conditions 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 central pain related to stroke, multiple sclerosis, spinal cord injury, arachnoiditis, neoplasms, syringomyelia, Parkinson's and epilepsia.
  • compounds of formula (I) in combination with another drug used for pain therapy.
  • another drug may be an opiate or a non-opiate such as baclofen.
  • another drug may be an opiate or a non-opiate such as baclofen.
  • coadministration with gabapentin is preferred.
  • Other compounds that may be used include acetaminophen, a non-steroidal antiinflammatory drug, a narcotic analgesic, a local anaesthetic, an NMDA antagonist, a neuroleptic agent, an anticonvulsant, an anti-spasmodic, an antidepressant or a muscle relaxant.
  • Compounds (1) may be prepared by any suitable method known in the art and/or by the following process. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see “Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wuts.
  • a process for preparing compounds of general formula (1) comprises reacting a compound of formula (2) where X is a leaving group with the corresponding aminoalcohol, followed by cyclisation
  • the aminoalcohols and the carbonyl derivatives are either commercially available or readily obtained from commercially available materials by people who are skilled in the art of synthetic organic chemistry. This procedure is shown in the following Scheme.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
  • any suitable route of administration can be used.
  • any of oral, topical, parenteral, ocular, rectal, vaginal, inhalation, buccal, sublingual and intranasal delivery routes may be suitable.
  • 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.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyeryl distearate may be employed. They may also be coated by the techniques described in the US4256108, US4166452 and US4265874, to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occuring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters dervied from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose,
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occuring gums, for example gum acacia or gum tragacanth, naturally-occuring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example gycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglyce rides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (1) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (1) are employed.
  • topical application includes mouth washes and gargles.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • 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 therapy.
  • test compound the test compound
  • Group size: n 8 Protocol and Study Design:
  • mice are weighed, individually identified on the tail with a permanent marker and administered by oral route with either vehicle or test compound in a volume of 10 ml/kg adapted to the body weight.
  • Mice receive an intraperitoneal (i.p.) injection of 1 mg/kg LPS in a volume of 5 ml/kg of body weight.
  • Samples are put on ice until they are prepared by centrifugation (6000 x g for 5 min at 4°C), aliquoted and stored at -20 0 C until use.
  • TNF ⁇ levels are measured in duplicate by ELISA technique in plasma samples. Data are reported as IL-10 and TNF ⁇ (pg/mL), mean ⁇ S. E. M.
  • % effect are calculated according to the following formula: (Mean test or reference substance - Mean vehicle)/Mean vehicle x 100.
  • Inter-group deviations are statistically analyzed by a one-way analysis of variance (ANOVA).
  • ANOVA analysis of variance
  • comparisons versus the vehicle group are carried out using Dunnett's test.
  • equal variance test fails, a Kruskal-Wallis one-way analysis of variance on ranks followed by a Dunn's test is proposed. p ⁇ 0.05 is considered statistically significant.
  • Figure 1 is a diagram showing the effect of vehicle and the test compound on LPS-induced TNF ⁇ plasma levels in mice (pg/ml; x axis); and Figure 2 is a diagram showing the effect of vehicle and the test compound on LPS-induced IL-10 plasma levels in mice (pg/ml; x axis).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (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 porte sur un composé utile pour la thérapie d'une douleur ou d'un état inflammatoire. Ce composé est représenté par la formule (I) : dans laquelle R1 représente aryle ou hétéroaryle et est facultativement substitué par un ou plusieurs groupes choisis parmi alkyle, CF3, OR6, OCOR6, CONH2, CN, Cl, Br, I, N(R6)2, NO2, NHCHO, NHCONH2, NHSO2R6, CON(R6)2, S(O)nR6, CH2OH et OCON(R6)2, où n est 0-2; R2 et R3 représentent chacun H, alkyle, cycloalkyle ou CH2OH, ou CR2R3 forme un cycle; R4 représente H ou alkyle; et R6 représente H, alkyle ou cycloalkyle; ou un sel de ce composé.
PCT/GB2010/050401 2009-03-09 2010-03-09 Hydroxymorpholines et leur utilisation pour le traitement de troubles inflammatoires et de la douleur WO2010103312A1 (fr)

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GBGB0904044.5A GB0904044D0 (en) 2009-03-09 2009-03-09 The treatment of inflammatory disorders and pain
GB0904044.5 2009-03-09

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US20140128354A1 (en) * 2010-10-29 2014-05-08 Biocopea Limited Compositions and Methods for Treating Severe Pain
US9308213B2 (en) 2010-10-29 2016-04-12 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US9504664B2 (en) 2010-10-29 2016-11-29 Infirst Healthcare Limited Compositions and methods for treating severe pain
US9737500B2 (en) 2010-10-29 2017-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
US9744132B2 (en) 2010-10-29 2017-08-29 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US9750810B2 (en) 2010-10-29 2017-09-05 Infirst Healthcare Limited Compositions and methods for treating chronic inflammation and inflammatory diseases
US10695432B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US10695431B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US11202831B2 (en) 2010-10-29 2021-12-21 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US11224659B2 (en) 2010-10-29 2022-01-18 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US11730709B2 (en) 2010-10-29 2023-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain

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