WO2012163456A1 - Nouveaux antagonistes de p2x7r et leur utilisation - Google Patents

Nouveaux antagonistes de p2x7r et leur utilisation Download PDF

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WO2012163456A1
WO2012163456A1 PCT/EP2012/001869 EP2012001869W WO2012163456A1 WO 2012163456 A1 WO2012163456 A1 WO 2012163456A1 EP 2012001869 W EP2012001869 W EP 2012001869W WO 2012163456 A1 WO2012163456 A1 WO 2012163456A1
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indol
hydroxyoxetan
methyl
ethyl
chloro
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Michael Boes
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Affectis Pharmaceuticals AG
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Affectis Pharmaceuticals AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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

Definitions

  • the present application relates to novel P2X7R antagonists that are N-indol- 3-yl-acetamide and N-azaindol-3-yl-acetamide compounds, pharmaceutical compositions comprising these compounds and to their use in the
  • P2X7R is an ATP-gated ion channel belonging to the P2X ionotropic channel family.
  • the gene was first isolated from rat brain (Surprenant et al. (1996) 272:735-738) and subsequently from a human monocyte library (Rassendren et al. (1997) J. Biol. Chem. 272:5482-5486; Genbank accession numbers NM_002562, Y09561) by virtue of its sequence homology with the other members of the P2X family. It was later found that P2X7R corresponded to the unidentified P2Z receptor which mediates the permeabilising action of ATP on mast cells and macrophages (Dahlqvist and Diamant (1974) Acta Physiol.
  • the P2X7R has two hydrophobic membrane-spanning domains, an extracellular loop, and forms transmembrane ion channels. P2X7R bears a pharmacological profile markedly different from other P2X homo- or heteromers (North and
  • P2X7R requires levels of ATP in excess of 1 mM to achieve activation, whereas other P2X receptors activate at ATP concentrations of ⁇ 100 ⁇ (Steinberg et al. (1987) J. Biol. Chem. 262:8884-8888; Greenberg et al.
  • the channels formed by the P2X7R can rapidly transform into pores that can allow the passage of molecules of up to 900 Dalton (Virginio et al. (1999) J. Physiol. 519:335-346).
  • P2X7R is expressed in haematopoietic cells, mast cells, lymphocytes, erythrocytes, fibroblast, Langerhans cells, and macrophages (Surprenant et al., 1996, Science 272:3118-3122).
  • P2X7R expression has been reported in glial cells, Schwann cells, astrocytes, as well as in neurons (Ferrari et al. (1996) J.
  • P2X7R is involved in the regulation of the immune function and inflammatory response. Activation of P2X7R by ATP in macrophages is associated with mitogenic stimulation of T cells (Baricordi et al. (1996) Blood 87:682-690), the release of cytokines (Griffiths et al. (1995) J. Immol. 154:2821-2828), and formation of macrophage polykarions (Falzoni et al. (1995) J. Clin. Invest. 95:1207-1216).
  • P2X7R is involved in the processing and release of active interleukin-1beta (IL-1 ⁇ ) from proinflammatory cells (Perregaux and Gabel (1998) J Biol Chem 269:15195-15203; Ferrari et al., (2006) J Immunol 176: 3877-3883). Stimulation of the P2X7R by ATP can also result in apoptosis and cell death by triggering the formation of non-selective plasma membrane pores (Di Virgilio et al. (1998) Cell Death Differ. 5:191-199).
  • IL-1beta active interleukin-1beta
  • P2X7R Upregulation of P2X7R has been observed during ischemic damage and necrosis induced by occlusion of middle cerebral artery in rat brain (Collo et al. (1997) Neuropharmacol 36:1277-1283). Recent studies indicate a role of P2X7R in the generation of superoxide in microglia, and upregulation of P2X7R has been detected around amyloid plaques in a transgenic mouse models for Alzheimer's disease (Parvathenani et al. (2003) J Biol Chem 278:13300-13317) and in multiple sclerosis lesions from autopsy brain sections (Narcisse et al. (2005) Glia, 49:245-258).
  • P2X7 can improve symptoms in a model of multiple sclerosis (Matute et al. (2007) J Neurosci 27:9525-9533). Studies from mice lacking P2X7R resulted in absence of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli, indicating a link between P2X7R and inflammatory and neuropathic pain (Chessell et al. (2005) Pain 114:386-396). Antagonists of P2X7R significantly improved functional recovery and decreased cell death in spinal cord injury in animal models (Wang et al. (2004) Nature Med 10:B21-B27). P2X7 has also been shown to be involved in depression and anxiety (Basso et al. (2009) Behav Brain Res 198:83-90; WO 2009/019503); bipolar affective disorders (Barden et al. (2006) Am J Med Genet B 141 B:374-382); glaucoma (Resta et al.
  • adamantane derivatives WO 99/29660, WO 99/29661 , WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/080579, WO 04/074224, WO 05/014529, WO 06/025783, WO 06/059945
  • piperidine and piperazine compounds WO 01/44213, WO 01/46200, WO 08/005368;
  • WO 2008/125600; WO 2008/124153; WO 2008/119825; WO 2008/013494; WO 2009/070116; WO 2009/053459 WO 2009/077559; WO 2009/132000; WO 2009/118175; WO 2010/118921) are antagonists of P2X7R while
  • Oxidized ATP acts as an irreversible inhibitor of the receptor (Chen et al., J. Biol. Chem., 268 (1993), 8199-8203). Methods for synthesising oxetanes are disclosed in Wuitschik et al., J. Med. Chem., 53 (2010) 3227- 3246.
  • degenerative conditions associated with disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, Parkinson's disease, multiple sclerosis, glaucoma, age-related macular degeneration, uveitis, neuropathic pain, depression, bipolar affective disorders, anxiety, meningitis, traumatic brain injury, acute spinal cord injury, neuropathic pain, osteoporosis, burn injury, ischemic heart disease, myocardial infarction, stroke, and varicose veins.
  • the object on the present invention is to provide a novel series of compound which can inhibit P2X7R activity and can be used in the treatment of the above-mentioned diseases.
  • the present invention relates to novel P2X7R antagonists that are N-indol-3- yl-acetamide and N-azaindol-3-yl-acetamide compounds represented by the general formula (I):
  • R-i is a mono- or bicycloalkylalkyl group
  • R 2 is selected from hydrogen, -OH, -NH2, or halogen (i.e., CI, F, Br or i);
  • R3, R5, F?6 are at each occurrence independently selected from hydrogen, halogen (i.e., CI, F, Br or I), d-C 6 alkyl, hydroxy, Ci-C 6 alkoxy, cyano, or trifluoromethyl; n equals 1 or 2; a, b, c, d, x are at each occurrence independently selected from carbon, or nitrogen; or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of Formula (I), wherein R 3 , R4, Rs, R6 are at each occurrence independently selected from hydrogen, halogen, methyl, hydroxy, methoxy, cyano, or trifluoromethyl.
  • Ri is a mono- or bicycloalkylalkyi group selected from cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, adamantanyl-methyl, or adamantanyl-ethyl thereof are preferred.
  • R 2 is selected from -OH or fluoride.
  • R 3 , R 4 , R 5 and R 6 are hydrogen.
  • R 4 and R 6 are H, wherein R 3 and R 5 are defined as above, or R 4 -R 6 are H, wherein R 3 is defined as above, wherein Ci-C 6 alkyl is preferably methyl and C C 6 alkoxy is preferably methoxy. If necessitated by valency, R 3 -R6 may also be absent.
  • Examples of novel N-indol-3-yl-acetamide and N-azaindol-3-yl-acetamide compounds are disclosed in examples 1-66.
  • the invention further relates to a compound of Formula (I) or a
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass 25 number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Examples below, by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent.
  • Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine and procaine.
  • nontoxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentaneproprionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
  • glucoheptonate glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulphate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oieate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulphate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulphate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the present application is directed to a
  • composition comprising a compound of Formula (I) of the present invention.
  • the pharmaceutical composition according to the present invention may further comprise an additional active compound in separate or unit dosage form for simultaneous or sequential administration.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cells, such as but not limited to monocytes and/or macrophages.
  • the present invention also relates to the treatment of an IL-1 or cytokine mediated condition.
  • an "IL-1 mediated condition” and “cytokine mediated condition” includes, but is not limited to, a disease or disorder selected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening
  • arthritis including
  • a host reaction comprising administering to said mammal an amount of a compound to Formula (I), effective in treating such a condition.
  • the present invention relates to a pharmaceutical composition for the treatment of an IL-1 mediated condition in a mammal, including a human, comprising an amount of a compound of Formula (I), effective in treating such a condition and a pharmaceutically acceptable carrier.
  • the compounds of the invention are useful for the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, meningitis,
  • COPD chronic obstructive pulmonary disease
  • osteoporosis burn injury, ischemic heart disease, stroke and varicose veins.
  • the invention further provides a pharmaceutical
  • composition for treating osteoarthritis which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the invention further provides a pharmaceutical composition for effecting immunosuppression (e.g., in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises a
  • the invention also provides a pharmaceutical composition for treating an obstructive airways disease (e.g. asthma or COPD) which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • an obstructive airways disease e.g. asthma or COPD
  • a pharmaceutical composition for treating an obstructive airways disease which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the present invention yet further provides a pharmaceutical composition for treating a mammal susceptible to or afflicted with conditions that are causally related to abnormal activity of the P2X7 receptor, such as neurodegenerative diseases and disorders including, for example, Parkinson's disease, multiple sclerosis, glaucoma, age-related macular degeneration, uveitis, neuropathic pain, diseases and disorders which are mediated by or result in
  • neurodegenerative diseases and disorders including, for example, Parkinson's disease, multiple sclerosis, glaucoma, age-related macular degeneration, uveitis, neuropathic pain, diseases and disorders which are mediated by or result in
  • neuromfiammation such as, for example traumatic brain injury and
  • encephalitis centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety,
  • schizophrenia, eating disorders, sleep disorders and cognition disorders, epilepsy and seizure disorders comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the pharmaceutical composition according to the present invention may be used for the treatment of affective disorders.
  • the affective disorder is selected from depression, anxiety, bipolar disorder and schizophrenia.
  • the pharmaceutical composition according to the present invention is useful for the treatment of neurodegenerative diseases and disorders, diseases and disorders which are mediated by or result in neuroinflammation and centrally-mediated neuropsychiatric diseases and disorders.
  • the pharmaceutical composition according to the present invention may particular/ be useful for the treatment of pain, inflammatory processes, and degenerative conditions.
  • the inflammatory process is selected from rheumatoid arthritis, osteoporosis and chronic obstructive pulmonary disease.
  • composition according to the present invention may be used for the treatment of neuropathic pain.
  • Dosage, pharmaceutical preparation and delivery of a compound of Formula (I) for use in accordance with the present invention can be formulated in conventional manner according to methods found in the art, using one or more physiological carriers or excipient, see, for example Ansel et al.,
  • P2X7R modulating agent and its physiologically acceptable salts and solvates can be formulated for administration by inhalation, insufflation (either through the mouth, or nose), oral, buccal, parenteral, or rectal administration.
  • the pharmaceutical composition of a compound of Formula (I) can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc, silica
  • disintegrants e
  • composition can be administered with a physiologically acceptable carrier to a patient, as described herein.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium ion, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • These compositions can be in the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the
  • aforementioned compounds preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparation can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl-p- hydroxycarbonates, soric acids).
  • the preparations can also contain buffer salts, flavouring, coloring and sweetening agents as deemed appropriate.
  • Preparations for oral administration can be suitably formulated to give controlled release of a compound of Formula (I).
  • a compound of Formula (I) of the present invention is conveniently delivered in the form of an aerosol spray
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatine, for use in an inhaler or insufflator can be formulated containing a powder mix of a compound of Formula (I) and a suitable powder base such as lactose or starch.
  • a compound of Formula (I) of the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.
  • Site of injections include intra-venous, intra-peritoneal or sub-cutaneous.
  • Formulations for injection can be presented in units dosage form (e.g., in phial, in multi-dose container), and with an added preservative.
  • a compound of Formula (I) of the present invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, or dispersing agents.
  • the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • a compound of Formula (I) of the present invention can be formulated for transdermal administration.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well- known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • the compounds of this invention can also be administered by a transdermal device. Accordingly, transdermal
  • administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • composition of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • a compound of Formula (I) of the present invention can also, if desired, be presented in a pack, or dispenser device which cancontain one or more unit dosage forms containing the said agent.
  • the pack can for example comprise metal or plastic foil, such as blister pack.
  • the pack or dispenser device can be accompanied with instruction for administration.
  • a compound of Formula (I) of the present invention can be administered as sole active agent or can be adminstered in combination with other agents.
  • agents include non-steroidal anti-inflammatory drug (NSAIDS) such as celecoxib, rofecoxib, cimicoxib, etoricoxib, lumiracoxib, valdecoxib, deracoxib, N-(2-cyclohexyloxynitrophenyl)methane sulphonamide, COX189, ABT963, JTE-522, GW-406381 , LAS-34475, CS-706, PAC-10649, SVT- 2016, GW-644784, tenidap, acetylsalicylic acid (aspirin), amoxiprin, benorilate, choline magnesium salicylate, diflunisal, urgencylamine, methyl salicylate, magnesium salicylate, salicyl salicylate (salsalatee), diclofenac, aceclofenac, ace
  • a compound of Formula (I) of the present invention can be combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel), low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold.
  • TNF-a inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel), low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold.
  • a compound of Formula (I) of the present invention can also be administered in combination with an inhibitor of proTNFalpha convertase enzyme (TACE) such as 3-Amino-N-hydroxy-a-(2-methylpropyl)-3-[4-[(2-methyl-4- quinolinyl)methoxy]phenyl]-2-oxo-1-pyrrolidineacetamide, 2(S),3(S)- Piperidinedicarboxamide, N3-hydroxy-1-methyl-N-2-[4-[(2-methyl-4- quinolinyl)methoxy]phenyl], 3-Thiomorpholinecarboxamide, 4-[[4-(2- butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl, 5-Hexenoic acid, 3- [(hydroxyamino)carbonyl]-2-(2-methylpropyl)-6-phenyl-, 2-(2-methylpropyl)-2- (methylsulfonyl)hydrazide, (2R,
  • Pentanamide 3-(formylhydroxyamino)-4-methyl-2-(2-methylpropyl)-N- [(1S,2S)-2-methyl-1-[(2-pyridinylamino)carbonyl]butyl]-, (2R.3S), 2- Propenamide, N-hydroxy-3-[3-[[(4-methoxyphenyl)sulfonyl](1- methylethyl)amino]phenyl]-3-(3-pyridinyl)-, (2E), Benzamide, N-(2,4-dioxo- 1 ,3,7-triazaspiro[4.4]non-9-yl)-4-[(2-methyl-4-quinolinyl)methoxy],
  • TACE inhibitors N-[(1-acetyl-4-piperidinyl)(2,5-dioxo-4-imidazolidinyl)methyl]-4- [(2-meth- yl-4-quinolinyl)methoxy], or 2,4-lmidazolidinedione, 5-methyl-5-[[[4- [(2-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]methyl].
  • TACE inhibitors are described in WO 99/18074, WO 99/65867, U.S. Pat. No.
  • a compound of Formula (I) of the present invention can also be administered in combination with a corticosteroid such as budesonide, corticosterone, Cortisol, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone,
  • a corticosteroid such as budesonide, corticosterone, Cortisol, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone,
  • a compound of Formula (I) of the present invention can further be
  • a p2-adrenergic receptor agonist such as formoterol, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, bambuterol, clenbuterol.
  • a compound of Formula (I) of the present invention can further be any compound of Formula (I) of the present invention.
  • an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, amitriptyline, citalopram, duloxetine, mirtazapine, nortriptyline, imipramine, lithium.
  • an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, amitriptyline, citalopram, duloxetine, mirtazapine, nortriptyline, imipramine, lithium.
  • a compound of Formula (I) of the present invention can further be any compound of Formula (I) of the present invention.
  • an antipsychotic drug such as
  • chlorpromazine fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, pimozide, melperone, benperidol, triperidol, clozapine , olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone , bifeprunox, aripiprazole.
  • a compound of Formula (I) of the present invention can also be administered in combination with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5- LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, for example, zileuton; ABT-761 ; fenleuton; tepoxalin; nicaraven; VIA-2291 ;
  • a leukotriene biosynthesis inhibitor for example, zileuton; ABT-761 ; fenleuton; tepoxalin; nicaraven; VIA-2291 ;
  • etalocib ketoprofen, Abt-79175; Abt-8576 ; N-(5-substituted) thiophene-2- alkylsulfonamides; TDT-070; licofelone; PEP-03; tenoxicam; 2,6-di-tert- butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB- 210661 ; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739-010; 2-cyanoquinoline compounds such as L-746- 530; indole and quinoline compounds such as MK-591 , MK-886, and BAY x 1005.
  • a compound of Formula (I) of the present invention can be administered in combination with a receptor antagonists for leukotrienes LTB4, LTC4, LTD4, and LTE, for example, phenothiazin-3-ones such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontezolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, praniukast, verlukast (MK-679), RG- 12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195; masilukast.
  • a compound of Formula (I) of the present invention can also be administered in combination with a PDE4 inhibitor including inhibitors of the isoform PDE4D.
  • a compound of Formula (I) of the present invention can also be administered in combination with a antihistaminic Hi receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
  • a antihistaminic Hi receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
  • a compound of Formula (I) of the present invention can further be any compound of Formula (I) of the present invention.
  • a compound of Formula (I) of the present invention can yet further be administered in combination with an a1- and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agent, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.
  • a compound of Formula (I) of the present invention can be administered in combination with anticholinergic agents including ipratropium bromide;
  • the present invention still further relates to the combination of a compound of the invention together with a ⁇ - to p 4 -adrenoceptor agonists including
  • metaproterenol metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline and aminophylline; sodium cromoglycate; or muscarinic receptor (M1 , M2, and M3) antagonist.
  • M1 , M2, and M3 muscarinic receptor
  • a compound of Formula (I) of the present invention can be administered in combination with an insulin-like growth factor type I (IGF-1) mimetic.
  • IGF-1 insulin-like growth factor type 1
  • a compound of Formula (I) of the present invention can be administered in combination with an inhaled glucocorticoid with reduced systemic side effects, including, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone
  • a compound of Formula (I) of the present invention can be administered in combination with (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists; (c) interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors including VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6 phosphate
  • dehydrogenase inhibitors (i) kinin-Bi- and B2-receptor antagonists; j) anti- gout agents, e.g., colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I) uricosuric agents, e.
  • telomere growth factor transforming growth factor
  • PDGF platelet- derived growth factor
  • fibroblast growth factor e.g., basic fibroblast growth factor (bFGF)
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream e.g., capsaicin cream
  • and NK 3 receptor antagonists such as NKP-608C; SB-233412 (talnetant); and D- 4418
  • elastase inhibitors such as UT-77 and ZD-0892.
  • a compound of Formula (I) of the present invention can be administered in combination with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 ( MP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin- 3 (MMP-11).
  • MMPs matrix metalloproteases
  • a compound of Formula (I) of the present invention can be administered in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VEGF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine.
  • anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VEGF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and
  • a compound of Formula (I) of the present invention can be administered in combination with antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antisepsis compounds such as Valant.
  • a compound of Formula (I) of the present invention can be administered in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as stating, fibrates, beta-blockers, ACE inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
  • a compound of Formula (I) of the present invention can be administered in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide
  • CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide
  • a compound of Formula (I) of the present invention can be administered in combination with osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate.
  • osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax
  • immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate.
  • the combined organic layer is washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • XlntOI was purified by flash column chromatography using 60-120 mesh silica gel and 3% ethyl acetate/hexane as eluent.
  • Mass/charge ratio 428.19 (100.0%), 430.18 (32.0%), 429.19 (26.4%), 431.19 (8.6%), 430.19 (4.1 %), 432.19 (1.3%); Elemental analysis: C, 67.20; H, 6.81 ; CI, 8.27; N, 6.53; O, 11.19.
  • Mass/charge ratio 472.14 (100.0%), 474.13 (97.3%), 473.14 (26.4%), 475.14 (25.9%), 474.14 (4.1%), 476.14 (3.9%); Elemental analysis: C, 60.89; H, 6.17; Br, 16.88; N, 5.92; O, 10.14.
  • Mass/charge ratio 442.20 (100.0%), 444.20 (32.2%), 443.21 (27.5%), 445.20 (8.9%), 444.21 (4.3%), 446.21 (1.2%); Elemental analysis: C, 67.78; H, 7.05; CI, 8.00; N, 6.32; O, 10.84.
  • Mass/charge ratio 486.15 (100.0%), 488.15 (97.5%), 487.16 (27.5%), 489.15 (27.1%), 488.16 (4.3%), 490.16 (3.6%); Elemental analysis: C, 61.60; H, 6.41 ; Br, 16.39; N, 5.75; O, 9.85.
  • N-indol-3-yl-acetamide and N-azaindol-3-yl-acetamide compounds antagonise P2X7R activity
  • the Hek293 cells are human embryo kidney cells that do not express endogenous P2X7R (Surprenant et al. (1996) Science 272:735-738). Hek293 cells expressing P2X7R were generated by lipofectamine transfection of the human P2X7R cDNA (Genbank accession number BC011913) under the control of the human cytomegalovirus immediate-early (CMV) promoter and inserted into the pcDNA3.1 vector (Invitrogen).
  • CMV cytomegalovirus immediate-early
  • DMEM Dulbecco's modified eagles medium
  • FEM heat-inactivated foetal calf serum (10% v/v)
  • 2 mM L-glutamine heat-inactivated foetal calf serum (10% v/v)
  • penicillin 100 units/ml
  • streptomycin 100 units/ml
  • Geneticin G418 750 pg/ml Geneticin G418 (GibcoBRUInvitrogen).
  • HBSS Balanced Salt
  • IC50 half-maximal inhibitory concentration
  • Dilution of LPS (stock solution 1 mg/ml): 1 ⁇ of stock solution in 1ml of PBS (concentration at 1 Mg/ml).
  • 80 ⁇ of diluted LPS are added to 8 ml of blood to reach the concentration of 10 ng/ml as stimulation probe, and 1 ml of unstimulated whole blood probe are kept as control.
  • the tubes are incubated for 4 hours in the incubator (37°C, 5% CO 2 ) on a shaker.
  • test compound is diluted from stock concentration (10 mM in 100% DMSO).
  • a serial dilution (1/3) is prepared in 100% DMSO, 10
  • the stimulation is stopped by adding 90 ⁇ of cold PBS and by cetrifugation at 1500 rpm (400 g) for 5 min at 4°C. 30 ⁇ of the supernatant (plasma-like, diluted 3 times) are taken and transferred into a new 96-well plate. Taking red blood cells, which interfere with the IL-1 ⁇ ELISA, should be avoided.
  • the diluted plasma is freezed at -80°C until cytokine measurement.
  • the cytokine level in diluted plasma is analysed with a dilution of 1/25 in dilution buffer (see supplier instruction) with IL-1 beta ELISA kit R&D DY201.
  • Optima excel tables are generated with OD 45 onm and export for IC 50 calculation.
  • IC 50 values are calulated using GraphPad Prism software and a four- parameter log fit log (agonist) vs. response - Variable slope (four
  • Y Bottom + (Top- Bottom)/(1+10 A ((LoglC50-X) * HillSlope)) where X is the logarithm of concentration and Y is the IL-1 beta concentration. Y starts at Bottom and goes to Top with a sigmoid shape.
  • P2X7 has a role in secretion of mature IL-1 beta and has been shown, that monocytes express P2X7.
  • human whole blood is incubated with LPS in order to stimulate the production of pro-IL-1beta, and treated with ATP to initiate mature IL-1 ⁇ secretion.
  • LPS LPS
  • ATP ATP
  • IL-1 beta is a very potent pro-inflammatory cytokine in chronic inflammatory conditions and is involved in pathological conditions such as neuropathic pain, rheumatoid arthritis, multiple sclerosis and other
  • N-(4-chloro-1-((3- hydroxyoxetan-3-yl)methyl)-1 H-indol-3-yl)-2-cyclopentylacetamide has therefore been shown to exhibit anti-inflammatory properties on human blood samples.
  • Example of the IL-1 beta secretion dose response curves to N-(4-chloro-1-((3- hydroxyoxetan-3-yl)methyl)-1 H-indol-3-yl)-2-cyclopentylacetamide The IC 50 values were determined on four different donors. Two dose response curves are shown. The IC 50 values for the four donors are noted in table 1 above. Two donors showed an IC 50 value of 3.8 ⁇ while the other two donors showed IC50 vaues of 5.3 ⁇ and 6.1 ⁇ respectively.
  • mice Five groups of 8 female CH3 mice (Janvier) were enrolled in the study.
  • the first group (control group) was treated with the vehicle (Kleptose 40% in water) intraperitoneally at 10 ml/kg.
  • the second group was treated orally with Dexamethasone (Memphamoson-4) at 1mg/kg.
  • animals were treated with N-(4-chloro-1-((3-hydroxyoxetan-3- yl)methyl)-1 H-indol-3-yl)-2-cyclopentylacetamide at 15, 50 and 150 mg/kg respectively.
  • the compound was dissolved in the vehicle at a final concentration of 1.5, 5 and 15 mg/ml respectively and the different solutions were administrated intraperitoneally at 10 ml/kg.
  • animals in the five groups were injected with Lipopolysaccharide (LPS, Sigma) intraperitoneally at 50 pg/ml.
  • LPS Lipopolysaccharide
  • animals were subsequently injected intraperitoneally with 10 mM ATP (Sigma).
  • 10 mM ATP Sigma
  • animals were sacrificed and 3 ml of PBS containing protease inhibitors (Roche) and Heparin (Liquemin) were injected into the peritoneal cavity and peritoneal lavages were collected.

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Abstract

La présente invention concerne des nouveaux antagonistes de P2X7R qui sont des composés de N- indol-3-yl-acétamide et de N-azaindol-3-yl-acétamide, des compositions pharmaceutiques contenant ces composés et leur utilisation pour le traitement prophylactique ou thérapeutique de maladies induites par l'activité de P2X7R.
PCT/EP2012/001869 2011-05-27 2012-04-30 Nouveaux antagonistes de p2x7r et leur utilisation Ceased WO2012163456A1 (fr)

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Cited By (3)

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CN103420951A (zh) * 2013-09-03 2013-12-04 天津全和诚科技有限责任公司 一种合成氧杂环丁烷-3-甲醛的方法
WO2020150417A3 (fr) * 2019-01-17 2020-08-27 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
US12503436B2 (en) 2021-08-10 2025-12-23 Novartis Pharma Ag Compounds and compositions for treating conditions associated with STING activity

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