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WO2012163792A1 - Novel p2x7r antagonists and their use - Google Patents

Novel p2x7r antagonists and their use Download PDF

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Publication number
WO2012163792A1
WO2012163792A1 PCT/EP2012/059693 EP2012059693W WO2012163792A1 WO 2012163792 A1 WO2012163792 A1 WO 2012163792A1 EP 2012059693 W EP2012059693 W EP 2012059693W WO 2012163792 A1 WO2012163792 A1 WO 2012163792A1
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WO
WIPO (PCT)
Prior art keywords
indole
carboxamide
hydroxyoxetan
methyl
ethyl
Prior art date
Application number
PCT/EP2012/059693
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French (fr)
Inventor
Michael Boes
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Affectis Pharmaceuticals Ag
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Publication date
Application filed by Affectis Pharmaceuticals Ag filed Critical Affectis Pharmaceuticals Ag
Publication of WO2012163792A1 publication Critical patent/WO2012163792A1/en

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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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to novel P2X7R antagonists that are indol-3 carboxamide and azaindol-3 carboxamide compounds, pharmaceutical compositions comprising these compounds and to their use in the prophylactic and therapeutic treatment of diseases and disorders mediated by P2X7R.
  • 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.
  • 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. Scand. 34:368-384; Steinberg and Silverstein (1987) J. Biol. Chem. 262:31 18-3122; Gordon (1986) Biochem. J. 233:309-319).
  • 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 Surprenant (2000) Annual Rev.
  • P2X7R is expressed in haematopoietic cells, mast cells, lymphocytes, erythrocytes, fibroblast, Langerhans cells, and macrophages (Surprenant et al., 1996, Science 272:31 18-3122).
  • P2X7R expression has been reported in glial cells, Schwann cells, astrocytes, as well as in neurons (Ferrari et al. (1996) J. Immunol 156:1531-1539; Collo et al. (1997) Neuropharmacology 36: 1277- 1283; Anderson and Nedergaard (2006) Trends Neuroscien 29: 257-262).
  • 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-1 beta (I L-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 a!. (1998) Cell Death Differ. 5:191 -199).
  • 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). Inhibition of P2X7 can improve symptoms in a model of multiple sclerosis (Matute et al. (2007) J Neurosci 27:9525-9533).
  • 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 1 14:386-396).
  • 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.
  • 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 2010/125103), benzamide and heteroarylamide compounds (WO 03/042191 , WO 04/058731 , WO 04/058270, WO 04/099146, WO 05/019182, WO 06/003500, WO 06/003513, WO 06/067444), substituted tyrosine derivatives (WO 00/71529,
  • 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 lndol-3 carboxamide and azaindol-3 carboxamide compounds represented by the general formula (I):
  • Ri is a mono- or bicycioaikylaikyl group
  • R 2 is selected from hydrogen, -OH, -NH2, or halogen (i.e., CI, F, Br or i);
  • R.3, R 4 , R5, Re are at each occurrence independently selected from hydrogen, halogen (i.e. CI, F, Br or I), d-Ce alkyl, hydroxy, C1-C6 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 (whereby x must have a hydrogen substituent if it is carbon).
  • halogen i.e. CI, F, Br or I
  • d-Ce alkyl hydroxy, C1-C6 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 (whereby x must have a hydrogen substituent if it is carbon).
  • R 3 , R 4 , R 5 , R 6 are at each occurrence independently selected from hydrogen, halogen, methyl, hydroxy, methoxy, cyano, or trifluoromethyl.
  • R-i is a group selected from mono- or bicycioaikylaikyl group selected from cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, bicyclo[2.2.2]octan-1-ylmethyl, bicyclo[2.2.2]octan-1-ylethyl, adamantanyl-methyl, or adamantanyl-ethyl thereof are preferred.
  • R 2 is selected from -OH or fluoride.
  • R 3 , R 4 , R5 and R 6 are hydrogen.
  • R 4 and R 6 are H, wherein R3 and R 5 are defined as above, or R4-R6 are H, wherein R 3 is defined as above, wherein C C 6 alkyl is preferably methyl and C1-C6 alkoxy is preferably methoxy. If necessitated by valency, R 3 -R 6 may also be absent.
  • the invention further relates to a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, being:
  • 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, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 3 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 8 F, and 35 CI, respectively.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. 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, oleate, oxalate, palmitate, pamoate, pectinate, per
  • 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 pharmaceutical composition comprising a compound of Formula (I) of the present invention.
  • 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, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.
  • COPD chronic obstructive pulmonary disease
  • 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • a pharmaceutical composition for effecting immunosuppression e.g., in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
  • a pharmaceutical composition for effecting immunosuppression e.g., in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
  • a pharmaceutical composition for effecting immunosuppression e.g., in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
  • 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 neuromfiammation such as, for example traumatic brain injury and encephalitis: centrally-mediated neuropsychlatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, scnizopnrsnia, eaung Qisoraers, sieep aisoraers ano cognition aisoraers, epiiepsy 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.
  • neurodegenerative diseases and disorders including, for example, Parkinson's
  • 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 particulary 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., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999.
  • the 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.
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystailine cellulose, calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc, silica
  • disintegrants e.g., potato starch, sodium starch glycolate
  • wetting agents e.g., sodium lauryl sulphate
  • the pharmaceutical composition can be administered with a physiologically acceptable carrier to a patient, as described herein.
  • 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 administered.
  • 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.
  • the composition if desired, 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.
  • composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • 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 presentation from a pressurised pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • 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 ciLj ⁇ UULi UUi i Ur. VV Mcirfci ⁇ ⁇ ⁇ ', ⁇ UUTilpU iLiUii Uai i cUSU iiivJiUU ⁇ ci owiUiJiiiZ.ii iy 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 iyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • 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. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • 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, benoriiate, choline magnesium salicylate, diflunisal, urgencylamine, methyl salicylate, magnesium salicylate, salicyl salicylate (salsalatee), diclofenac, aceclofenac
  • 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-hvdroxv-a-i2-methvlDroDvlV3-r4-ri2-methvl-4-auinolinvnmethoxvlDhenvll-2- oxo-1 -pyrrolidineacetamide, 2(S),3(S)-Piperidinedicarboxamide, N3-hydroxy-1 - ⁇
  • TACE proTNFalpha convertase enzyme
  • 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-methyipropyi)-2-(methyisulfonyl)hydrazide, (2R,3S,5E), 2-
  • Piperidinecarboxamide N,5-dihydroxy-1 -[[4-(1 - naphthalenylmethoxy)phenyl]sulfonyl]-, (2R.5R), Pentanamide, 3- (formylhydroxyamino)-4-methyl-2-(2-methylpropyl)-N-[(1 S,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], Benzamide, N-[(
  • TACE inhibitors are described in WO 99/18074, WO 99/65867, U.S. Pat. No. 6,225,31 1 , WO 00/00465, WO 00/09485, WO 98/38179, WO 02/18326, WO 02/096426, WO 03/079986, WO 03/055856, WO 03/053941 , WO 03/040103, WO 03/031431 , WO 03/024899, WO 03/016248, WO 04/096206, WO 04/033632, WO 04/108086, WO 04/043349, WO 04/032846, WO 04/012663, WO 04/006925, WO 07/016597.
  • 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, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone.
  • a corticosteroid such as budesonide, corticosterone, Cortisol, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone.
  • a compound of Formula (I) of the present invention can further be administered in combination with a receptor agonist such as formoterol, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, bambuterol, clenbuterol.
  • a 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 administered in combination with an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, am!triptyl!ne, citaiopram, duloxetine, mirtazapine, nortriptyline, imipramine, lithium.
  • an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, am!triptyl!ne, citaiopram, duloxetine, mirtazapine, nortriptyline, imipramine, lithium.
  • a compound of Formula (I) of the present invention can further be administered in combination with 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.
  • an antipsychotic drug such as chlorpromazine, fluphenazine, perphenazine, prochlorperazine,
  • 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 ; fenieuton; tepoxalin; nicaraven; VIA-2291 ; etalocib; ketoprofen, Abt-79175; Abt- 85761 ; 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;
  • 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 receptor antagonists for leukotrienes LTB4, LTC4, LTD4, and LTE for example, phenothiazin-3-ones such as L-651 ,392; amidino compounds such as C
  • a compound of Formula (I) of the present invention can also be administered in combination with a PDE4 inhibitor includina inhibitors of the isoform PDE4D.
  • a compound of Formula (I) of the present invention can further be administered in combination with with a gastroprotective H 2 receptor antagonist.
  • 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.
  • an a1 - and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agent including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydroch
  • a compound of Formula (I) of the present invention can be administered in combination with anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine
  • anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine
  • the present invention still further relates to the combination of a compound of the invention together with a ⁇ - to 4 -adrenoceptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline and aminophylline; sodium cromoglycate; or muscar
  • 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 I
  • 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, fluniso!ide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone r ⁇ .
  • 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-B-i- and B 2 -receptor antagonists; j) anti-gout agents, e.g., colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I) uricosuric agents, e.
  • g., probenecid, sulfinpyrazone, and benzbromarone (m) growth hormone secretagogues; (n) transforming growth factor (TGFP); (o) platelet- derived growth factor (PDGF); (p) fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (q) granulocyte macrophage colony stimulating factor (GM-CSF); (r) capsaicin cream; (s) Tachykinin NKi and NK 3 receptor antagonists such as NKP-608C; SB-233412 (talnetant); and D-4418; and (t) elastase inhibitors such as UT-77 and ZD-0892.
  • TGFP transforming growth factor
  • PDGF platelet- derived growth factor
  • bFGF fibroblast growth factor
  • bFGF basic fibroblast growth factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream (s) Tachy
  • 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 (MMP-1 ), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1 1 ).
  • 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.
  • antiviral agents such as Viracept, AZT, aciclovir and famciclovir
  • antisepsis compounds such as Valant.
  • a compound of Formula (!) 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-
  • a compound of Formula (I) of the present invention can be administered in combination with CNS agents such as antidepressants (such as sertraline), antiparkinsonian 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 synthase), and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
  • CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitor
  • 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.
  • Figure 1 Analgesic and Anti-inflammatory Effects in a model of pain and inflammation ( * ** p ⁇ 0.001 ).
  • Inhibition of P2X7R activity by the compounds of the present invention is assessed by measuring calcium influx in Hek293 cells (ECACC No. 85120602) which have been stably transfected with a cDNA for the human P2X7R.
  • 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 BC01 1913) 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 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 750 pg/ml Geneticin G418 (GibcoBRL/lnvitrogen).
  • the cells were incubated in 50 ⁇ of assay buffer containing 100 ⁇ Fluo-4 AM fluorescent dye per well for 1 hour at room temperature.
  • the assay buffer containing the Fluo-4 AM fluorescent dye was then removed, the cells were washed once with assay buffer (without Fluo-4 AM), 100 ⁇ of assay buffer (without Fluo-4 AM) containing the test compounds was then added per well.
  • the analgesic and anti-inflammatory therapeutic benefits of the compounds of the present invention were assessed using a carrageenan-induced paw edema model of inflammation.
  • the development of pain in this model is a biphasic phenomenon (Beena et al. (2008) Indian J Physiol Pharmacol 52: 178-182).
  • the early phase is caused by a release of histamine and serotonin causing vasodialation and increased permeability of capillaries resulting in an increase in vascular permeability.
  • the late phase is characterised by infiltrate of leucocytes due to the release of bradykinin, prostaglandins, protease and lysosomal enzymes which regulate the process of adhesion of molecules (Higgs et al.
  • Carrageenan-induced paw edema model is one of the most reliable method to screen anti-inflammatory agents and analgesics.
  • Example 7 The compound disclosed in Example 7 was prepared in 5% dimethyl sulfoxide (DMSO), 25% triethylene glycol (TEG), and 70% (2-hydroxypropy!-beta-cyc!odextrin ( ⁇ - ⁇ -CD) and injected intraperitonea!ly 1 .5 hours after carrageenan challenge. Control treated animals were injected intraperitoneally with vehicle (5% DMSO, 25% TEG, 70% ⁇ - ⁇ -CD).
  • DMSO dimethyl sulfoxide
  • TEG triethylene glycol
  • ⁇ - ⁇ -CD 2-hydroxypropy!-beta-cyc!odextrin
  • Mean Difference of PWL PWL for Left hind paw (Contralateral) - PWL for Right Hind paw (Ipsilateral). A decrease in mean difference of withdrawal latency in compound treated animals as compared to control vehicle treated animals is considered as an analgesic effect of the treatment and calculated as percentage inhibition.
  • Results are illustrated in Figure 1 .
  • a statistically significant (p ⁇ 0.001 ) reduction of ⁇ 42% in paw withdrawal latency in response to the heat stimulus was observed after administration of 50 mg/kg of the compound when compared to vehicle treated animals. This result supports the analgesic use of the compounds of the present invention for the treatment of pain.
  • a statistically significant (p ⁇ 0.001 ) reduction of 47% in carrageenan induced paw edema was observed after administration of 50 mg/kg of the compound when compared to vehicle treated animals. This result supports the anti-inflammatory use of the compounds of the present invention for the treatment of inflammatory diseases.

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Abstract

The present application is directed to novel P2X7R antagonists that are lndol-3 carboxamide and azaindol-3 carboxamide compounds, pharmaceutical compositions comprising the same and their use for the prophylactic or therapeutic treatment of diseases mediated by P2X7R activity.

Description

NOVEL P2X7R ANTAGONISTS AND THEIR USE
The present application relates to novel P2X7R antagonists that are indol-3 carboxamide and azaindol-3 carboxamide compounds, pharmaceutical compositions comprising these compounds and to their use in the prophylactic and therapeutic treatment of diseases and disorders mediated by P2X7R.
BACKGROUND
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. Scand. 34:368-384; Steinberg and Silverstein (1987) J. Biol. Chem. 262:31 18-3122; Gordon (1986) Biochem. J. 233:309-319). 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 Surprenant (2000) Annual Rev. Pharmacology Toxicology 40:563-580). P2X7R requires levels of ATP in excess of 1 mM to achieve activation, whereas other P2X receptors activate at ATP concentrations of -=d 00 μΜ (Steinberg et al. (1987) J. Biol. Chem. 262:8884-8888; Greenberg et al. (1988) J. Biol. Chem. 263:10337-10343). While all P2X receptors demonstrate non-selective channel-like properties following ligation, 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 272:31 18-3122). In the central nervous system, P2X7R expression has been reported in glial cells, Schwann cells, astrocytes, as well as in neurons (Ferrari et al. (1996) J. Immunol 156:1531-1539; Collo et al. (1997) Neuropharmacology 36: 1277- 1283; Anderson and Nedergaard (2006) Trends Neuroscien 29: 257-262).
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-1 beta (I L-1 β) 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 a!. (1998) Cell Death Differ. 5:191 -199).
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). Inhibition of 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 1 14:386-396). 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. (2007) Eur J Neurosci 25:2741-2754); inflammatory bowel diseases (Cesaro et al. (2010) Am J Physiol-Gastr L 299:G32-42); cancer (Sun (2010) Mol Neurobiol 41 :351 -355; Di Virgilio et al. (2009) Purinergic Signal 5:251 - 256); and graft-versus-host disease (Wilhelm et al. (2010) Nat Med 16:1434-1438).
Compounds which modulate P2X7R have been reported. For example, Brilliant Blue (Jiang et al., Mol. Phamacol. 58 (2000), 82-88), the isoquinolines 1-[N,O-Bis(5- isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine and N-[1 -[N-methyl-p-(5 isoquinolinesulfonyl) benzyl]-2-(4-phenylpiperazine)ethyl]-5-isoquinolinesulfonamide (Humphreys et al., Mol. Pharmacol., 54 (1998), 22-32), 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 2010/125103), benzamide and heteroarylamide compounds (WO 03/042191 , WO 04/058731 , WO 04/058270, WO 04/099146, WO 05/019182, WO 06/003500, WO 06/003513, WO 06/067444), substituted tyrosine derivatives (WO 00/71529, WO 03/047515, WO 03/059353), imidazole compounds (WO 05/014555), amino- tetrazoles compounds (WO 05/1 1 1003), cyanoamidine (WO 06/017406), bicycloheteroaryl derivatives (WO 05/009968, WO 06/102588, WO 06/102610, WO 07/028022, WO 07/109154, WO 07/109160, WO 07/109172, WO 07/109182, WO 07/109192, WO 07/109201 ), acylhydrazide (WO 06/1 10516), and other examples (WO 99/29686, WO 04/106305, WO 05/039590, WO 06/080884, WO 06/086229, WO 06/136004, WO 07/025366, WO 07/056046, WO 07/056091 , WO 07/141267, WO 07/141269, WO 08/003697; WO 2008/138876; WO 2008/125600; WO 2008/124153; WO 2008/1 19825; WO 2008/013494; WO 2009/0701 16; WO 2009/053459 WO 2009/077559; WO 2009/132000; WO 2009/1 18175; WO 2010/1 18921 ) are antagonists of P2X7R while Oxidized ATP (oATP) 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.
Consequently, there is strong evidence that compounds acting on P2X7R can be used in the treatment of pain, inflammatory processes, and 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.
Thus, 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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel P2X7R antagonists that are lndol-3 carboxamide and azaindol-3 carboxamide compounds represented by the general formula (I):
Figure imgf000006_0001
wherein,
Ri is a mono- or bicycioaikylaikyl group;
R2 is selected from hydrogen, -OH, -NH2, or halogen (i.e., CI, F, Br or i);
R.3, R4, R5, Re are at each occurrence independently selected from hydrogen, halogen (i.e. CI, F, Br or I), d-Ce alkyl, hydroxy, C1-C6 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 (whereby x must have a hydrogen substituent if it is carbon).
Compounds of Formula (I), wherein R3, R4, R5, R6 are at each occurrence independently selected from hydrogen, halogen, methyl, hydroxy, methoxy, cyano, or trifluoromethyl.
Compounds of Formula (I), wherein R-i is a group selected from mono- or bicycioaikylaikyl group selected from cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, bicyclo[2.2.2]octan-1-ylmethyl, bicyclo[2.2.2]octan-1-ylethyl, adamantanyl-methyl, or adamantanyl-ethyl thereof are preferred.
Preferred are also compounds, wherein R2 is selected from -OH or fluoride.
Furthermore, it is preferred that at least two of R3, R4, R5 and R6 are hydrogen. In further preferred embodiments, R4 and R6 are H, wherein R3 and R5 are defined as above, or R4-R6 are H, wherein R3 is defined as above, wherein C C6 alkyl is preferably methyl and C1-C6 alkoxy is preferably methoxy. If necessitated by valency, R3-R6 may also be absent.
Additionally, it is preferred that a, b, c, and d are CH or one of a, b, c and d is N. Preferred are also compounds wherein n=2 and x is N.
Examples of novel lndol-3 carboxamide and azaindol-3 carboxamide compounds are disclosed in examples 1-74.
The invention further relates to a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, being:
- 4-chloro-N-(cyclopentylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cyclopentylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cyclohexylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cyclohexylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide - N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-chloro-1 -((3-hydroxyoxetan-3-yI)methyl)-1 H- indole-3-carboxamide
- N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-bromo-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(adamantane-1 yl-methyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-Bromo-N-(adamantane-1 yl-methyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(2-cyclopentylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cyclopentylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptylethy!)-1 -((3-hydroxyoxetan-3-yI)methyI)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxannide
- N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-chloro-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- N-(2-(bicyclo[2.2.2]octan-1-yl)ethyl)-4-bromo-1-((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(adamantane-1 yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyI)-1 H-indole-3- carboxamide
- 4-bromo-N-(adamantane-1yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyI)-4-methyl-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-4-hydroxy-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide - N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-4-methoxy-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-cyano-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cyclopentylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cyclopentylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyI)-1 H-indole-3- carboxamide
- 4-chloro-N-(cyclohexylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cyclohexylmethyl)-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3-
- N-((bicyclo[2.2.2]octan-1 -yl)methy!)-4-chloro-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- N-((bicycio[2.2.2]octan-1 -yl)methyi)-4-bromo-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(adamantane-1yl-methyl)-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(adamantane-1yl-methyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide - 4-bromo-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- N-(2-(bicyclo[2.2.2]octan-1-yl)ethyl)-4-chloro-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- N-(2-(bicyclo[2.2.2]octan-1-yl)ethyl)-4-bromo-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(adamantane-1 yl-ethyl)-1 -{2-(3-hydroxyoxetan-3-yl)ethyI)-1 H-indole-3- carboxamide
- 4-bromo-N-(adamantane-1 yl-ethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-4-methyl-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-4-hydroxy-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxarnide
- N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-4-methoxy-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- 4-cyano-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- 4-cyano-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3-carboxamide
- 4-bromo-N-(cycloheptyImethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3-carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3-carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -((oxetari-3-yl)methyl)-1 H-indole-3-carboxamide - 1 -((3-aminooxetan-3-yl)methyl -4-chloro-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1-((3-aminooxetan-3-yl)methyl -4-bromo-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1-((3-aminooxetan-3-yl)methyl -4-chloro-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 1 -((3-aminooxetan-3-yl)methyl -4-bromo-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl) 1 -((3-f luorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethy ■1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptylethyi; ■1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl -1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl) 1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-carboxamide
- 4-bromo-N-(cycloheptylmethyr•1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-carboxamide
- 4-chloro-N-(2-cycloheptylethyl) 1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-carboxamide
- 4-bromo-N-(2-cycloheptylethyl ■1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-carboxamide
- 4-chloro-N-(2-cycloheptylethyl) 1 -(2-(oxetan-3-yl)ethyl)-1 H-indoie-3-carboxamide
- 4-bromo-N-(2-cycloheptylethyl ■1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-carboxamide
- 1 -(2-(3-aminooxetan-3-yl)ethyl -4-chloro-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1-(2-(3-aminooxetan-3-yl)ethyl -4-bromo-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1-(2-(3-aminooxetan-3-yl)ethyi -4-chloro-N-(2-cycloheptylethyl)-1 H-iridole-3- carboxamide
- 1-(2-(3-aminooxetan-3-yl)ethyl -4-bromo-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl) 1 -(2-(3-fluorooxetan-3-yl)ethyi)-1 H-indole-3- carboxamide - 4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1-((3-hydroxyoxetan-3-yl)methyl)-1 H-pyrrolo[2,3- b]pyridine-3-carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-pyrrolo[2,3- b]pyridine-3-carboxamide
- 6-bromo-4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-bromo-6-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indazole-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indazole-3- carboxarnlde
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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 3C, 14C, 15N, 180, 170, 31P, 32P, 35S, 8F, and 35CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, 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.
Examples of further pharmaceutically acceptable, 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. Other pharmaceutically acceptable 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, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulphate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative 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.
In a further embodiment the present application is directed to a pharmaceutical 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.
As defined herein, 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 of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, neurotrauma, spinal cord injury, neuro- degenerative disorders, Alzheimer's disease, Parkinson's disease, glaucoma, age- related macular degeneration, uveitis, neuropathic pain, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmune disorders, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, graft vs. host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, or muscle degeneration, in a mammal, including a human, 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, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.
In another aspect, 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
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.
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 neuromfiammation such as, for example traumatic brain injury and encephalitis: centrally-mediated neuropsychlatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, scnizopnrsnia, eaung Qisoraers, sieep aisoraers ano cognition aisoraers, epiiepsy 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.
In particular embodiment the pharmaceutical composition according to the present invention may be used for the treatment of affective disorders. In a preferred embodiment the affective disorder is selected from depression, anxiety, bipolar disorder and schizophrenia.
In an alternative embodiment 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. Furthermore, the pharmaceutical composition according to the present invention may particulary be useful for the treatment of pain, inflammatory processes, and degenerative conditions. In a more preferred embodiment the inflammatory process is selected from rheumatoid arthritis, osteoporosis and chronic obstructive pulmonary disease.
Moreover, the pharmaceutical 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., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999. Thus, the 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.
For oral administration, the pharmaceutical composition of a compound of Formula (I)
(Jdii ίαΚΘ LMB ίϋΓΓίϊ ϋί , ϊϋΓ cXciu ipiS, iak)iSi Ui CapSUicS i c cu cU Dy ΟΟΠν'ΘΠϋΟΠαί means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystailine 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). The pharmaceutical composition can be administered with a physiologically acceptable carrier to a patient, as described herein. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. 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. The composition, if desired, 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 suppository, with traditional binders and carriers such as triglycerides. 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).
For administration by inhalation, a compound of Formula (I) of the present invention is conveniently delivered in the form of an aerosol spray presentation from a pressurised pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurised aerosol, 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. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic ciLj ϋ UULi UUi i Ur. VV Mcirfci ίΐϋ ϋΰ ϋΓγ', ΙΓΙϋ UUTilpU iLiUii Uai i cUSU iiivJiUU^ ci owiUiJiiiZ.ii iy agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry iyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, 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. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water- miscible ointment base. Alternatively, 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.
The pharmaceutical 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. These 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, benoriiate, choline magnesium salicylate, diflunisal, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate (salsalatee), diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, suprofen, mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, nimesulide, licofelone, paracetamol.
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.
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-hvdroxv-a-i2-methvlDroDvlV3-r4-ri2-methvl-4-auinolinvnmethoxvlDhenvll-2- oxo-1 -pyrrolidineacetamide, 2(S),3(S)-Piperidinedicarboxamide, N3-hydroxy-1 - ^
rTlSiriyi-i - i- ^- ^ -iTiSiriyi-^-qUiiiUiiri 'i iTicinuxyj rifcjriyij, -
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-methyipropyi)-2-(methyisulfonyl)hydrazide, (2R,3S,5E), 2-
Piperidinecarboxamide, N,5-dihydroxy-1 -[[4-(1 - naphthalenylmethoxy)phenyl]sulfonyl]-, (2R.5R), Pentanamide, 3- (formylhydroxyamino)-4-methyl-2-(2-methylpropyl)-N-[(1 S,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], Benzamide, 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]. Other examples of TACE inhibitors are described in WO 99/18074, WO 99/65867, U.S. Pat. No. 6,225,31 1 , WO 00/00465, WO 00/09485, WO 98/38179, WO 02/18326, WO 02/096426, WO 03/079986, WO 03/055856, WO 03/053941 , WO 03/040103, WO 03/031431 , WO 03/024899, WO 03/016248, WO 04/096206, WO 04/033632, WO 04/108086, WO 04/043349, WO 04/032846, WO 04/012663, WO 04/006925, WO 07/016597.
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, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone.
A compound of Formula (I) of the present invention can further be administered in combination with a
Figure imgf000022_0001
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 administered in combination with an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, am!triptyl!ne, citaiopram, duloxetine, mirtazapine, nortriptyline, imipramine, lithium.
A compound of Formula (I) of the present invention can further be administered in combination with 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 ; fenieuton; tepoxalin; nicaraven; VIA-2291 ; etalocib; ketoprofen, Abt-79175; Abt- 85761 ; 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 includina inhibitors of the isoform PDE4D.
/— v uui i i uunu v_/i wi i i iu ia \ ) ui pi c ci ii i vci luui au αι υ Uc aui ι i n i i ici i l l combination with a antihlstaminic Hi receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
A compound of Formula (I) of the present invention can further be administered in combination with with a gastroprotective H2 receptor antagonist.
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; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine The present invention still further relates to the combination of a compound of the invention together with a βι- to 4-adrenoceptor agonists including 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.
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.
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, fluniso!ide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone r ί.
Li ί vju Lt2.
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-B-i- and B2-receptor antagonists; j) anti-gout agents, e.g., colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I) uricosuric agents, e. g., probenecid, sulfinpyrazone, and benzbromarone; (m) growth hormone secretagogues; (n) transforming growth factor (TGFP); (o) platelet- derived growth factor (PDGF); (p) fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (q) granulocyte macrophage colony stimulating factor (GM-CSF); (r) capsaicin cream; (s) Tachykinin NKi and NK3 receptor antagonists such as NKP-608C; SB-233412 (talnetant); and D-4418; and (t) 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 (MMP-1 ), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1 1 ).
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.
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 (!) 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), antiparkinsonian 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 synthase), and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
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.
DESCRIPTION OF THE FIGURES:
Figure 1 . Analgesic and Anti-inflammatory Effects in a model of pain and inflammation (*** p<0.001 ).
EXAMPLES
Example 1
General Synthetic Procedure I
Figure imgf000027_0001
General Procedure for the preparation ofXIntOI
To a solution of an indole or azaindole derivative X in acetic acid was added sodium cyano borohydride (NaBH3CN) at 0°C and the solution was stirred at room temperature for 16 hours. The excess of acetic acid was distilled off and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture of desired product and N-acetyl compound in almost 1 :1 ratio. This material was subjected to hydrolysis by treating it with 6N HCI at reflux temperature for 12 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate to pH=8 and extracted with ethyl acetate. 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. General Procedure for the preparation ofXYInt02:
A solution of XIntOI and an oxetane aldehyde derivative Y in methanol was stirred for 3 hours at room temperature. Sodium cyano borohydride was added at 0°C and the mixture was stirred for another 3 hours at room temperature. The solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by column chromatography with 3% ethyl acetate / hexane yielded XYInt02.
General Procedure for the preparation ofXYInt03:
To a solution of XYInt02 in 1 ,4-dioxane was added 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone (DDQ) at room temperature and the solution was allowed to stir for 1 hour. The solvent was removed under vacuum and the residue was purified by column chromatography with 4% ethyl acetate / hexane yielding XYInt03.
General Procedure for the preparation ofXYInt04:
To a solution of XYInt03 in N , N~dimethylformamide (DMF) at 0°C was added iriflouro acetic anhydride drop-wise and the solution was allowed to stir for 4 hours. The reaction mixture was diluted with a solution of saturated sodium bicarbonate and extracted with ether. The combined organic layer was washed with water, with brine solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was triturated with pentane to yield XYInt04.
General Procedure for the preparation ofXYZ:
To a solution of XYInt04 in tetrahydrofuran (THF) at -78°C lithium bis(trimethylsilyl)amide (LiHMDS) was added slowly and the solution was allowed to stir for 20 minutes, followed by the addition of a mono- or bicycloalkylalkyl amine derivative Z at -78°C. The reaction mixture was warmed to room temperature and then refluxed for 16 hours at 75°C. The reaction was quenched with ice water and extracted with ethyl acetate. The combined organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by flash column chromatography on silica gel with 2% methanol/chloroform to yield XYZ.
Example 2
Figure imgf000029_0001
General Procedure for the preparation ofXYIntOI
To a solution of an indole or azaindole derivative X in DMF was added the activated (L=tosylate, mesylate, bromide, chloride or iodide) oxetane derivative Y and the mixture was heated to 60°C. After completion of the reaction water was added and the layers were extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Purification by column chromatography with 4% ethyl acetate / hexane yielded XYlntOL
General Procedure for the preparation ofXYInt02:
To a solution of XYlntOI in Ν,Ν-dimethylformamide (DMF) at 0°C was added triflouro acetic anhydride drop-wise and the solution was allowed to stir for 4 hours. The reaction mixture was diluted with a solution of saturated sodium bicarbonate and extracted with ether. The combined organic layer was washed with water, with brine solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was triturated with pentane to yield XYInt02.
General Procedure for the preparation ofXYZ:
To a solution of XYInt02 in tetrahydrofuran (THF) at -78°C LiHMDS was added slowly and the solution was allowed to stir for 20 minutes, followed by the addition of a mono- or bicycloalkylalkyl amine derivative Z at -78°C. The reaction mixture was warmed to room temperature and then refluxed for 16 hours at 75°C. The reaction was quenched with ice water and extracted with ethyl acetate. The combined organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by flash column chromatography on silica gel with 2% methanol/chloroform to yield XYZ.
Example 3
4-chloro-N-(cyclopentyImethyl)-1 -((3-hydroxyoxetan-3-yl)met yl)-1 H-indole-3- carboxamide
Figure imgf000030_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclopentylmethylamine. Formula: C 9H23CIN203; Molecular Weight: 362.14; Mass/charge ratio: 362.14 (100.0%), 364.14 (32.7%), 363.14 (21 .4%), 365.14 (6.7%), 364.15 (2.1 %); Elemental analysis: C, 62.89; H, 6.39; CI, 9.77; N, 7.72; O, 13.23. Example 4
4-bromo-N-(cyclopentylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000031_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclopentylmethylamine. Formula: Ci9H23BrN203; Molecular Weight: 407.3; Mass/charge ratio: 406.09 (100.0%), 408.09 (98.0%), 407.09 (21 .4%), 409.09 (20.4%), 410.09 (2.7%), 408.10 (2.1 %); Elemental analysis: C, 56.03; H, 5.69; Br, 19.62; N, 6.88; O, 1 1 .78.
4-chloro-N-(cycIohexyImethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000031_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclohexylmethylamine. Formula: C20H25CIN2O3; Molecular Weight: 376.88; Mass/charge ratio: m/e: 376.16 (100.0%), 378.15 (32.0%), 377.16 (22.0%), 379.16 (7.2%), 378.16 (3.0%); Elemental analysis: C, 63.74; H, 6.69; CI, 9.41 ; N, 7.43; O, 12.74. Example 6
4-bromo-N-(cyclohexylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000032_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclohexylmethylamine. Formula: C2oH25BrN203; Molecular Weight: 421 .33; Mass/charge ratio: 420.10 (100.0%), 422.10 (97.3%), 421 .1 1 (22.0%), 423.1 1 (21 .7%), 422.1 1 (3.1 %), 424.1 1 (2.9%); Elemental analysis: C, 57.01 ; H, 5.98; Br, 18.96; N, 6.65; O, 1 1 .39.
Example 7
4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yi)methyl)-1 H-indole-3- carboxamide
Figure imgf000032_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C21 H27CIN2O3; Molecular Weight: 390.9; Mass/charge ratio: 390.17 (100.0%), 392.17 (32.1 %), 391 .17 (23.5%), 393.17 (7.7%), 392.18 (3.2%), 394.17 (1 .0%); Elemental analysis: C, 64.52; H, 6.96; CI, 9.07; N, 7.17; O, 12.28. Example 8
4-bromo-N-(cycloheptyImethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000033_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C2i H27BrN203; Molecular Weight: 435.35; Mass/charge ratio: 434.12 (100.0%), 436.12 (98.1 %), 435.12 (23.6%), 437.12 (23.2%), 436.13 (2.6%), 438.13 (2.5%); Elemental analysis: C, 57.94; H, 6.25; Br, 18.35; N, 6,43; O, 1 1 .03
Example 9
N-((bicyclo[2.2.2]octan-1 -yI)methyl)-4-chloro-1 -((3-hydroxyoxetan-3-yl)methyl)- 1 H-indole-3-carboxamide
Figure imgf000033_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is (bicyclo[2.2.2]octan-1 - yl)methylamine. Formula: C-22H27CIN2O3; Molecular Weight: 402.91 ; Mass/charge ratio: 402.17 (100.0%), 404.17 (32.1 %), 403.17 (24.5%), 405.17 (8.0%), 404.18 (3.4%), 406.17 (1 .1 %); Elemental analysis: C, 65.58; H, 6.75; CI, 8.80; N, 6.95; O, 1 1 .91 . Example 10
N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-bromo-1 -((3-hydroxyoxetan-3-yl)methyI)- 1 H-indole-3-carboxamide
Figure imgf000034_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is (bicyclo[2.2.2]octan-1- yl)methylamine. Formula: C22H27BrN203; Molecular Weight: 447.37; Mass/charge ratio: 446.12 (100.0%), 448.12 (98.1 %), 447.12 (24.6%), 449.12 (24.3%), 448.13 (2.8%), 450.13 (2.8%); Elemental analysis: C, 59.06; H, 6.08; Br, 17.86; N, 6.26; O, 10.73.
Exampie 11
4-ch!oro-N-(adamantane-1 y!-methy!)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
Figure imgf000034_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is adamantane-1yl-methylamine. Formula: C24H29CIN2O3; Molecular Weight: 428.95; 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, 1 1 .19. Example 12
4-Bromo-N-(adamantane-1 yl-methyl)-1 -((3- ydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
Figure imgf000035_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is adamantane-1yl-methylamine. Formula: C24H29BrN203; Molecular Weight: 473.4; 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.
Example 13
4-chloro-N-(2-cyclopentylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000035_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclopentylethylamine. Formula: C20H25CIN2O3; Molecular Weight: 376.88; Mass/charge ratio: 376.16 (100.0%), 378.15 (32.0%), 377.16 (22.0%), 379.16 (7.2%), 378.16 (3.0%); Elemental analysis: C, 63.74; H, 6.69; CI, 9.41 ; N, 7.43; O, 12.74. Example 14
4-bromo-N-(2-cyclopentylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000036_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclopentylethylamine. Formula: C2oH25BrN203; Molecular Weight: 421 .33; Mass/charge ratio: 420.10 (100.0%), 422.10 (97.3%), 421 .1 1 (22.0%), 423.1 1 (21.7%), 422.1 1 (3.1 %), 424.1 1 (2.9%); Elemental analysis: C, 57.01 ; H, 5.98; Br, 18.96; N, 6.65; O, 1 1 .39.
Example 15
4-chloro-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indol carboxamide
Figure imgf000036_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclohexylethylamine. Formula: C21 H27CIN2O3; Molecular Weight 390.9; Mass/charge ratio: 390.17 (100.0%), 392.17 (32.1 %), 391.17 (23.5%), 393.17 (7.7%), 392.18 (3.2%), 394.17 (1 .0%); Elemental analysis: C, 64.52; H, 6.96; CI, 9.07; N, 7.17; O, 12.28. Example 16
4-bromo-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000037_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cyclohexylethylamine. Formula: C2iH27BrN203; Molecular Weight: 435.35; Mass/charge ratio: 434.12 (100.0%), 436.12 (98.1 %), 435.12 (23.6%), 437.12 (23.2%), 436.13 (2.6%), 438.13 (2.5%); Elemental analysis: C, 57.94; H, 6.25; Br, 18.35; N, 6.43; O, 1 1 .03.
4-chloro-N-(2-cycloheptylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- carboxamide
Figure imgf000037_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H29CIN2O3; Molecular Weight: 404.93; Mass/charge ratio: 404.19 (100.0%), 406.18 (32.0%), 405.19 (24.2%), 407.19 (7.9%), 406.19 (3.5%), 408.19 (1 .1 %); Elemental analysis: C, 65.25; H, 7.22; CI, 8.76; N, 6.92; O, 1 1 .85. Example 18
4-bromo-N-(2-cycloheptylethyl)- -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3-
Figure imgf000038_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H29Br 203; Molecular Weight: 449.38; Mass/charge ratio: 448.14 (100.0%), 450.13 (97.3%), 449.14 (24.2%), 451.14 (23.8%), 450.14 (3.5%), 452.14 (3.3%); Elemental analysis: C, 58.80; H, 6.50; Br, 17.78; N, 6.23; O, 10.68.
Example 19
N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-chloro-1 -((3-hydroxyoxetan-3-yl)methyl)-
1 H-indole-3-carhovamiHt»
Figure imgf000038_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chIoro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is (bicycio[2.2.2]octan-1- yl)ethylamine. Formula: C-23H29CIN2O3; Molecular Weight: 416.94; Mass/charge ratio: 416.19 (100.0%), 418.18 (32.0%), 417.19 (25.3%), 419.19 (8.3%), 418.19 (3.8%), 420.19 (1 .2%); Elemental analysis: C, 66.26; H, 7.01 ; CI, 8.50; N, 6.72; O, 1 1 .51 .
Example 20
N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-bromo-1 -((3-hydroxyoxetan-3-yl)methyl)- 1 H-indole-3-carboxamide
Figure imgf000039_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is (bicyclo[2.2.2]octan-1 - yl)ethylamine. Formula: C23H2gBrN203; Molecular Weight: 461 .39; Mass/charge ratio: 460.14 (100.0%), 462.13 (97.3%), 461 .14 (25.3%), 463.14 (24.8%), 462.14 (3.8%), 464.14 (3.6%); Elemental analysis: C, 59.87; H, 6.34; Br, 17.32; N, 6.07; 0, 10.40.
[Example 21
4-chloro-N-(adamantane-1yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
Figure imgf000039_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is adamantane-1 yl-ethylamine. Formula: C25H31CIN2O3; Molecular Weight: 442.98; 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.
Example 22
4-bromo-N-(adamantane-1yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
Figure imgf000040_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is adamantane-1 yl-ethylamine. Formula: C25H3iBrN203; Molecular Weight: 487.43; 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.
Example 23
N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-4-methyI-1 H-indole-3- carboxamide
Figure imgf000041_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-methyl indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C22H30N2O3; Molecular Weight: 370.49; Mass/charge ratio: 370.23 (100.0%), 371 .23 (24.3%), 372.23 (3.5%); Elemental analysis: C, 71 .32; H, 8.16; N, 7.56; O, 12.96.
Example 24
N-(cycloheptyImeihyl)-4-hydroxy-1 -((3-hydroxyoxetan-3-yi)ineiriyi)-1 H-indoie-3- carboxamide
Figure imgf000041_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-hydroxy indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C21 H28N2O4; Molecular Weight: 372.46; Mass/charge ratio: 372.20 (100,0%), 373.21 (23.2%), 374.21 (3.6%); Elemental analysis: C, 67.72; H, 7.58; N, 7.52; O, 17.18.
Example 25
N-(cycloheptylmethyl)-1 -{(3-hydroxyoxetan-3-yI)methyI)-4-methoxy-1 H-indole-3- carboxamide
Figure imgf000042_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4- methoxy indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycioheptylmethylamine. Formula: C22H3oN204; Molecular Weight: 386.48; Mass/charge ratio: 386.22 (100.0%), 387.22 (24.7%), 388.23 (2.8%), 388.22 (1 .0%); Elemental analysis: C, 68.37; H, 7.82; N, 7.25; O, 16.56.
Example 26
N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
Figure imgf000042_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4- trifluoromethyl indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C-22H27F3N2O3; Molecular Weight: 424.46; Mass/charge ratio: 424.20 (100.0%), 425.20 (24.2%), 426.20 (3.5%); Elemental analysis: C, 62.25; H, 6.41 ; F, 13.43; N, 6.60; O, 1 1 .31 .
Example 27
4 yano-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000043_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-cyano indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C22H27N3O3; Molecular Weight: 381 .47; Mass/charge ratio: 381 .21 (100.0%), 382.21 (24.2%), 383.21 (3.7%), 382.20 (1 .1 %); Elemental analysis: C, 69.27; H, 7.13; N, 1 1 .02; O, 12.58.
Example 28
4-chloro-N-(cyclopentylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000043_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclopentylmethylamine. Formula: C20H25CIN2O3; Molecular Weight: 376.88; Mass/charge ratio: 376.16 (100.0%), 378.15 (32.0%), 377.16 (22.0%), 379.16 (7.2%), 378.16 (3.0%); Elemental analysis: C, 63.74; H, 6.69; CI, 9.41 ; N, 7.43; O, 12.74.
Example 29
4-bromo-N-(cyclopentylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000044_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclopentylmethylamine. Formula: C2oH25BrN203; Molecular Weight: 421 .33; Mass/charge ratio: 420.10 (100.0%), 422.10 (97.3%), 421.1 1 (22.0%), 423.1 1 (21 .7%), 422.11 (3.1 %), 424.1 1 (2.9%); Elemental analysis C, 57.01 ; H, 5.98; Br, 18.96; N, 6.65; O, 1 1 .39.
Example 30
4-chloro-N-(cyclohexylmethyl)-1 -(2-(3-hydroxyoxetan-3-yI)ethyl)-1 H-indole-3- carboxamide
Figure imgf000045_0001
Synihesised according to the procedure disclosed in Example 1 where X is 4-chioro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclohexylmethylamine. Formula: C21 H27CIN2O3; Molecular Weight 390.9; Mass/charge ratio: 390.17 (100.0%), 392.17 (32.1 %), 391 .17 (23.5%), 393.17 (7.7%), 392.18 (3.2%), 394.17 (1 .0%); Elemental analysis: C, 64.52; H, 6.96; CI, 9.07; N, 7.17; O, 12.28.
Example 31
4-bromo-N-(cyclohexylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000045_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclohexylmethylamine. Formula: C2i H27Br 203; Molecular Weight: 435.35; Mass/charge ratio: 434.12 (100.0%), 436.12 (98.1 %), 435.12 (23.6%), 437.12 (23.2%), 436.13 (2.6%), 438.13 (2.5%); Elemental analysis: C, 57.94; H, 6.25; Br, 18.35; N, 6.43; O, 1 1 .03.
Example 32
4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yI)ethyI)-1 H-indoIe-3- carboxamide
Figure imgf000046_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H29CIN2O3; Molecular Weight 404.93; Mass/charge ratio: 404.19 (100.0%), 406.18 (32.0%), 405.19 (24.2%), 407.19 (7.9%), 406.19 (3.5%), 408.19 (1.1 %); Elemental analysis: C, 65.25; H, 7.22; CI, 8.76; N, 6.92; O, 1 1.85.
Example 33
4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-lndole-3- carboxamide
Figure imgf000046_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H29BrN203; Molecular Weight: 449.38; Mass/charge ratio: 448.14 (100.0%), 450.13 (97.3%), 449.14 (24.2%), 451 .14 (23.8%), 450.14 (3.5%), 452.14 (3.3%); Elemental analysis: C, 58.80; H, 6.50; Br, 17.78; N, 6.23; O, 10.68.
Example 34
N-((bicyclo[2.2.2]octan-1 -yl)methy[)-4-chloro-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)- 1 H-indole-3-carboxamide
Figure imgf000047_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is (bicyclo[2.2.2]octan-1- yl)methylamine. Formula: C-23H29CIN2O3; Molecular Weight: 416.94; Mass/charge ratio: 416.19 (100.0%), 418.18 (32.0%), 417.19 (25.3%), 419.19 (8.3%), 418.19 (3.8%), 420.19 (1.2%); Elemental analysis: C, 66.26; H, 7.01 ; CI, 8.50; N, 6.72; O, 1 1 .51 .
Example 35
N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-bromo-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)- 1 H-indole-3-carboxamide
Figure imgf000048_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is (bicyclo[2.2.2]octan-1 - yl)methylamine. Formula: C23H29Br 203; Molecular Weight 461.39; Mass/charge ratio: 460.14 (100,0%), 462.13 (97.3%), 461 .14 (25.3%), 463.14 (24.8%), 462.14 (3.8%), 464.14 (3.6%); Elemental analysis: C, 59.87; H, 6.34; Br, 17.32; N, 6.07; O, 10.40.
Example 36
4-chloro-N-(adamantane-1 y!-methy!)-1 -(2-(3-hydroxyoxetan-3-yl)ethyI)-1 H- indole-3-carboxamide
Figure imgf000048_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is adamantane-1yl- methylamine. Formula: C25H31CIN2O3; Molecular Weight: 442.98; 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.
Example 37
4-bromo-N-(adamantane-1yl-methyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
Figure imgf000049_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is. Formula: C25H3iBrN203; Molecular Weight: 487.43; 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.
Example 38
4-chloro-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000050_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chioro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclopentylethylamine. Formula: C21H27CI 2O3; Molecular Weight: 390.9; Mass/charge ratio: 390.17 (100.0%), 392.17 (32.1 %), 391 .17 (23.5%), 393.17 (7.7%), 392.18 (3.2%), 394.17 (1 .0%); Elemental analysis: C, 64.52; H, 6.96; CI, 9.07; N, 7.17; O, 12.28.
Example 39
4-bromo-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000050_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclopentylethylamine. Formula: C2iH27BrN203; Molecular Weight: 435.35; Mass/charge ratio: 434.12 (100.0%), 436.12 (98.1 %), 435.12 (23.6%), 437.12 (23.2%), 436.13 (2.6%), 438.13 (2.5%); Elemental analysis: C, 57.94; H, 6.25; Br, 18.35; N, 6.43; O, 1 1 .03.
Example 40
4-chloro-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000051_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclohexylethylamine. Formula: C22H29CIN2O3; Molecular Weight: 404.93; Mass/charge ratio: 404.19 (100.0%), 406.18 (32.0%), 405.19 (24.2%), 407.19 (7.9%), 406.19 (3.5%), 408.19 (1 .1 %); Elemental analysis: C, 65.25; H, 7.22; CI, 8.76; N, 6.92; O, 1 1 .85.
Example 41
4-bromo-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000051_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cyclohexylethylamine. Formula: C22H29BrN203; Molecular Weight: 449.38; Mass/charge ratio: 448.14 (100.0%), 450.13 (97.3%), 449.14 (24.2%), 451 .14 (23.8%), 450.14 (3.5%), 452.14 (3.3%); Elemental analysis: C, 58.80; H, 6.50; Br, 17.78; N, 6.23; O, 10.68.
Example 42
4-chloro-N-(2-cycloheptylethyl -1 -(2-(3-hydroxyoxetan-3-yl)ethyI)-1 H-indole-3-
Figure imgf000052_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is. Formula: C23H31CIN2O3; Molecular Weight: 418.96; Mass/charge ratio: 418.20 (100.0%), 420.20 (32.1 %), 419.21 (25.3%), 421 .20 (8.2%), 420.21 (3.7%), 422.21 (1.0%); Elemental analysis: C, 65.94; H, 7.46; CI, 8.46; N, 6.69; O, 1 1 .46.
Example 43
4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-hydroxyoxetan-3-yI)ethyl)-1 H-indole-3- carboxamide
Figure imgf000053_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylethylamine. Formula: C23H31BrN203; Molecular Weight: 463.41 ; Mass/charge ratio: 462.15 (100.0%), 464.15 (97.5%), 463.16 (25.3%), 465.15 (25.0%), 464.16 (3.7%), 466.16 (3.0%); Elemental analysis: C, 59.61 ; H, 6.74; Br, 17.24; N, 6.05; O, 10.36.
Example 44
N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-chloro-1 -{2-(3-hydroxyoxetan-3-yl)ethyl)- 1 H-indole-3-carboxamide
Figure imgf000053_0002
Synthesised according to the procedure disclosed in bxample 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is (bicyclo[2.2.2]octan-1- yl)ethylamine. Formula: C24H3iCIN203; Molecular Weight: 430.97; Mass/charge ratio:
430.20 (100.0%), 432.20 (32.2%), 431.21 (26.4%), 433.20 (8.6%), 432.21 (4.0%),
434.21 (1 .1 %); Elemental analysis: C, 66.89; H, 7.25; CI, 8.23; N, 6.50; 0, 1 1 .14.
Example 45
N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-bromo-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)- 1 H-indole-3-carboxamide
Figure imgf000054_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is (bicyclo[2.2.2]octan-1- yl)ethylamine. Formula: C24H3 BrN203; Molecular Weight: 475.42; Mass/charge ratio:
474.15 (100.0%), 476.15 (97.5%), 475.16 (26.4%), 477.15 (26.1 %), 476.16 (4.0%),
478.16 (3.3%); Elemental analysis: C, 60.63; H, 6.57; Br, 16.81 ; N, 5.89; O, 10.10.
Example 46
4-chloro-N-(adamantane-1yl-ethyl)-1 -(2-{3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-
3-carboxamide
Figure imgf000055_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is adamantane-1yl-ethylamine. Formula: C26H33CIN2O3; Molecular Weight: 457; Mass/charge ratio: 456.22 (100.0%), 458.22 (36.6%), 457.22 (29.4%), 459.22 (9.2%), 460.22 (1 .5%); Elemental analysis: C, 68.33; H, 7.28; CI, 7.76; N, 6.13; O, 10.50.
Example 47
4-bromo-N-(adamantane-1 yl-ethyl)-1 -(2-{3-hydroxyoxetan-3-y[)ethyl)-1 H-indoie- 3-carboxamide
Figure imgf000055_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is adamantane-1yl-ethylamine. Formula: C26H33BrN203; Molecular Weight: 501 .46; Mass/charge ratio: 502.17 (100.0%), 500.17 (98.1 %), 501 .17 (28.1 %), 503.17 (27.3%), 504.17 (4.5%); Elemental analysis: C, 62.27; H, 6.63; Br, 15.93; N, 5.59; O, 9.57.
Example 48
N-(cycloheptylmethyl)-1 -(2-(3- ethyl)-4-methyl-1 H-indole-3-
Figure imgf000056_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-methyl indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C23H32N2O3; Molecular Weight: 384.51 ; Mass/charge ratio: 384.24 (100.0%), 385.24 (25.6%), 386.25 (3.7%); Elemental analysis: C, 71 .84; H, 8.39; N, 7.29; O, 12.48.
Example 49
N-(cycloheptylmethyl)-4-hydro -1 -(2-(3-hydroxyoxetan-3-yI)ethyl)-1 H-indole-3-
Figure imgf000057_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-hydroxy indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H3oN204; Molecular Weight: 386.48; Mass/charge ratio: 386.22 (100.0%), 387.22 (24.7%), 388.23 (2.8%), 388.22 (1 .0%); Elemental analysis: C, 68.37; H, 7.82; N, 7.25; O, 16.56.
N-(cyc!oheptylmethy!)-1 -(2-(3-hydroxyoxetan-3-yI)ethy!)-4-methoxy-1 H-indoie-3- carboxamide
Figure imgf000057_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4- methoxy indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C23H32N2O4; Molecular Weight: 400.51 ; Mass/charge ratio: 400.24 (100.0%), 401 .24 (25.4%), 402.24 (4.0%); Elemental analysis: C, 68.97; H, 8.05; N, 6.99; O, 15.98. Example 51
N-(cycIoheptylmethyl)-4-(trifluoromethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
Figure imgf000058_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4- trifluoromethyl indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C23H29F3N2O3; Molecular Weight: 438.48; Mass/charge ratio: 438.21 (100.0%), 439.22 (25.3%), 440.22 (3.7%); Elemental analysis: C, 63.00; H, 6.67; F, 13.00; N, 6.39; O, 10.95,
Example 52
4-cyano-N-(cycloheptylmethyl)-1 - 2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole-3-
Figure imgf000058_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-cyano indole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C23H29N3O3; Molecular Weight: 395.49; Mass/charge ratio: 395.22 (100.0%), 396.22 (26.0%), 397.23 (3.7%); Elemental analysis: C, 69.85; H, 7.39; N, 10.62; O, 12.14.
Example 53
4-chIoro-N-(cycloheptyImethyl)-1 -({oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000059_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is oxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C21 H27CIN2O2; Molecuiar Weight: 374.9; Mass/charge ratio: 374.18 (100.0%), 376.17 (32.0%), 375.18 (23.1 %), 377.18 (7.5%), 376.18 (3.1 %); Elemental analysis: C, 67.28; H, 7.26; CI, 9.46; N, 7.47; O, 8.54.
Example 54
4-bromo-N-(cycloheptylmethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000059_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is oxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C2iH27BrN202; Molecular Weight: 419.36; Mass/charge ratio: 418.13 (100.0%) 420.12 (97.3%), 419.13 (23.1 %), 421.13 (22.6%), 420.13 (3.1 %), 422.13 (2.9%) Elemental analysis: C, 60.15; H, 6.49; Br, 19.05; N, 6.68; O, 7.63.
Example 55
4-chloro-N-(2-cycloheptyIethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000060_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is oxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H29CIN2O2; Molecular Weight: 388.93; Mass/charge ratio: 88.19 (100.0%), 390.19 (32.1 %), 389.20 (24.2%), 391 .19 (7.9%), 390.20 (3.2%); Elemental analysis: C, 67.94; H, 7.52; CI, 9.12; N, 7,20; O, 8,23.
Example 56
4-bromo-N-(2-cycloheptylethyl)-1 -((oxetan-3-yl)methyl)-1 H- carboxamide
Figure imgf000060_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is oxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H29BrN202; Molecular Weight: 433.38; Mass/charge ratio: 432.14 (100.0%), 434.14 (97.5%), 433.14 (24.5%), 435.14 (24.0%), 434.15 (3.2%), 436.15 (2.7%); Elemental analysis: C, 60.97; H, 6.74; Br, 18.44; N, 6.46; O, 7.38.
Example 57
4-chloro-N-(cycloheptylmethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indoIe-3- carboxamide
Figure imgf000061_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-fluorooxetane-3-carbaldehyde, Z is cycloheptvlmethylamine. Formula: C21 H26CIFN2O2; Molecular Weight: 392.89; Mass/charge ratio: 392.17 (100.0%),
Figure imgf000061_0002
17 (23.1 %), 395.17 (7.5%), 394.17 (3.1 %); Elemental analysis:
C, 64.20; H, 6.67; CI, 9.02; F, 4.84; N, 7.13; O, 8.14.
Example 58
4-bromo-N-{cycloheptylmethyI)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000061_0003
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-fluorooxetane-3-carba!dehyde, Z is cycloheptylmethylamine. Formula: C2 H26BrFN202; Molecular Weight: 437.35; Mass/charge ratio: 436.12 (100.0%), 438.1 1 (97.3%), 437.12 (23.1 %), 439.12 (22.6%), 438.12 (3.1 %), 440.12 (2.9%); Elemental analysis: C, 57.67; H, 5.99; Br, 18.27; F, 4.34; N, 6.41 ; O, 7.32.
Example 59
4-chloro-N-(2-cycloheptylethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
Figure imgf000062_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 3-fluorooxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H28CIFN2O2; Molecular Weight: 406.92; Mass/charge ratio: 406.18 (100.0%), 408.18 (32.1 %), 407.19 (24.2%), 409.18 (7.9%), 408.19 (3.2%); Elemental analysis: C, 64.94; H, 6.94; CI, 8.71 ; F, 4.67; N, 6.88; O, 7.86.
Example 60
4-bromo-N-(2-cycloheptylethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H
carboxamide
Figure imgf000063_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 3-fluorooxetane-3-carbaldehyde, Z is cycloheptylethylamine. Formula: C22H28BrFN202; Molecular Weight: 451.37; Mass/charge ratio: 450.13 (100.0%), 452.13 (97.5%), 451 .14 (24.2%), 453.13 (23.9%), 452.14 (3.2%), 454.14 (2.7%); Elemental analysis: C, 58.54; H, 6.25; Br, 17.70; F, 4.21 ; N, 6.21 ; O, 7.09.
Example 61
4-chloro-N-(cycloheptylmethyI)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000063_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(oxetan-3-y!)aceta!dehyde, Z is cyc!ohepty!methylamine. Formula: C22H29CIN2O2; Molecular Weight: 388.93; Mass/charge ratio: 388.19 (100.0%), 390.19 (32.1 %), 389.20 (24.2%), 391 .19 (7.9%), 390.20 (3.2%); Elemental analysis: C, 67.94; H, 7.52; CI, 9.12; N, 7.20; O, 8.23.
Example 62
4-bromo-N-(cycloheptylmethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000064_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(oxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H29BrN202; Molecular Weight: 433.38; Mass/charge ratio: 432.14 (100.0%), 434.14 (97.5%), 433.14 (24.5%), 435.14 (24.0%), 434.15 (3.2%), 436.15 (2.7%); Elemental analysis: C, 60.97; H, 6.74; Br, 18.44; N, 6.46; O, 7.38.
Example 63
4-chloro-N-(2-cycloheptylethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3-
Figure imgf000064_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(oxetan-3-yl)acetaldehyde, Z is cycloheptylethylamine. Formula: C23H3iCIN202; Molecular Weight: 402.96; Mass/charge ratio: 402.21 (100.0%), 404.20 (32.0%), 403.21 (25.3%), 405.21 (8.1 %), 404.21 (3.6%), 406.21 (1 .1 %); Elemental analysis: C, 68.55; H, 7.75; CI, 8.80; N, 6.95; O, 7.94.
Example 64
4-bromo-N-(2-cycloheptylethyl)-1 - 2-(oxetan-3-yl)ethyl)-1 H-indole-3-
Figure imgf000065_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo Indole, Y is 2-(oxetan-3-yl)acetaldehyde, Z is cycloheptylethylamine. Formula: C23H3iBrN202; Molecular Weight: 447.41 ; Mass/charge ratio: 446.16 (100.0%), 448.15 (97.3%), 447.16 (25.3%), 449.16 (24.7%), 448.16 (3.6%), 450.16 (3.6%); Elemental analysis: C, 61 .74; H, 6.98; Br, 17.86; N, 6.26; O, 7.15
Example 65
4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-fluorooxetan-3-yI)ethyl)-1 H-indole-3- carboxamide
Figure imgf000066_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-fluorooxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H28CIFN2O2; Molecular Weight: 406.92; Mass/charge ratio: 406.18 (100.0%), 408.18 (32.1 %), 407.19 (24.2%), 409.18 (7.9%), 408.19 (3.2%); Elemental analysis: C, 64.94; H, 6.94; CI, 8.71 ; F, 4.67; N, 6.88; O, 7.86.
Example 66
4-bromo-N-(cycloheptylmethyl)-1 -{2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000066_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-fluorooxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C22H28BrFN202; Molecular Weight: 451 .37; Mass/charge ratio: 450.13 (100.0%), 452.13 (97.5%), 451 .14 (24.2%), 453.13 (23.9%), 452.14 (3.2%), 454.14 (2.7%); Elemental analysis: C, 58.54; H, 6.25; Br, 17.70; F, 4.21 ; N, 6.21 ; O, 7.09.
Example 67
4-chloro-N-(2-cyclo eptylethyl)-1 -(2-(3-fluorooxetan-3-yl)et yi)-1 H-indole-3- carboxamide
Figure imgf000067_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro indole, Y is 2-(3-fluorooxetan-3-yl)acetaldehyde, Z is cycloheptylethylamine. Formula: C23H30CIFN2O2; Molecular Weight: 420.95; Mass/charge ratio: 420.20 (100.0%), 422.20 (35.5%), 421 .20 (26.0%), 423.20 (8.1 %), 424.20 (1 .2%); Elemental analysis: C, 65.62; H, 7.18; CI, 8.42; F, 4.51 ; N, 6.65; O, 7.60.
Example 68
4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
Figure imgf000067_0002
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo indole, Y is 2-(3-fluorooxetan-3-yl)acetaldehyde, Z is cycloheptylethylamine. Formula: C23H3oBrFN202; Molecular Weight: 465.4; Mass/charge ratio: 466.15 (100.0%), 464.15 (99.2%), 465.15 (25.1 %), 467.15 (24.4%), 468.15 (3.5%); Elemental analysis: C, 59.36; H, 6.50; Br, 17.17; F, 4.08; N, 6.02; O, 6.88.
Example 69
4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- pyrrolo[2,3-b]pyridine-3-carboxamide
Figure imgf000068_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-chloro azaindole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C-20H26CIN3G3; Molecular Weight: 391 .89; Mass/charge ratio: 391 .17 (100.0%), 393.16 (32.0%), 392.17 (22.0%), 394.17 (7.2%), 393.17 (3.1 %), 392.16 (1 .1 %); Elemental analysis: C, 61 .30; H, 6.69; CI, 9.05; N, 10.72; O, 12.25.
Example 70
4-bromo-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- pyrrolo[2,3-b]pyridine-3-carboxamide
Figure imgf000069_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo azaindole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C2oH26BrN303; Molecular Weight: 436.34; Mass/charge ratio: 435.12 (100.0%), 437.1 1 (97.3%), 436.12 (22.0%), 438.12 (21 .6%), 437.12 (3.1 %), 439.12 (2.9%), 436.1 1 (1 .1 %), 438.1 1 (1 .1 %); Elemental analysis: C, 55.05; H, 6.01 ; Br, 18.31 ; N, 9.63; O, 11.00.
Example 71
6-bromo-4-chloro-N-{cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
Figure imgf000069_0002
Synthesised according to the procedure disclosed in Example 1 where X is 6-bromo- 4-chloro indole, Y is 3-hydroxyoxetane-3-carbaidehyde, Z is cycloheptylmethylamine. Formula: C2iH26BrCIN203; Molecular Weight: 469.8; Mass/charge ratio: 470.08 (100.0%), 468.08 (77.3%), 472.08 (24.8%), 471 .08 (23.6%), 469.08 (18.1 %), 473.08 (5.6%), 472.09 (2.6%), 470.09 (2.4%); Elemental analysis: C, 53.69; H, 5.58; Br, 17.01 ; CI, 7.55; N, 5.96; O, 10.22.
Example 72
4-bromo-6-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)- H- indole-3-carboxamide
Figure imgf000070_0001
Synthesised according to the procedure disclosed in Example 1 where X is 4-bromo- 6-chloro indole, Y is 3-hydroxyoxetane-3-carbaldehyde, Z is cycloheptylmethylamine. Formula: C2iH26BrCIN203; Molecular Weight: 469.8; Mass/charge ratio: 470.08 (100.0%), 468.08 (77.3%), 472.08 (24.8%), 471 .08 (23.6%), 469.08 (18.1 %), 473.08 (5.6%), 472.09 (2.6%), 470.09 (2.4%); Elemental analysis: C, 53.69; H, 5.58; Br, i / .U I , i, i . u, IN , . yu, , I \j.£.£..
Example 73
4-chloro-N-(cycloheptylmethyl -1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indazole-3-
Figure imgf000070_0002
Synthesised according to the procedure disclosed in Example 2 where X is 4-chloro azaindole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C21 H28CIN3O3; Molecular Weight: 405.92; Mass/charge ratio: 405.18 (100.0%), 407.18 (32.2%), 406.19 (23.1 %), 408.18 (7.7%), 407.19 (3.2%), 406.18 (1 .1 %); Elemental analysis: C, 62.14; H, 6.95; CI, 8.73; N, 10.35; O, 1 1 .82.
Example 74
4-bromo-N-(cycloheptylmethyl -1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indazole-3-
Figure imgf000071_0001
Synthesised according to the procedure disclosed in Example 2 where X is 4-bromo azaindole, Y is 2-(3-hydroxyoxetan-3-yl)acetaldehyde, Z is cycloheptylmethylamine. Formula: C2iH28BrN303; Molecular Weight: 450.37; Mass/charge ratio: 449.13 (100.0%), 451 .13 (97.5%), 450.13 (23.8%), 452.13 (23.3%), 451 .14 (3.2%), 453,14 (2.5%); Elemental analysis: C, 56.00; H, 6.27; Br, 17.74; N, 9.33; O, 10.66.
Example 75
!ndol-3 carboxamide and azaindol-3 carboxamide compounds antagonise P2X7R activity
Inhibition of P2X7R activity by the compounds of the present invention is assessed by measuring calcium influx in Hek293 cells (ECACC No. 85120602) which have been stably transfected with a cDNA for the human P2X7R.
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 BC01 1913) under the control of the human cytomegalovirus immediate-early (CMV) promoter and inserted into the pcDNA3.1 vector (Invitrogen). Cells were cultivated at 37°C with 8.5% C02 in Dulbecco's modified eagles medium (DMEM; GibcoBRL/lnvitrogen) supplemented with heat- inactivated foetal calf serum (10% v/v), 2 mM L-glutamine, 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 750 pg/ml Geneticin G418 (GibcoBRL/lnvitrogen).
Inhibition of Bz-ATP-stimulated P2X7R by test compounds was monitored by measuring changes in calcium influx using the Fluo-4-AM fluorescent dye according to the manufacturer's recommendations (Molecular Devices Corporation, U.S.A.). Briefly, Hek293 cells expressing P2X7R were cultured in 96-well plates at a final density of approximately 10,000 cells per well. On the day of the experiment, the culture medium was completely removed from the wells and cells were washed one time in assay buffer (1X Hank's Balanced Salt (HBSS) solution containing 20 mM Hepes buffer pH 7.4 and 250 mM Probenecid; GibcoBRL/lnvitrogen). The cells were incubated in 50 μΙ of assay buffer containing 100 μΜ Fluo-4 AM fluorescent dye per well for 1 hour at room temperature. The assay buffer containing the Fluo-4 AM fluorescent dye was then removed, the cells were washed once with assay buffer (without Fluo-4 AM), 100 μΙ of assay buffer (without Fluo-4 AM) containing the test compounds was then added per well. After a 15 minute incubation, 100 μΜ Bz-ATP was added and fluorescence was measured in a FlexStation II (Molecular Devices, U.S.A.) according to the following parameters: 485 nm Excitation Wavelength; 525 nm Emission Wavelength; 515 nm Emission Cut-off; 100 μΙ Pipette Height; 25 μΙ Transfer Volume; 5 fold Compound Concentration; 3 rate Addition Speed. Test compounds were added at concentrations of 0.001 μΜ up to 60 μΜ. The fluorescence data were processed using a lag time of 15 seconds, recording 45 seconds, zero baseline calibrated using 2 points, and % baseline multiplier set at 3. Then, the area of the resulting curve was calculated and the half-maximal inhibitory concentration (IC50) for each test compound was determined using SoftMax Pro software (Molecular Devices, U.S.A.). Compounds of the present invention can inhibit P2X7R activity with an IC50 between 1 μΜ and 0.001 μΜ. For example, the IC50 of compound described in Example 7 is approximately 0.018 μΜ. Example 76
Analgesic and Anti-inflammatory Effects
The analgesic and anti-inflammatory therapeutic benefits of the compounds of the present invention were assessed using a carrageenan-induced paw edema model of inflammation. The development of pain in this model is a biphasic phenomenon (Beena et al. (2008) Indian J Physiol Pharmacol 52: 178-182). The early phase is caused by a release of histamine and serotonin causing vasodialation and increased permeability of capillaries resulting in an increase in vascular permeability. The late phase is characterised by infiltrate of leucocytes due to the release of bradykinin, prostaglandins, protease and lysosomal enzymes which regulate the process of adhesion of molecules (Higgs et al. (1984) Ann Clin Res 16: 287-299). Subcutaneous injection of carrageenan into the rat paw produces accumulation of plasma and fluid. Plasma protein exudation also takes place along with neutrophil extravasations (Zulfkar et al. (2009) J Pharm Sci 22:287-290). The development of paw edema and inflammation is derived from the release of cytoplasmic enzymes and serotonin from mast cells and the increase of prostaglandin in the inflammatory area. The macrophages in carrageenan-insulted dermal tissue release interleukin-1 causing accumulation of polymorphic nuclear cells (PMNs) in the inflammatory area; the activated PMNs then release lysosomal enzymes and active oxygen, which induces paw swelling and pain. The early phase of inflammation begins immediately after carrageenan injection and extends up to 6 hours whereas the late phase remains up to 24 hours (Rachchh and Jain (2008) Indian J Pharmacol 40:271 -275). Carrageenan-induced paw edema model is one of the most reliable method to screen anti-inflammatory agents and analgesics.
Adult male Sprague Dawley rats were challenged by a subcutaneous injection of λ- carrageenan (1 % suspension, 0.1 ml; Sigma Aldrich), in the plantar side of the right hind paw. As an illustrative example, the compound disclosed in Example 7 was prepared in 5% dimethyl sulfoxide (DMSO), 25% triethylene glycol (TEG), and 70% (2-hydroxypropy!)-beta-cyc!odextrin (ΗΡ-β-CD) and injected intraperitonea!ly 1 .5 hours after carrageenan challenge. Control treated animals were injected intraperitoneally with vehicle (5% DMSO, 25% TEG, 70% ΗΡ-β-CD). Analgesic activity was assessed two hours after carrageenan administration using the plantar test. Rats from compound treated and vehicle groups were placed on a preheated glass stand. Both of the hind paws of the animal were stimulated with a radiant heat source. The latency of paw withdrawal (PWL) from the stimuli was recorded. Five readings of PWL were taken for ipsilateral as well as contra-lateral paw for each animal. Out of five reading, lowest and highest reading was discarded considering them as out-liar. Remaining three readings were considered to get the average withdrawal latency. Decrease in PWL for each animal is calculated by subtracting PWL for right hind paw from PWL for left hind paw. Mean Difference of PWL = PWL for Left hind paw (Contralateral) - PWL for Right Hind paw (Ipsilateral). A decrease in mean difference of withdrawal latency in compound treated animals as compared to control vehicle treated animals is considered as an analgesic effect of the treatment and calculated as percentage inhibition.
Anti-inflammatory activity was assessed after completion of plantar test using a water Plethysmometer which measures paw edema. The paw was marked with indelible ink at the level of the lateral malleolus so that the paw can be immersed in the Plethysmometer cell up to this mark. Paw volume was taken for ipsilateral as well as contralateral paw for each animal. Increase in paw volume for each animal is calculated by subtracting left hind paw volume from right hind paw volume. Difference in Paw Volume = Right Hind paw volume (Ipsilateral)— Left hind paw volume (Contralateral). A decrease in difference of paw volume in compound treated animals as compared to control vehicle treated animals is considered as the antiinflammatory effect of the treatment and calculated as percentage inhibition. All observed results were verified statistically using ANOVA Tukey's multiple comparison tests.
Results are illustrated in Figure 1 . A statistically significant (p<0.001 ) reduction of ~ 42% in paw withdrawal latency in response to the heat stimulus was observed after administration of 50 mg/kg of the compound when compared to vehicle treated animals. This result supports the analgesic use of the compounds of the present invention for the treatment of pain. A statistically significant (p<0.001 ) reduction of = 47% in carrageenan induced paw edema was observed after administration of 50 mg/kg of the compound when compared to vehicle treated animals. This result supports the anti-inflammatory use of the compounds of the present invention for the treatment of inflammatory diseases.

Claims

Claims
A compound of the general formula:
Figure imgf000076_0001
wherein,
Ri is a mono- or bicycloalkylalkyl group;
R2 is selected from hydrogen, -OH, -NH2, or halogen;
R3, R4, R5, Re are at each occurrence independently selected from hydrogen, halogen, C C6 alkyl, hydroxy, Ci-C6 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.
A compound of claim 1 , wherein R3, R4, R5, R6 are at each occurrence independently selected from hydrogen, halogen, methyl, hydroxy, methoxy, cyano, or trifluoromethyl.
A compound according to claim 1 or 2, wherein R-i is a mono- or bicycloalkylalkyl group selected from cyclopentylmethyi, cyclopentyiethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, bicyclo[2.2.2]octan-1-ylmethyl, bicyclo[2.2.2]octan-1-ylethyl, adamantanyl- methyl, or adamantanyl-ethyl.
4. A compound according to any one of claims 1 to 3, wherein F is -OH or fluoride.
5. A compound according to any one of claims 1 to 4, wherein at least two of R3, R4, R5 and R6 are hydrogen.
6. A compound of claim 5, wherein R4 and Re are H and R3 and R5 are defined as in claim 1 or 2.
7. A compound of claim 5, wherein R4-R6 are H and R3 is as defined in claim 1 or 2.
8. A compound according to any of claims 1 to 7 , wherein x is C.
9. A compound according to any of claims 1 to 7, wherein n=2 and x is N.
10. A compound according to any one of ciaims 1 to 9, wherein a, b, c, and d are C.
1 1 . A compound according to any one of claims 1 to 9, wherein one of a, b, c and d is N.
12. A compound according to any one claims 1 to 1 1 selected from:
- 4-chloro-N-(cyclopentylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cyc!openty!rnethyl)-1 -((3-hydroxyoxetan-3-y!)methyl)-1 H-indo!e- 3-carboxamide - 4-chloro-N-(cyclohexylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cyclohexylmethyl)-1-((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyI)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-chloro-1 -((3-hydroxyoxetan-3- yl)methyl)-1 H-indole-3-carboxamide
- N-((bicyclo[2.2.2]octan-1 -yl)methyl)-4-bromo-1 -((3-hydroxyoxetan-3- y!)methyl)-1 H-indole-3-carboxamide
- 4-chloro-N-(adamantane-1 yl-methyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-Bromo-N-(adamantane-1yl-methyl)-1-((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(2-cyclopentylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cyc!openty!ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cyclohexylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indoie- 3-carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- N-(2-(bicyclo[2.2.2]octan-1-yl)ethyl)-4-chloro-1 -((3-hydroxyoxetan-3- yl)methyl)-1 H-indole-3-carboxamide
- N-(2-(bicyc!o[2.2.2]octan-1 -yl)ethy!)-4=bromo-1 =((3-hydroxyoxetan-3- yl)methyl)-1 H-indole-3-carboxamide - 4-chloro-N-(adamantane-1 yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- 4-bromo-N-(adamantane-1 yl-ethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-4-methyl-1 H-indole- 3-carboxamide
- N-(cycloheptylmethyl)-4-hydroxy-1-((3-hydroxyoxetan-3-yl)methyl)-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-4-methoxy-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)- 1 H-indole-3-carboxamide
- 4-cyano-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(cyclopentylmethyl)-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cyclopentylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(cyc!ohexy!methy!)-1 -(2-(3-hydroxyoxetan-3-y!)eihy!)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cyclohexylmethyl)-1 -(2-(3-hydroxyoxetan-3-yi)ethyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- N-((bicyclo[2.2.2]octan-1-yl)methyl)-4-chloro-1 -(2-(3-hydroxyoxetan-3- yl)ethyl)-1 H-indole-3-carboxamide
- N-((bicyclo[2.2.2]octan-1-yl)methyl)-4-bromo-1 -(2-(3-hydroxyoxetan-3- yl)ethyl)-1 H-indole-3-carboxamide
- 4-ch!oro-N-(3damantane-1yl-meihy!)-1 -(2-(3-hydroxyoxetan-3-yl)et y!)-1 H- indole-3-carboxamide - 4-bromo-N-(adamantane-1 yl-methyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- 4-chloro-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cyclopentylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cyclohexylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- N-(2-(bicyclo[2.2.2]octan-1 -yl)ethyl)-4-chloro-1 -(2-(3-hydroxyoxetan-3- yl)ethyI)-1 H-indole-3-carboxamide
- N-(2-(bicyclo[2.2.2]octan-1-yl)ethyl)-4-bromo-1 -(2-(3-hydroxyox6tan-3- yl)ethyl)-1 H-indole-3-carboxamide
- 4-chloro-N-(adamantane-1 yl-ethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethy!)-1 H- indole-3-carboxamide
- 4-bromo-N-(adamantane-1 yl-ethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyi)-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-4-methyl-1 H-indole- 3-carboxamide
- N-(cycloheptylmethyl)-4-hydroxy-1-(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-4-methoxy-1 H- indole-3-carboxamide
- N-(cycloheptylmethyl)-4-(trifluoromethyl)-1-(2-(3-hydroxyoxetan-3-yl)ethyl)- 1 H-indole-3-carboxamide
- 4-cyano-N-(cyclohepty!rnethy!)-1 -(2-(3-hydroxyoxetan-3-y!)ethy!)-1 H-indole- 3-carboxamide - N-(cycloheptylmethyl)-4-(trifluoromethyl)-1 -(2-(3-hydroxyoxetan-3-yI)ethyl)- 1 H-indole-3-carboxamide
- 4-cyano-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H-indole- 3-carboxamide
- 4-chIoro-N-(cycloheptylmethyl)-1 -((oxetan-3-yi)methyl)-1 H-indoIe-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chIoro-N-(2-cycloheptylethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -((oxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 1 -((3-aminooxetan-3-yl)methyl)-4-chloro-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1 -((3-aminooxetan-3-yl)methyl)-4-bromo-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1 -((3-aminooxetan-3-yl)methyl)-4-chloro-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 1 -((3-aminooxetan-3-yl)methyl)-4-bromo-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycioheptylmethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptylethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -((3-fluorooxetan-3-yl)methyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 =(2=(oxetan-3-y!)ethy!)-1 H-indole-3- carboxamide - 4-chloro-N-(2-cycloheptylethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(2-cycloheptyIethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(oxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 1 -(2-(3-aminooxetan-3-yl)ethyl)-4-chloro-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1 -(2-(3-aminooxetan-3-yl)ethyl)-4-bromo-N-(cycloheptylmethyl)-1 H-indole-3- carboxamide
- 1 -(2-(3-aminooxetan-3-yl)ethyl)-4-chloro-N-(2-cycloheptylethyl)-1 H-indole-3- carboxamide
- 1 -(2-(3-aminooxetan-3-yl)ethyl)-4-bromo-N-(2-cycloheptylethyl)-1 H-indole-
3-carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-bromo-N-(cycloheptylmethy!)-1 -(2-(3-fluorooxetan-3-yl)ethyl}-1 H-indo!e-3- carboxamide
- 4-chioro-N-(2-cycioheptyiethyi)-1 -(2-(3-fluorooxetan-3-yi)ethyl)-1 H-indoie-3- carboxamide
- 4-bromo-N-(2-cycloheptylethyl)-1 -(2-(3-fluorooxetan-3-yl)ethyl)-1 H-indole-3- carboxamide
- 4-chloro-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- pyrrolo[2 , 3-b] pyrid i ne-3-carboxa m ide
- 4-bromo-N-(cycloheptylmethyl)-1 -((3-hydroxyoxetan-3-yl)methyl)-1 H- pyrrolo[2,3-b]pyridine-3-carboxamide
- 6-bromo-4-chloro-N-(cycloheptylmethy!)-1-((3-hydroxyoxetan-3-yl)methyl)- 1 H-indole-3-carboxamide
- 4-bromo-6-ch!oro-N-(cycloheptyimethyl)-1-((3-hydroxyoxetan-3-yi)meihyl)- 1 H-indole-3-carboxamide - 4-chloro-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indazole-3-carboxamide
- 4-bromo-N-(cycloheptylmethyl)-1 -(2-(3-hydroxyoxetan-3-yl)ethyl)-1 H- indazole-3-carboxamide
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12.
14. The pharmaceutical composition according to claim 13 further comprising an additional active compound in separate or unit dosage form for simultaneous or sequential administration.
15. The pharmaceutical composition according to claim 13 or 14 for use in 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.
16. The pharmaceutical composition according to claims 13 to 15 for use in the prophylactic or therapeutic treatment of an IL-1 or cytokine mediated condition.
17. The pharmaceutical composition according to claims 13 to 16 for use in the prophylactic or therapeutic treatment of 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, hyperresponsiveness of the airway, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, allergic dermatitis psoriasis, sunburn, cancer, myoblastic leukemia, diabetes, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, ischemic heart disease, head trauma, neurotrauma, spinal cord injury, neuro- degenerative disorders, Alzheimer's disease, Parkinson's disease, glaucoma, age-related macular degeneration, uveitis, neuropathic pain, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmune disorders, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, graft vs. host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, or muscle degeneration, in a mammal, including a human.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103420951A (en) * 2013-09-03 2013-12-04 天津全和诚科技有限责任公司 Method for synthesizing oxetane-3-carbaldehyde
JP2016511252A (en) * 2013-03-01 2016-04-14 バイエル・ファルマ・アクティエンゲゼルシャフト Substituted imidazopyridazine
US20160168090A1 (en) * 2014-12-15 2016-06-16 Merck Patent Gmbh Novel indole derivatives and their use in neurodegenerative diseases
US9388197B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9388198B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9409917B2 (en) 2012-01-20 2016-08-09 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9556117B2 (en) 2012-12-18 2017-01-31 Actelion Pharmaceuticals Ltd. Indole carboxamide derivatives as P2X7 receptor antagonists
US9718774B2 (en) 2012-12-12 2017-08-01 Idorsia Pharmaceuticals Ltd Indole carboxamide derivatives as P2X7 receptor antagonist

Citations (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998038179A1 (en) 1997-02-26 1998-09-03 Glaxo Group Limited Reverse hydroxamate derivatives as metalloprotease inhibitors
WO1999018074A1 (en) 1997-10-03 1999-04-15 Britol-Myers Squibb Pharma Company Novel lactam metalloprotease inhibitors
WO1999029686A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Novel compounds
WO1999029660A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO1999029661A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO1999065867A1 (en) 1998-06-17 1999-12-23 Du Pont Pharmaceuticals Company Cyclic hydroxamic acids as metalloproteinase inhibitors
WO2000000465A1 (en) 1998-06-26 2000-01-06 F. Hoffmann-La Roche Ag Hydrazine derivatives
WO2000009485A1 (en) 1998-08-12 2000-02-24 Pfizer Products Inc. Hydroxy pipecolate hydroxamic acid derivatives as mmp inhibitors
WO2000061569A1 (en) 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2000071529A1 (en) 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
WO2001042194A1 (en) 1999-12-09 2001-06-14 Astrazeneca Ab Adamantane derivatives
WO2001044170A1 (en) 1999-12-17 2001-06-21 Astrazeneca Ab Adamantane derivatives
WO2001044213A1 (en) 1999-12-17 2001-06-21 Astrazeneca Ab New p2x7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases
WO2001046200A1 (en) 1999-12-22 2001-06-28 Astrazeneca Ab Novel piperidine and piperazine derivatives
WO2001094338A1 (en) 2000-06-07 2001-12-13 Astrazeneca Ab Admantane derivatives
WO2002018326A1 (en) 2000-08-31 2002-03-07 Wakunaga Pharmaceutical Co., Ltd. Novel propenohydroxamic acid derivatives
WO2002096426A1 (en) 2001-05-25 2002-12-05 Bristol-Myers Squibb Company Hydantion derivatives as inhibitors of matrix metalloproteinases
WO2003016248A2 (en) 2001-08-17 2003-02-27 Bristol-Myers Squibb Company Patent Department Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or tnf-$g(a) converting enzyme (tace)
WO2003024899A2 (en) 2001-09-17 2003-03-27 Bristol-Myers Squibb Company CYCLIC HYDROXAMIC ACIDS AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003031431A1 (en) 2001-10-09 2003-04-17 Bristol-Myers Squibb Company Cyclic sulfone derivatives as inhibitors of matrix metalloproteinases and/or tnf-$g(a) converting enzyme (tace)
WO2003040103A1 (en) 2001-11-02 2003-05-15 Bristol-Myers Squibb Company β-SULFONE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003041707A1 (en) 2001-11-16 2003-05-22 Astrazeneca Ab N-adamantylmethyl derivates and intermediates as pharmaceutical compositions and processes for their preparation
WO2003042190A1 (en) 2001-11-12 2003-05-22 Pfizer Products Inc. N-alkyl-adamantyl derivatives as p2x7-receptor antagonists
WO2003042191A1 (en) 2001-11-12 2003-05-22 Pfizer Products Inc. Benzamide and heteroarylamide as p2x7 receptor antagonists
WO2003047515A2 (en) 2001-11-30 2003-06-12 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services P2x7 receptor antagonists
WO2003053941A2 (en) 2001-12-20 2003-07-03 Bristol-Myers Squibb Company Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases
WO2003055856A2 (en) 2001-10-17 2003-07-10 Bristol-Myers Squibb Company BICYCLIC LACTAM DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003059353A1 (en) 2001-12-21 2003-07-24 King Pharmaceuticals Research And Development, Inc. Tyrosyl derivatives and their use as p2x7 receptor modulators
WO2003080579A1 (en) 2002-03-25 2003-10-02 Astrazeneca Ab Novel adamantane derivatives
WO2003079986A2 (en) 2002-03-18 2003-10-02 Bristol-Myers Squibb Company Uracil derivatives as inhibitors of tnf-alpha converting enzyme (tace) and matrix metalloproteinases
WO2004006925A1 (en) 2002-07-13 2004-01-22 Astrazeneca Ab N-sulfonylpiperidines as metalloproteinase inhibitors (tace)
WO2004012663A2 (en) 2002-08-01 2004-02-12 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme
WO2004033632A2 (en) 2002-10-04 2004-04-22 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme (tace)
WO2004032846A2 (en) 2002-10-07 2004-04-22 Bristol-Myers Squibb Company Triazolone and triazolethione derivatives
WO2004043349A2 (en) 2002-11-06 2004-05-27 Bristol-Myers Squibb Company Isoxazoline derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme
WO2004058270A1 (en) 2002-12-31 2004-07-15 Pfizer Products Inc. 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases
WO2004058731A1 (en) 2002-12-31 2004-07-15 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor
WO2004074224A1 (en) 2003-02-21 2004-09-02 Astrazeneca Ab Adamantane derivatives, processes for their preparation and pharmaceutical composition containing them
WO2004096206A2 (en) 2003-04-25 2004-11-11 Pharmacia Corporation Therapeutic combination of a cox-2 inhibitor and a tace inhibitor
WO2004099146A1 (en) 2003-05-12 2004-11-18 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor
WO2004106305A1 (en) 2003-06-02 2004-12-09 Astrazeneca Ab New p2x7 receptor antagonists and their use
WO2004108086A2 (en) 2003-06-05 2004-12-16 Bristol-Myers Squibb Company HYDANTOIN DERIVATIVES AS INHIBITORS OF TUMOR NECROSIS FACTOR-α CONVERTING ENZYME (TACE)
WO2005009968A1 (en) 2003-07-28 2005-02-03 Astrazeneca Ab Quinoline derivates and their use in therapy
WO2005014555A1 (en) 2003-07-21 2005-02-17 Aventis Pharmaceuticals Inc. 4,5-dihydro-imidazole as p2x7 ion channel blockers
WO2005014529A1 (en) 2003-08-08 2005-02-17 Astrazeneca Ab 2- adamantyl derivatives as p2x7 receptor antagonists.
WO2005019182A1 (en) 2003-08-20 2005-03-03 Bayer Healthcare Ag Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists
WO2005039590A1 (en) 2003-10-21 2005-05-06 Inspire Pharmaceuticals, Inc. Non-nucleotide compositions and method for treating pain
WO2005111003A1 (en) 2004-04-29 2005-11-24 Abbott Laboratories Amino-tetrazoles analogues and methods of use
WO2006003513A1 (en) 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-`1,2,4!-triazin-2-yl!benzamide derivatives with p2x7 inhibiting activity by reaction of the derivative unsubstituted in 4-position of the triazine with an oxiran in the presence of a lewis acid
WO2006003500A1 (en) 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h`1,2,4!triazin-2-yl!-benzamide derivatives by deprotecting the hydroxyl-protected precursers
WO2006017406A1 (en) 2004-08-02 2006-02-16 Abbott Laboratories Cyanoamidine p2x7 antagonists for the treatment of pain
WO2006025783A1 (en) 2004-08-30 2006-03-09 Astrazeneca Ab Adamantyl derivates as p2x7 receptor antagonists
WO2006059945A1 (en) 2004-11-30 2006-06-08 Astrazeneca Ab Novel compounds
WO2006067444A1 (en) 2004-12-24 2006-06-29 Astrazeneca Ab Amide derivatives
WO2006080884A1 (en) 2005-01-27 2006-08-03 Astrazeneca Ab Novel biaromatic compounds, inhibitors of the p2x7-receptor
WO2006086229A1 (en) 2005-02-08 2006-08-17 Abbott Laboratories The use of selective p2x7 receptor antagonists
WO2006102610A2 (en) 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006110516A1 (en) 2005-04-11 2006-10-19 Abbott Laboratories Acylhydrazide p2x7 antagonists and uses thereof
WO2006136004A1 (en) 2005-05-05 2006-12-28 Medicure International Inc. Inhibition of atp-mediated, p2x7 dependent pathways by pyridoxal-5-phosphaste and vitamin b6 related compounds
WO2007016597A2 (en) 2005-07-29 2007-02-08 The Regents Of The University Of California Targeting tnf-alpha converting enzyme (tace)-dependent growth factor shedding in cancer therapy
WO2007025366A1 (en) 2005-08-29 2007-03-08 Irma Bernatchez-Lemaire Use of histogranin and histogranin-like compounds as inhibitors of p2x7 receptor function and as anti-arthritic agents
WO2007028022A2 (en) 2005-09-01 2007-03-08 Renovis, Inc. Novel compounds as p2x7 modulators and uses thereof
WO2007056091A2 (en) 2005-11-09 2007-05-18 Abbott Laboratories 2-phenyl-2h-pyraz0le derivatives as p2x7 receptor antagonists and uses thereof
WO2007056046A1 (en) 2005-11-07 2007-05-18 Abbott Laboratories P2x7 receptor antagonists and methods of use
WO2007109182A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109160A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109201A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109192A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109154A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109172A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007141267A1 (en) 2006-06-06 2007-12-13 Glaxo Group Limited N- (phenylmethyl) -2- (1h-pyraz0l-4-yl) acetamide derivatives as p2x7 antagonists for the treatment of pain, inflammation and neurodegeneration
WO2007141269A1 (en) 2006-06-06 2007-12-13 Glaxo Group Limited Novel receptor antagonists and their methods of use
WO2008003697A1 (en) 2006-07-06 2008-01-10 Glaxo Group Limited Substituted n-phenylmethyl -5-oxo-proline-2-amides as p2x7-receptor antagonists and their methods of use
WO2008005368A2 (en) 2006-06-30 2008-01-10 Abbott Laboratories Piperazines as p2x7 antagonists
WO2008013494A1 (en) 2006-07-27 2008-01-31 Astrazeneca Ab Quinoline derivatives as p2x7 receptor antagonist and their use in the treatment of rheumatoid arthritis, osteoarthritis, copd and ibd
WO2008119825A2 (en) 2007-04-03 2008-10-09 Glaxo Group Limited Imidazolidine carboxamide derivatives as p2x7 modulators
WO2008124153A1 (en) 2007-04-10 2008-10-16 H. Lundbeck A/S Heteroaryl amide analogues as p2x7 antagonists
WO2008125600A2 (en) 2007-04-11 2008-10-23 Glaxo Group Limited Pyrazole derivatives as p2x7 modulators
WO2008138876A1 (en) 2007-05-10 2008-11-20 Glaxo Group Limited Pyrazole derivatives as p2x7 modulators
WO2009019503A2 (en) 2007-08-03 2009-02-12 Astrazeneca Ab P2x7 antagonists for use in the treatment of mood disorders
WO2009023623A1 (en) * 2007-08-10 2009-02-19 H, Lundbeck A/S Heteroaryl amide analogues
WO2009053459A1 (en) 2007-10-26 2009-04-30 Glaxo Group Limited 4-benz0yl-1-substituted-piperazin-2-0ne derivatives as p2x7 modulators
WO2009070116A1 (en) 2007-11-30 2009-06-04 Astrazeneca Ab A quinoline derivative acting as a p2x7-receptor antagonist
WO2009077559A2 (en) 2007-12-18 2009-06-25 Glaxo Group Limited 5-oxo-3-pyrrolidinecarboxamide derivatives as p2x7 modulators
WO2009118175A1 (en) 2008-03-25 2009-10-01 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2009132000A1 (en) 2008-04-22 2009-10-29 Janssen Pharmaceutica Nv Quinoline or isoquinoline substituted p2x7 antagonists
WO2010118921A1 (en) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2010125103A1 (en) 2009-04-29 2010-11-04 Glaxo Group Limited Diketopiperazine derivatives as p2x7 modulators

Patent Citations (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998038179A1 (en) 1997-02-26 1998-09-03 Glaxo Group Limited Reverse hydroxamate derivatives as metalloprotease inhibitors
WO1999018074A1 (en) 1997-10-03 1999-04-15 Britol-Myers Squibb Pharma Company Novel lactam metalloprotease inhibitors
WO1999029686A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Novel compounds
WO1999029660A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO1999029661A1 (en) 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO1999065867A1 (en) 1998-06-17 1999-12-23 Du Pont Pharmaceuticals Company Cyclic hydroxamic acids as metalloproteinase inhibitors
WO2000000465A1 (en) 1998-06-26 2000-01-06 F. Hoffmann-La Roche Ag Hydrazine derivatives
WO2000009485A1 (en) 1998-08-12 2000-02-24 Pfizer Products Inc. Hydroxy pipecolate hydroxamic acid derivatives as mmp inhibitors
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
WO2000061569A1 (en) 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2000071529A1 (en) 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
WO2001042194A1 (en) 1999-12-09 2001-06-14 Astrazeneca Ab Adamantane derivatives
WO2001044170A1 (en) 1999-12-17 2001-06-21 Astrazeneca Ab Adamantane derivatives
WO2001044213A1 (en) 1999-12-17 2001-06-21 Astrazeneca Ab New p2x7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases
WO2001046200A1 (en) 1999-12-22 2001-06-28 Astrazeneca Ab Novel piperidine and piperazine derivatives
WO2001094338A1 (en) 2000-06-07 2001-12-13 Astrazeneca Ab Admantane derivatives
WO2002018326A1 (en) 2000-08-31 2002-03-07 Wakunaga Pharmaceutical Co., Ltd. Novel propenohydroxamic acid derivatives
WO2002096426A1 (en) 2001-05-25 2002-12-05 Bristol-Myers Squibb Company Hydantion derivatives as inhibitors of matrix metalloproteinases
WO2003016248A2 (en) 2001-08-17 2003-02-27 Bristol-Myers Squibb Company Patent Department Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or tnf-$g(a) converting enzyme (tace)
WO2003024899A2 (en) 2001-09-17 2003-03-27 Bristol-Myers Squibb Company CYCLIC HYDROXAMIC ACIDS AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003031431A1 (en) 2001-10-09 2003-04-17 Bristol-Myers Squibb Company Cyclic sulfone derivatives as inhibitors of matrix metalloproteinases and/or tnf-$g(a) converting enzyme (tace)
WO2003055856A2 (en) 2001-10-17 2003-07-10 Bristol-Myers Squibb Company BICYCLIC LACTAM DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003040103A1 (en) 2001-11-02 2003-05-15 Bristol-Myers Squibb Company β-SULFONE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003042190A1 (en) 2001-11-12 2003-05-22 Pfizer Products Inc. N-alkyl-adamantyl derivatives as p2x7-receptor antagonists
WO2003042191A1 (en) 2001-11-12 2003-05-22 Pfizer Products Inc. Benzamide and heteroarylamide as p2x7 receptor antagonists
WO2003041707A1 (en) 2001-11-16 2003-05-22 Astrazeneca Ab N-adamantylmethyl derivates and intermediates as pharmaceutical compositions and processes for their preparation
WO2003047515A2 (en) 2001-11-30 2003-06-12 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services P2x7 receptor antagonists
WO2003053941A2 (en) 2001-12-20 2003-07-03 Bristol-Myers Squibb Company Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases
WO2003059353A1 (en) 2001-12-21 2003-07-24 King Pharmaceuticals Research And Development, Inc. Tyrosyl derivatives and their use as p2x7 receptor modulators
WO2003079986A2 (en) 2002-03-18 2003-10-02 Bristol-Myers Squibb Company Uracil derivatives as inhibitors of tnf-alpha converting enzyme (tace) and matrix metalloproteinases
WO2003080579A1 (en) 2002-03-25 2003-10-02 Astrazeneca Ab Novel adamantane derivatives
WO2004006925A1 (en) 2002-07-13 2004-01-22 Astrazeneca Ab N-sulfonylpiperidines as metalloproteinase inhibitors (tace)
WO2004012663A2 (en) 2002-08-01 2004-02-12 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme
WO2004033632A2 (en) 2002-10-04 2004-04-22 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme (tace)
WO2004032846A2 (en) 2002-10-07 2004-04-22 Bristol-Myers Squibb Company Triazolone and triazolethione derivatives
WO2004043349A2 (en) 2002-11-06 2004-05-27 Bristol-Myers Squibb Company Isoxazoline derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme
WO2004058270A1 (en) 2002-12-31 2004-07-15 Pfizer Products Inc. 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases
WO2004058731A1 (en) 2002-12-31 2004-07-15 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor
WO2004074224A1 (en) 2003-02-21 2004-09-02 Astrazeneca Ab Adamantane derivatives, processes for their preparation and pharmaceutical composition containing them
WO2004096206A2 (en) 2003-04-25 2004-11-11 Pharmacia Corporation Therapeutic combination of a cox-2 inhibitor and a tace inhibitor
WO2004099146A1 (en) 2003-05-12 2004-11-18 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor
WO2004106305A1 (en) 2003-06-02 2004-12-09 Astrazeneca Ab New p2x7 receptor antagonists and their use
WO2004108086A2 (en) 2003-06-05 2004-12-16 Bristol-Myers Squibb Company HYDANTOIN DERIVATIVES AS INHIBITORS OF TUMOR NECROSIS FACTOR-α CONVERTING ENZYME (TACE)
WO2005014555A1 (en) 2003-07-21 2005-02-17 Aventis Pharmaceuticals Inc. 4,5-dihydro-imidazole as p2x7 ion channel blockers
WO2005009968A1 (en) 2003-07-28 2005-02-03 Astrazeneca Ab Quinoline derivates and their use in therapy
WO2005014529A1 (en) 2003-08-08 2005-02-17 Astrazeneca Ab 2- adamantyl derivatives as p2x7 receptor antagonists.
WO2005019182A1 (en) 2003-08-20 2005-03-03 Bayer Healthcare Ag Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists
WO2005039590A1 (en) 2003-10-21 2005-05-06 Inspire Pharmaceuticals, Inc. Non-nucleotide compositions and method for treating pain
WO2005111003A1 (en) 2004-04-29 2005-11-24 Abbott Laboratories Amino-tetrazoles analogues and methods of use
WO2006003513A1 (en) 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-`1,2,4!-triazin-2-yl!benzamide derivatives with p2x7 inhibiting activity by reaction of the derivative unsubstituted in 4-position of the triazine with an oxiran in the presence of a lewis acid
WO2006003500A1 (en) 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h`1,2,4!triazin-2-yl!-benzamide derivatives by deprotecting the hydroxyl-protected precursers
WO2006017406A1 (en) 2004-08-02 2006-02-16 Abbott Laboratories Cyanoamidine p2x7 antagonists for the treatment of pain
WO2006025783A1 (en) 2004-08-30 2006-03-09 Astrazeneca Ab Adamantyl derivates as p2x7 receptor antagonists
WO2006059945A1 (en) 2004-11-30 2006-06-08 Astrazeneca Ab Novel compounds
WO2006067444A1 (en) 2004-12-24 2006-06-29 Astrazeneca Ab Amide derivatives
WO2006080884A1 (en) 2005-01-27 2006-08-03 Astrazeneca Ab Novel biaromatic compounds, inhibitors of the p2x7-receptor
WO2006086229A1 (en) 2005-02-08 2006-08-17 Abbott Laboratories The use of selective p2x7 receptor antagonists
WO2006102610A2 (en) 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006102588A1 (en) 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006110516A1 (en) 2005-04-11 2006-10-19 Abbott Laboratories Acylhydrazide p2x7 antagonists and uses thereof
WO2006136004A1 (en) 2005-05-05 2006-12-28 Medicure International Inc. Inhibition of atp-mediated, p2x7 dependent pathways by pyridoxal-5-phosphaste and vitamin b6 related compounds
WO2007016597A2 (en) 2005-07-29 2007-02-08 The Regents Of The University Of California Targeting tnf-alpha converting enzyme (tace)-dependent growth factor shedding in cancer therapy
WO2007025366A1 (en) 2005-08-29 2007-03-08 Irma Bernatchez-Lemaire Use of histogranin and histogranin-like compounds as inhibitors of p2x7 receptor function and as anti-arthritic agents
WO2007028022A2 (en) 2005-09-01 2007-03-08 Renovis, Inc. Novel compounds as p2x7 modulators and uses thereof
WO2007056046A1 (en) 2005-11-07 2007-05-18 Abbott Laboratories P2x7 receptor antagonists and methods of use
WO2007056091A2 (en) 2005-11-09 2007-05-18 Abbott Laboratories 2-phenyl-2h-pyraz0le derivatives as p2x7 receptor antagonists and uses thereof
WO2007109160A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109182A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109201A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109192A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109154A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007109172A2 (en) 2006-03-16 2007-09-27 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2007141267A1 (en) 2006-06-06 2007-12-13 Glaxo Group Limited N- (phenylmethyl) -2- (1h-pyraz0l-4-yl) acetamide derivatives as p2x7 antagonists for the treatment of pain, inflammation and neurodegeneration
WO2007141269A1 (en) 2006-06-06 2007-12-13 Glaxo Group Limited Novel receptor antagonists and their methods of use
WO2008005368A2 (en) 2006-06-30 2008-01-10 Abbott Laboratories Piperazines as p2x7 antagonists
WO2008003697A1 (en) 2006-07-06 2008-01-10 Glaxo Group Limited Substituted n-phenylmethyl -5-oxo-proline-2-amides as p2x7-receptor antagonists and their methods of use
WO2008013494A1 (en) 2006-07-27 2008-01-31 Astrazeneca Ab Quinoline derivatives as p2x7 receptor antagonist and their use in the treatment of rheumatoid arthritis, osteoarthritis, copd and ibd
WO2008119825A2 (en) 2007-04-03 2008-10-09 Glaxo Group Limited Imidazolidine carboxamide derivatives as p2x7 modulators
WO2008124153A1 (en) 2007-04-10 2008-10-16 H. Lundbeck A/S Heteroaryl amide analogues as p2x7 antagonists
WO2008125600A2 (en) 2007-04-11 2008-10-23 Glaxo Group Limited Pyrazole derivatives as p2x7 modulators
WO2008138876A1 (en) 2007-05-10 2008-11-20 Glaxo Group Limited Pyrazole derivatives as p2x7 modulators
WO2009019503A2 (en) 2007-08-03 2009-02-12 Astrazeneca Ab P2x7 antagonists for use in the treatment of mood disorders
WO2009023623A1 (en) * 2007-08-10 2009-02-19 H, Lundbeck A/S Heteroaryl amide analogues
WO2009053459A1 (en) 2007-10-26 2009-04-30 Glaxo Group Limited 4-benz0yl-1-substituted-piperazin-2-0ne derivatives as p2x7 modulators
WO2009070116A1 (en) 2007-11-30 2009-06-04 Astrazeneca Ab A quinoline derivative acting as a p2x7-receptor antagonist
WO2009077559A2 (en) 2007-12-18 2009-06-25 Glaxo Group Limited 5-oxo-3-pyrrolidinecarboxamide derivatives as p2x7 modulators
WO2009118175A1 (en) 2008-03-25 2009-10-01 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2009132000A1 (en) 2008-04-22 2009-10-29 Janssen Pharmaceutica Nv Quinoline or isoquinoline substituted p2x7 antagonists
WO2010118921A1 (en) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2010125103A1 (en) 2009-04-29 2010-11-04 Glaxo Group Limited Diketopiperazine derivatives as p2x7 modulators

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
ANDERSON; NEDERGAARD, TRENDS NEUROSCIEN, vol. 29, 2006, pages 257 - 262
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
BARDEN ET AL., AM J MED GENET B, vol. 141, no. B, 2006, pages 374 - 382
BARICORDI ET AL., BLOOD, vol. 87, 1996, pages 682 - 690
BASSO ET AL., BEHAV BRAIN RES, vol. 198, 2009, pages 83 - 90
BEENA ET AL., INDIAN J PHYSIOL PHARMACOL, vol. 52, 2008, pages 178 - 182
CESARO ET AL., AM J PHYSIOL-GASTR L, vol. 299, 2010, pages G32 - 42
CHEN ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 8199 - 8203
CHESSELL ET AL., PAIN, vol. 114, 2005, pages 386 - 396
COLLO ET AL., NEUROPHARMACOL, vol. 36, 1997, pages 1277 - 1283
COLLO ET AL., NEUROPHARMACOLOGY, vol. 36, 1997, pages 1277 - 1283
DAHLQVIST; DIAMANT, ACTA PHYSIOL. SCAND., vol. 34, 1974, pages 368 - 384
DI VIRGILIO ET AL., PURINERGIC SIGNAL, vol. 5, 2009, pages 251 - 256
DI VIRGILIO, CELL DEATH DIFFER., vol. 5, 1998, pages 191 - 199
FALZONI ET AL., J. CLIN. INVEST., vol. 95, 1995, pages 1207 - 1216
FERRARI ET AL., J IMMUNOL, vol. 176, 2006, pages 3877 - 3883
FERRARI ET AL., J. IMMUNOL, vol. 156, 1996, pages 1531 - 1539
GORDON, BIOCHEM. J., vol. 233, 1986, pages 309 - 319
GREENBERG ET AL., J. BIOL. CHEM., vol. 263, 1988, pages 10337 - 10343
GRIFFITHS ET AL., J. IMMOL., vol. 154, 1995, pages 2821 - 2828
HIGGS ET AL., ANN CLIN RES, vol. 16, 1984, pages 287 - 299
HUMPHREYS ET AL., MOL. PHARMACOL., vol. 54, 1998, pages 22 - 32
JIANG ET AL., MOL. PHAMACOL., vol. 58, 2000, pages 82 - 88
MATUTE ET AL., J NEUROSCI, vol. 27, 2007, pages 9525 - 9533
NARCISSE ET AL., GLIA, vol. 49, 2005, pages 245 - 258
NORTH; SURPRENANT, ANNUAL REV. PHARMACOLOGY TOXICOLOGY, vol. 40, 2000, pages 563 - 580
PARVATHENANI ET AL., J BIOL CHEM, vol. 278, 2003, pages 13300 - 13317
PERREGAUX; GABEL, J BIOL CHEM, vol. 269, 1998, pages 15195 - 15203
RACHCHH; JAIN, INDIAN J PHARMACOL, vol. 40, 2008, pages 271 - 275
RASSENDREN ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 5482 - 5486
RESTA ET AL., EUR J NEUROSCI, vol. 25, 2007, pages 2741 - 2754
STEINBERG ET AL., J. BIOL. CHEM., vol. 262, 1987, pages 8884 - 8888
STEINBERG; SILVERSTEIN, J. BIOL. CHEM., vol. 262, 1987, pages 3118 - 3122
SUN, MOL NEUROBIOL, vol. 41, 2010, pages 351 - 355
SURPRENANT ET AL., SCIENCE, vol. 272, 1996, pages 3118 - 3122
SURPRENANT ET AL., SCIENCE, vol. 272, 1996, pages 735 - 738
VIRGINIO ET AL., J. PHYSIOL., vol. 519, 1999, pages 335 - 346
WANG ET AL., NATURE MED, vol. 10, 2004, pages B21 - B27
WILHELM ET AL., NAT MED, vol. 16, 2010, pages 1434 - 1438
WUITSCHIK ET AL., J. MED. CHEM., vol. 53, 2010, pages 3227 - 3246
ZULFKAR ET AL., J PHARM SCI, vol. 22, 2009, pages 287 - 290

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* Cited by examiner, † Cited by third party
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US9718774B2 (en) 2012-12-12 2017-08-01 Idorsia Pharmaceuticals Ltd Indole carboxamide derivatives as P2X7 receptor antagonist
US9556117B2 (en) 2012-12-18 2017-01-31 Actelion Pharmaceuticals Ltd. Indole carboxamide derivatives as P2X7 receptor antagonists
US9388197B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9388198B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
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