WO2003047515A2 - Antagonistes du recepteur p2x7 - Google Patents

Antagonistes du recepteur p2x7 Download PDF

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Publication number
WO2003047515A2
WO2003047515A2 PCT/US2002/038126 US0238126W WO03047515A2 WO 2003047515 A2 WO2003047515 A2 WO 2003047515A2 US 0238126 W US0238126 W US 0238126W WO 03047515 A2 WO03047515 A2 WO 03047515A2
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Prior art keywords
sulfonyl
carbonyl
compound
benzoyl
mammal
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PCT/US2002/038126
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English (en)
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WO2003047515A3 (fr
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Kenneth A. Jacobson
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The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Priority to AU2002359524A priority Critical patent/AU2002359524A1/en
Publication of WO2003047515A2 publication Critical patent/WO2003047515A2/fr
Publication of WO2003047515A3 publication Critical patent/WO2003047515A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4

Definitions

  • the present invention relates to compounds which block the P2X 7 receptor in an animal, pharmaceutical compositions comprising one or more of these compounds, and uses of these compounds in the treatment or prevention of a disease, state, or condition in an animal.
  • P2 receptors which are activated by ATP (adenosine 5'-triphosphate) and other purine/pyrimidine nucleotides, consist of two families: G protein-coupled receptors termed P2Y, of which five mammalian subtypes have been cloned, and ligand-gated cation channels (receptors) termed P2X, of which seven mammalian subtypes have been cloned.
  • P2Y G protein-coupled receptors
  • P2X ligand-gated cation channels
  • P2 receptors The nomenclature of P2 receptors and their various ligand specificities have been reviewed. Jacobson et al., Handbook of Experimental Pharmacology, 51:1, 129-175 (2001); Jacobson et al., The P2 Nucleotide Receptors, 81-108 (1997); Bhagwat et al., Eur. J. Med. Chem., 32:183-193 (1997); Fischer, Exp. Opin. Ther. Patents, .9:385-399 (1999).
  • the P2X- receptor (formerly the P2Z receptor) is expressed primarily in blood cells (monocytes, macrophages, and lymphocytes), in the brain (on microglial cells Ferrari et al., J. Biol.
  • a characteristic of the P2X 7 receptor is that at high ⁇ M concentrations of agonists, it forms or activates a large pore in addition to a cation channel. This pore increases permeability indiscriminately to molecules having a molecular weight of ⁇ 900.
  • BzATP 2'- and 3'-O-(4-benzoylbenzoyl)-ATP
  • BzATP is among the most potent agonists at P2X 7 receptors, but also has nanomolar potency at V2 X receptors.
  • IL-l ⁇ interleukin l ⁇
  • activation of the P2X 7 receptor activation leads to apoptosis or programmed cell death, Ferrari et al., Neuropharmacology, 36: 1295-1301 (1997); Coutinho-Silva et al., Am. J. Physiol., 276:Cl 139-1147 (1999); Humphreys et al., J. Biol. Chem., 275:26792-26798 (2000).
  • BzATP (5 mM) caused apoptosis in dendritic cells, which play a significant role in T- cell activation.
  • the present invention provides antagonists of the P2X 7 receptor in an animal.
  • the antagonists are substituted tyrosine derivatives, e.g., L-tyrosine derivatives, of the general structure R 1 -Tyr(OR 2 )-piperazinyl-R 3 .
  • a large hydrophobic group is present as R] on the alpha N of Tyr.
  • R 2 and R 3 are, for example, aryl or heteroaryl groups.
  • the present invention further provides a pharmaceutical composition comprising one or more of the antagonists.
  • the present invention also provides methods of treating an animal, e.g., a mammal, afflicted with a disease, or preventing a disease, state, or condition, comprising administering to the mammal at least one of the antagonists.
  • the present invention further provides a method of blocking an ATP-induced toxic process in the blood cell of an animal.
  • the present invention also provides a method of blocking a P2X 7 receptor in an animal.
  • the present invention also provides methods of inhibiting the binding of a ligand to a P2X 7 receptor.
  • Figure 1 depicts the formulas of known compounds 1 and 2, reported to be P2X 7 receptor antagonists.
  • Figure 2 depicts reaction schemes useful in the preparation of some P2X 7 receptor antagonists in accordance with an embodiment of the invention. The reaction schemes illustrate, for example, the introduction of quinoline- and isoquinoline- sulfonyl groups at the R group.
  • Figure 3 depicts reaction schemes useful in preparing some other P2X 7 receptor antagonists in accordance with an embodiment of the invention. The reaction schemes illustrate, for example, a method of varying the R 2 and R 3 groups.
  • Figure 4 depicts reaction schemes useful in preparing certain other P2X 7 receptor antagonists in accordance with an embodiment of the invention.
  • the reaction schemes illustrate, for example, a method of varying the substituent on the N ⁇ -atom and the D- configuration.
  • Figure 5 depicts an effect of certain P2X 7 receptor antagonists in hP2X 7 -HEK cells.
  • the adherent cells are pre-incubated with antagonists for 15 min prior to stimulation for 10 min with 3 mM ATP (final concentration).
  • K + content in these nitric acid extracts is assayed by atomic absorbance spectrophotometry. Duplicate or triplicate wells are run for all test conditions in each separate experiment.
  • hP2X ? -HEK cells are pre-incubated with or without 3 ⁇ M 1 prior to stimulation with 3 mM ATP.
  • Data points represent the mean ( ⁇ SD) K + content from 9 separate experiments.
  • hP2X 7 -HEK cells are pre-incubated with or without the indicated concentrations of selected antagonists prior to stimulation with 3 mM ATP.
  • Data points represent the mean ( ⁇ SD) K + contents from triplicate wells in a single experiment.
  • IC 50 values discussed in Example 2 are rough estimates from visual inspection of the concentration-response relationships.
  • Figure 6 depicts reaction scheme 1 useful in preparing certain P2X 7 receptor antagonists in accordance with another embodiment of the invention.
  • Figure 7 depicts reaction scheme 2 useful in preparing certain other P2X 7 receptor antagonists in accordance with another embodiment of the invention.
  • Figure 8 depicts reaction scheme 3 useful in preparing some P2X 7 receptor antagonists in accordance with another embodiment of the invention.
  • Figure 9 depicts reaction scheme 4 useful in preparing some other P2X 7 receptor antagonists in accordance with another embodiment of the invention.
  • Figure 10 depicts the formulas of certain dimeric P2X 7 receptor antagonists in accordance with an embodiment of the invention.
  • Figures 11-18 depict reaction schemes to prepare embodiments of the antagonists. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a compound of the formula:
  • R ⁇ -R 3 each independently is selected from the group consisting of H, alkyl sulfonyl, alkoxy sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, arylalkenyl sulfonyl, arylalkoxy sulfonyl, alkyl carbonyl, alkoxy carbonyl, alkoxyalkoxy carbonyl, arylalkoxy carbonyl, aryloxy carbonyl, aryl carbonyl, arylalkyl carbonyl, arylalkyl, and arylalkenyl carbonyl; wherein the aryl or heteroaryl portions of 0 R ⁇ -R may have 1-4 aromatic rings, preferably 1-3 aromatic rings, and each of the aromatic rings may be optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, halo
  • aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, biphenyl, and phenanthrenyl, preferably phenyl, naphthyl, and fluorenyl.
  • heteroaryl groups include quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, imidazolyl, 0 pyridyl, pyrimidinyl, and preferably quinolinyl and isoquinolinyl.
  • Ri is selected from the group consisting of heteroaryl sulfonyl, aryl sulfonyl, aryl carbonyl, arylalkoxy carbonyl, alkoxy carbonyl; and arylalkenyl carbonyl;
  • R 2 is selected from the group consisting of aryl sulfonyl and arylalkyl; and R 3 is selected from the group consisting of H, alkoxy 5 carbonyl, and arylalkoxy carbonyl.
  • the heteroaryl sulfonyl can be quinoline sulfonyl or isoquinoline sulfonyl; the aryl sulfonyl can be benzene sulfonyl, -toluene sulfonyl, or naphthalene sulfonyl; the aryl carbonyl can be benzoyl or toluoyl; arylalkoxy carbonyl can be benzyloxy carbonyl, or fluorenylmethoxy carbonyl; the alkoxy carbonyl can be t-butoxy carbonyl or ethoxy carbonyl; the arylalkyl can be 0 benzyl; and the arylalkenyl carbonyl can be phenylethenyl carbonyl.
  • R 4 is H and R R 3 are as follows: Ri is isoquinoline 5-sulfonyl; R 2 is isoquinoline 5-sulfonyl or quinoline 8-sulfonyl; R 3 is H or t-butoxy carbonyl; and; Ri and R 2 are quinoline 8-sulfonyl and R 3 is H or t-butoxy carbonyl; Ri is ethoxy carbonyl; R 2 is quinoline 8-sulfonyl; and R 3 is t-butoxy carbonyl; Ri is benzyloxy carbonyl or benzoyl; R 2 is quinoline 8-sulfonyl; and R 3 is t-butoxy carbonyl; Ri is benzene sulfonyl, -toluene sulfonyl, -methoxybenzene sulfonyl, or 1- naphthalene sulfonyl; R is quino
  • the compounds of the present invention can be monomeric or dimeric.
  • the dimeric compound includes two monomeric compounds such that R l3 R 2 , or R 3 of one of the two monomeric compounds is linked to R ls R 2 , or R 3 of the other of the two monomeric compounds through a linker.
  • Any suitable linker can be employed, for example, a linker comprising a thiourea group can be employed.
  • R 2 of one of the monomeric compounds is linked to R 2 of the other of the two monomeric compounds; R 2 or R 3 of one of the two monomeric compounds is linked to the R 3 of the two monomeric compounds.
  • a preferred dimeric compound has the formula shown below.
  • a preferred dimer is 222.
  • the compounds of the present invention can be prepared by any suitable method, for example, by the methods outlined in Figures 2-4 and 6-9 and described in Example 1.
  • compounds in accordance with an embodiment of the invention can be prepared by methods in which the i-R 3 positions are systematically varied in structure through facile acylation reactions.
  • Each of the three positions can be optimized in sequence, for example, through parallel synthesis alternating with biological evaluation, consisting of screening at a single concentration (e.g., initially 3 ⁇ M), leading to the identification and optimization of potent P2X 7 antagonists.
  • Boc is a group favorable for biological screening, and also as a preferred protecting group for synthetic intermediates.
  • Amides are formed readily using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-C1) as condensing agent.
  • BOP-C1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • Other amides and sulfonamides are prepared from the corresponding acyl chlorides or sulfonyl chlorides in the presence of 4-dimethylaminopyridine (DMAP).
  • the present invention provides pharmaceutically acceptable salts of the compounds described above.
  • pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulfonic acids.
  • An example of arylsulphonic acid isp- toluenesulphonic acid.
  • the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as described above.
  • the present invention further provides a composition comprising a pharmaceutically acceptable carrier and an effective (e.g., therapeutically or prophylactically effective) amount of at least one of the compounds set forth above.
  • the pharmaceutically acceptable (e.g., pharmacologically acceptable) carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • suitable formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, intraperitoneal, intrathecal, rectal, and vaginal adrninistration are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3- dioxolane-4-methanol, ethers, such as polyethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adju
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olef n sulfonates, alkyl, olef ⁇ n, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants. The quantity of surfactant in such formulations typically ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See for example, Pharmaceutics and Pharmacv Practice. J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Iniectable Drugs. Toissel, 4th ed., pages 622-630 (1986).
  • the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable methods of administering the compound of the present invention to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate or more effective reaction than another route. Accordingly, the methods described herein are merely exemplary and are in no way limiting.
  • the dose administered to an animal such as a mammal, particularly a human, in the context of the present invention should be sufficient to effect prophylactic or other therapeutic response in the animal over a reasonable period of time.
  • dosage will depend upon a variety of factors including the strength of the particular compound employed, the age, species, condition, and body weight of the animal, as well as the severity/stage of the disease or condition.
  • the size of the dose will also be determined by the route, timing, and frequency of administration of a particular compound and the desired physiological effect. It will be appreciated by one skilled in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In proper doses and with suitable administration of certain compounds, the present invention provides for a wide range of responses. Typically the dosages range from about 0.001 to about 1000 mg/kg body weight of the animal being treated/day. Preferred dosages range from about 0.01 to about 10 mg kg body weight day, and further preferred dosages range from about 0.01 to about 1 mg/kg body weight/day.
  • the present invention further provides a method of preventing or treating a disease, state, or condition in a mammal by the use of the compounds of the present invention.
  • the method involves preventing a disease, state, or condition.
  • the method involves treating an existing disease, state, or condition.
  • the present invention further provides a method of blocking, preferably selectively, a P2X 7 receptor in an animal, e.g., a mammal such as a human.
  • the method comprises administering to the mammal a compound of the present invention.
  • the present invention further provides a method of blocking an ATP-induced toxic process, e.g., a process involving release of interleukin-1 (e.g., IL-1/3), in a blood cell in a mammal comprising administering to the mammal a compound as described above.
  • the present invention provides a method for blocking P2X 7 receptor in blood cells, in the brain (on microglial cells), or in the salivary gland. Examples of blood cells include monocytes, macrophages, and lymphocytes.
  • the antagonists are also useful in treating septic shock or a neurodegenerative diseases, since the P2X 7 receptor activates astrocytes and microglial cells. Modulation of the P2X 7 receptor may also be beneficial in ophthalmic diseases or conditions, e.g., ophthalmic inflammation.
  • the P2X 7 receptor is expressed in high levels in dendritic cells and ATP acting at this site may serve as a signal to down modulate the immune response.
  • the present invention further provides a method of treating or preventing septic shock, inflammation, stroke, or a neurodegenerative disease in a mammal comprising administering to the mammal a compound as described above.
  • the compounds of the present invention are useful in medicine.
  • the compounds of the present invention are useful in the manufacture of a medicament for the treatment or prevention of septic shock, inflammation, stroke, or a neurodegenerative disease.
  • the antagonists of the present invention are useful in preventing apoptosis or programmed cell death.
  • the antagonists of the present invention are useful in preventing the release of TNF- ⁇ and other inflammatory cytokines such as interleukin-1.
  • the present invention further provides a method of inhibiting the binding of a ligand to a P2X 7 receptor of a substrate comprising contacting the substrate with a compound of the present invention so that the compound binds to the P2X 7 receptor and inhibits the ligand from binding to the P2X 7 receptor.
  • the contacting can be carried out in vitro or in vivo.
  • the present invention further provides a method of characterizing a P2X 7 receptor site in a substrate comprising contacting the substrate with a compound of the present invention and evaluating the interaction of the compound with the P2X 7 receptor.
  • the receptor site can be characterized pharmacologically to provide valuable information relating to the receptor including its occurrence in the tissue, its density, its activation characteristics, or its ability to couple to proteins.
  • "Characterizing” involves evaluation of the interaction of the antagonist with the receptor. The evaluation can provide qualitative information whether binding has occurred as well as quantitative information as to the extent of binding.
  • EXAMPLE 1 This Example illustrates a method of preparation of compounds in accordance with an embodiment of the invention. Synthetic reagents are purchased from Sigma Chemical Co. (St. Louis, MO) and
  • This Example illustrates some of the properties of the compounds in accordance with an embodiment of the present invention. This Example also illustrates a method of measuring the properties of the compounds.
  • P2X 7 Receptor Channel Activation All experiments are performed using adherent HEK293 cells stably transfected with cDNA encoding the human P2X 7 receptor.
  • Adherent cells on 12-well polylysine-coated plates are incubated at 37°C in 1 mL physiological salt solution (125 mM NaCl, 5 mM KC1, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 25 mM NaHEPES (pH 7.5), 10 mM D-glucose, 1 mg/mL BSA).
  • Antagonists are added from lOOOx stock solutions dissolved in DMSO.
  • both aryl sulfonyl and benzoyl groups lead to antagonism, while in the unsubstituted case a sulfonyl group is preferred over an acyl group (cf. 21 and 28).
  • a benzyl ether, 44 having the same substituents at Ri and R 3 inhibits to a comparable degree.
  • a variety of substitution of aryl sulfonates (21 - 26), including bicyclics, are generally tolerated for antagonism.
  • the approximate rank order of percent inhibition for aryl sulfonates is p-tolyl, 22; p-methoxyphenyl, 23; phenyl, 21 > ⁇ - naphthyl, 24; ⁇ -naphthyl, 25.
  • a benzoyl ester at the R 2 position, 28, inhibits to an intermediate degree.
  • N ⁇ -Cbz-Boc derivatives, 11 and 22, are nearly as potent as 1 as a P2X 7 receptor antagonist, with IC50 values of approximately 200 and 300 nM, respectively.
  • Compound 41 also is nearly as potent as 1.
  • the IC50 values of 1 and 41 are approximately 100 and 200 nM, respectively.
  • Ri position an aryl sulfonate at the R 2 position, and various acyl groups at the R 3 position.
  • aryl substituents are preferred over alkyl.
  • R 3 the structural requirements are the most restrictive of the three positions. Carbonyl attachment to the piperazinyl ring is allowed, and t-butyloxycarbonyl- and benzoyl groups are preferred.
  • EXAMPLE 3 This Example illustrates the antagonistic properties, i.e., effects on the function of human P2X 7 receptors expressed in HEK293 cells, of some of the compounds in accordance with an embodiment of the present invention.
  • the antagonistic properties are measured as in Example 2.
  • Ph-CH CH H Ph 62+4
  • Ph-CH CH 4-NO, Ph 72+4
  • Ph-CH CH H PI1-4-NO2 41+1
  • Ph-CH CH 4-NO 2 Ph-4-NO 2 43 ⁇ 14 MRS 2436 (trans)

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des antagonistes du récepteur P2X7, par exemple, un antagoniste de formule (I), qui peut être monomère ou dimère, formule dans laquelle R1 R3, par exemple, désigne un aryl sulfonyle ou un hétéroaryl sulfonyle, R4 désigne H ou un alkyle. L'invention concerne en outre des compositions pharmaceutiques comprenant un ou plusieurs de ces antagonistes, ainsi que des procédés d'utilisation de ces antagonistes, y compris le blocage d'un processus toxique induit par ATP dans les cellules sanguines d'un animal, par exemple, dans le traitement ou la prévention d'un choc septique, d'une inflammation, d'un infarctus ou d'une maladie neurodégénérative.
PCT/US2002/038126 2001-11-30 2002-11-27 Antagonistes du recepteur p2x7 WO2003047515A2 (fr)

Priority Applications (1)

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AU2002359524A AU2002359524A1 (en) 2001-11-30 2002-11-27 P2x7 receptor antagonists

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US33413001P 2001-11-30 2001-11-30
US60/334,130 2001-11-30

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WO2003047515A2 true WO2003047515A2 (fr) 2003-06-12
WO2003047515A3 WO2003047515A3 (fr) 2004-01-08

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1487449A1 (fr) * 2001-12-21 2004-12-22 King Pharmaceuticals Research and Development Inc. Derives de tyrosyle et leur utilisation comme modulateurs du recepteur p2x7
WO2007025366A1 (fr) * 2005-08-29 2007-03-08 Irma Bernatchez-Lemaire Utilisation de composes histogranine et du type histogranine comme inhibiteurs de la fonction du recepteur p2x7 et comme agents anti-arthritiques
EP2105164A1 (fr) 2008-03-25 2009-09-30 Affectis Pharmaceuticals AG Nouveaux antagonistes P2X7R et leur utilisation
WO2010118921A1 (fr) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
EP2386541A1 (fr) 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Nouveaux procédés de préparation d'antagonistes de P2X7R
WO2012110190A1 (fr) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Nouveaux antagonistes p2x7r et leur utilisation
WO2012163792A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2012163456A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation

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CHEN ET AL.: 'Functionalized congeners for tyrosine-based P2X7 receptor antagonists: probing multiple sites for linking and dimerization' vol. 13, 2002, pages 1100 - 1111, XP002965497 *
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1487449A1 (fr) * 2001-12-21 2004-12-22 King Pharmaceuticals Research and Development Inc. Derives de tyrosyle et leur utilisation comme modulateurs du recepteur p2x7
EP1487449A4 (fr) * 2001-12-21 2006-08-23 King Pharmaceuticals Res & Dev Derives de tyrosyle et leur utilisation comme modulateurs du recepteur p2x7
WO2007025366A1 (fr) * 2005-08-29 2007-03-08 Irma Bernatchez-Lemaire Utilisation de composes histogranine et du type histogranine comme inhibiteurs de la fonction du recepteur p2x7 et comme agents anti-arthritiques
EP2105164A1 (fr) 2008-03-25 2009-09-30 Affectis Pharmaceuticals AG Nouveaux antagonistes P2X7R et leur utilisation
WO2010118921A1 (fr) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
EP2386541A1 (fr) 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Nouveaux procédés de préparation d'antagonistes de P2X7R
WO2011141194A1 (fr) 2010-05-14 2011-11-17 Affectis Pharmaceuticals Ag Nouveaux procédés de préparation d'antagonistes du p2x7r
WO2012110190A1 (fr) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Nouveaux antagonistes p2x7r et leur utilisation
WO2012163792A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2012163456A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation

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WO2003047515A3 (fr) 2004-01-08
AU2002359524A1 (en) 2003-06-17

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