WO2008064432A1 - Composés moléculaires polycycliques - Google Patents

Composés moléculaires polycycliques Download PDF

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Publication number
WO2008064432A1
WO2008064432A1 PCT/AU2007/001857 AU2007001857W WO2008064432A1 WO 2008064432 A1 WO2008064432 A1 WO 2008064432A1 AU 2007001857 W AU2007001857 W AU 2007001857W WO 2008064432 A1 WO2008064432 A1 WO 2008064432A1
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Prior art keywords
optionally substituted
compound
formula
solvate
salt
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PCT/AU2007/001857
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English (en)
Inventor
Michael Kassiou
Mark Coster
Hendra Gunosewoyo
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The University Of Sydney
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Priority claimed from AU2006906739A external-priority patent/AU2006906739A0/en
Application filed by The University Of Sydney filed Critical The University Of Sydney
Publication of WO2008064432A1 publication Critical patent/WO2008064432A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
    • C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
    • C07C211/19—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/25—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/47—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of rings being part of condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/12—Saturated polycyclic compounds
    • C07C61/125—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/90—Ring systems containing bridged rings containing more than four rings

Definitions

  • This invention relates to compounds that bind the P2X 7 receptor with high affinity.
  • This invention also relates to methods for the diagnosis, treatment or monitoring of disorders in which the P2X 7 receptor is implicated.
  • the invention relates to methods for the diagnosis, treatment or monitoring of (the progression of) neuro inflammatory and neurodegenerative disorders in a subject.
  • the P2X 7 receptor is a non-desensitising cation selective ion channel directly gated by extracellular ATP.
  • the P2X 7 receptor functions both as a channel permeable to small cations and also as a cytolytic pore.
  • the P2X 7 receptor has been implicated in a variety of disorders, including: rheumatoid arthritis (US6812226, US6974812, US20070259920, WO99/29660, WO99/29661 , WO99/29686); osteoarthritis (US6812226); chronic obstructive pulmonary disease (US6812226); asthma (US6812226, WO99/29686); septic shock (WO99/29686); atherosclerosis (WO99/29686); neuropathic pain (US20070259920, Donnelly-Roberts & Jarvis 2007 British J Pharmacol 151 :571-9, Chessell et al 2005 Pain 114:386-96); chronic inflammatory pain (US20070259920, Donnelly-Roberts & Jarvis 2007 British J Pharmacol 151 :57I-9, Chessell
  • the analogue BzATP is the most potent agonist for P2X 7 receptor described in the art.
  • Novel compounds of the invention have been found to possess physiochemical properties particularly suitable for in vivo studies (molecular weight ⁇ 300 and lipophilicities (clogP) around 2.5).
  • the compounds provide structures for the development of suitable radiolabeled molecular probes for use in brain imaging of the P2X 7 receptor, e.g. using positron emission tomography (PET).
  • PET positron emission tomography
  • the compounds of the present invention have been demonstrated to bind with high affinity to the P2X7 receptor ex vivo and, morover, to have an effect in animal models.
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated; or a salt or solvate thereof.
  • v-V is not 3,5 difluorophenyl.
  • ⁇ Q is unsubstituted or substituted phenyl or pyridyl.
  • ⁇ o is substituted 2-pyridyl, 3-pyridyl, or 4-pyridyl.
  • the compound of formula (I) is a compound of formula (II), formula (III) or formula (IV):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a monovalent radical
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated.
  • n is preferably 0, 1, 2, 3, 4, 5, 6, 7 or 8. More preferably n is 0, 1 , 2, or 3. Even more preferably n is 0, 1 or 2.
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -OR ⁇ -SR", -SeR a , -OCOR b , -OCONR b 2j -NR h 2 , -NR b COOR b , -NR b CONR b 2 , -POR b 2 , -POR ⁇ OR 6 ) or -PO(OR b ); wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and where
  • R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR c 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -0R a , -SR a , -SeR 8 , -OCOR b , -OCONR b 2 , -NR b 2 , -NR b C00R b , or -NR e CONR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3, wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro.
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, -OR*, -SR a , or -NR b 2; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR * , -SR a , or -NR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR° 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and where
  • R 1 and R 3 are preferably each independently H or halogen.
  • R 4 is preferably H or -OR ⁇ wherein R 1 is optionally substituted alkyl.
  • R 1 and R 3 are each independently H, F or Cl;
  • R 2 and R 5 are each H; and
  • R 4 is H or methoxy.
  • the compound is preferably selected from
  • the compound . is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula of formula or a salt or solvate thereof.
  • the compound is a compound of formula of formula
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the current invention provides a compound of formula (Ia)
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated; said compound being radio labelled with a radioisotope; or a salt or solvate thereof.
  • the radioisotope is selected from 18 F, 123 I 1 76 Br, 124 I, 75 Br and 11 C.
  • ⁇ is not 3,5- difluorophenyl.
  • ⁇ is substituted phenyl or substituted pyridyl.
  • ⁇ * is 2-pyridyI, 3-pyridyl, or 4-pyridyl.
  • the compound of formula (Ia) is preferably a compound of formula (Ha), formula (Ilia) or formula (IVa):
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a monovalent radical
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated.
  • n is 0, 1, 2, 3, 4, 5, 6, 7 or 8. More preferably n is 0, 1, 2 or 3. Even more preferably n is 0, 1 or 2.
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkeny ⁇ optionally substituted alkynyl, optionally substituted aryl, -OH, -OR", -SR 8 , -SeR", -OCOR b , -OCONR b 2 , -NR b 2 , -NR b COOR b , -NR b CONR b 2 , -POR b 2 , -POR b (OR b ) or -PO(OR b ); wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3, wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloride
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR a , -SR", -SeR B , -OCOR b 7 -OCONR b 2 , -NR b 2 , -NR b COOR b , or -NR b CONR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3, wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR a , -SR", -S
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alky I, -OR', -SR*, or -NR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR C 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR", -SR a , or -NR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and — SiR C 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b
  • R 1 and R 3 are preferably each independently H or halo.
  • R 4 is preferably H or -OR a , wherein R' is optionally substituted alkyl.
  • R 1 and R 3 are each independently H, F or Cl; R 2 and R 5 are each
  • R is H or methoxy
  • the compound is selected from:
  • the compound is preferably a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the compound is a compound of formula or a salt or solvate thereof.
  • the current invention provides a process for the preparation of a compound of formula (I) as defined in any the first aspect comprising reacting a compound of general formula
  • R 6 is optionally substituted with one or more substituents
  • n 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bonds or bonds between the carbon atoms may be saturated or unsaturated, with a compound of general formula
  • VcV is defined according to the first aspect and L is a leaving group; and optionally forming a salt or solvate thereof.
  • the leaving group is a halogen, or an alcohol.
  • the current invention provides a radio labelled compound of formula (Ia) as defined in the second aspect comprising reacting a compound of general formula
  • n 0, 1 or an integer greater than I and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated, with a compound of general formula
  • vtV is defined according to the second aspect and L is a leaving group; and optionally forming a salt or solvate thereof.
  • the leaving group is a halogen, or an alcohol.
  • the current invention provides a compound of formula (I) according to the first aspect when made by the process according to the third aspect.
  • the current invention provides a radio labelled compound of formula (Ia) as defined according to the second aspect when made by the process of according to the fourth aspect.
  • the current invention provides a pharmaceutical composition comprising a compound of formula (I) as defined the first aspect, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the current invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (1) as defined in the first aspect radiolabelled with an isotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the isotope is selected from 18 F, 123 I, 76 Br, 124 1, 75 Br and ' 1 C, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the current invention provides a method of binding a P2X 7 receptor with high affinity in a subject, comprising administering to the subject a compound of formula (I) as defined in the first aspect or a pharmaceutically acceptable salt or solvate thereof.
  • the current invention provides a method of binding a P2X ? receptor with high affinity in a subject, comprising administering to the subject a compound of formula (II), (III) or (IV) as in the first aspect or a pharmaceutically acceptable salt or solvate thereof.
  • the compound administered to the subject is a compound according to the first aspect.
  • the current invention provides a method of imaging P2X 7 receptors in a subject, comprising administering to the subject a compound of formula (Ia) as defined the second aspect radiolabelled with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, and obtaining an image of the location of the radioisotope in the subject.
  • the radioisotope is selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and 11 C.
  • the current invention provides .method of imaging P2X 7 receptors in a subject, comprising administering to the subject a compound of formula (Ha), (Ilia) or (IVa) as defined in the second aspect radiolab led with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, and obtaining an image of the location of the radioisotope in the subject.
  • the radioisotope is selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and 11 C.
  • the compound of formula (Ia), (Ha), (UIa) or (IVa) is preferably radiolabeled with a radioisotope selected from 18 F, 123 1, 76 Br, 124 I and 75 Br. More preferably the compound of formula (Ia), (Ha), (HIa) or (IVa) is radiolabelled with 18 F.
  • the compound administered to the subject is a radiolabelled compound according to the second aspect.
  • the current invention provides a method for diagnosing or monitoring the progression of a disorder in a subject, the method comprising administering to the subject a compound of formula (Ia) according to the second aspect or a pharmaceutically acceptable salt or solvate thereof wherein said compound is labelled with a radioisotope, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the subject.
  • the current invention provides a method for diagnosing or monitoring the progression of a disorder in which the P2X 7 receptor is implicated in a subject, the method comprising administering to the subject a compound of formula (Ia) according to the second aspect or a pharmaceutically acceptable salt or solvate thereof wherein said compound is labelled with a radioisotope, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the subject.
  • the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, septic shock, atherosclerosis, neuropathic pain, chronic inflammatory pain, inflammation, depression, neurodegeneration, neuro inflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation
  • the cancer is selected from the group including uterine cancer, cervical cancer and thyroid cancer.
  • the current invention provides method for diagnosing or monitoring the progression of a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (Ia) as defined in the second aspect radiolabeled with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X ⁇ binding of the compound or salt or solvate thereof in the brain of the subject.
  • the radioisotope is selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and 11 C.
  • the current invention provides method for diagnosing or monitoring the progression of a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (Ha), (HIa) or (IVa) as defined the second aspect radio labelled with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the brain o f the subject.
  • the radioisotope is selected from 18 F, 123 I, 76 Br, 124 1, 75 Br and 11 C.
  • the compound of formula (Ha), (Ilia) or (IVa) or pharmaceutically acceptable salt or solvate thereof is preferably a radiolabeled compound as according to the second aspect.
  • the neuroinflammatory disorder or neurodegenerative disorder is a neuroinflammatory disorder or neurodegenerative disorder.
  • the current invention provides a method for treating a disorder in a subject, the method comprising administering to the subject a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof.
  • the current invention provides a method for treating a disorder in which the P2X 7 receptor is implicated in a subject, the method comprising administering to the subject a compound of formula (1) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof.
  • the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, septic shock, atherosclerosis, neuropathic pain, chronic inflammatory pain, inflammation, depression, neurodegeneration, neuroinflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation.
  • the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
  • the current invention provides method for treating a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof.
  • the current invention provides a method for treating a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (II), (III) or (IV) according to the first aspect or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula (II), (III), (IV) or pharmaceutically acceptable salt or solvate thereof is a compound according to the first aspect.
  • the neuro inflammatory disorder or neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumour or neuropathic pain.
  • the current invention provides use a compound of formula (I) as defined the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for binding a P2X 7 receptor with high affinity a subject.
  • the binding is antagonistic.
  • the current invention provides use of a compound of formula (II), (III), or (IV) as defined in the first aspect, or a pharmaceutical acceptable salt or solvate thereof, for the manufacture of a medicament for binding a P2X 7 receptor with high affinity in a subject.
  • the binding is antagonistic.
  • the current invention provides use a compound of formula (Ia) according to the second aspect radio labelled with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for imaging P2X 7 receptors in a subject.
  • the current invention provides use of a compound of formula (Ha), (Ilia), or (IVa) according to the second aspect, or a pharmaceutical acceptable salt or solvate thereof, for the manufacture of a medicament for imaging P2X 7 receptors in a subject, and obtaining an image of the location of the radioisotope in the subject.
  • the current invention provides use a compound of formula (Ia) according to the second aspect or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for diagnosing or monitoring the progression of a disorder in a subject wherein said compound is labelled with a radioisotope, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X7 binding of the compound or salt or solvate thereof in the subject.
  • the current invention provides use of a compound of formula (Ia) according to the second aspect or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for diagnosing or monitoring the progression of a disorder in which the P2X 7 receptor is implicated in a subject wherein said compound is labelled with a radioisotope, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the subject.
  • the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, septic shock, atherosclerosis, neuropathic pain, chronic inflammatory pain, inflammation, depression, neurodegeneration, neuroinflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation.
  • the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
  • the current invention provides use of a compound of formula (Ia) according to the second aspect radiolabeled with a radioisotope or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for diagnosing or monitoring the progression of a neuro inflammatory disorder or neurodegenerative disorder in a subject, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the brain of the subject.
  • the current invention provides use of a compound of formula (Ha), (INa) or (IVa) as defined in the second aspect radiolabelled with a radioisotope or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for diagnosing or monitoring the progression of a neuro inflammatory disorder or neurodegenerative disorder in a subject, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the brain of the subject.
  • the current invention provides use of a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a disorder in a subject.
  • the current invention provides use of a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a disorder in which the P2X7 receptor is implicated in a subject.
  • the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, septic shock, atherosclerosis, neuropathic pain, chronic inflammatory pain, inflammation, depression, ⁇ eurodegeneratio ⁇ , neuroinflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation.
  • the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
  • the current invention provides use of a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a neuroinflammatory disorder or neurodegenerative disorder in a subject.
  • the current invention provides use of a compound of formula (II), (III) or (IV) according to the first aspect, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a neuro inflammatory disorder or neurodegenerative disorder in a subject.
  • the current invention provides a compound for use as an intermediate in the production of a compound according to the first or second aspect having the following structure
  • R is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amine, or oxygen.
  • the compound is selected from:
  • the current invention provides a compound for use as an intermediate in the production of a compound according to the first or second aspect having the following structure
  • each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted amine.
  • the compound is selected from
  • the present invention provides a compound of formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 may be any of the monovalent radicals described below for R 1 , R 2 , R 3 , R 4 and R 5 in formula (II), provided that R 2 and R 4 are not fluoro.
  • the compound of formula (VIII) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(N-phenyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of formula (IX) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention provides a radiolabeled compound of formula (Villa) or (IXa):
  • the compound of formula (IXa) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2
  • the compounds of formula (VIII) and (IX), and salts and solvates thereof bind the P2X 7 receptor with hight affinity.
  • the compounds of formula (VIII) and (IX), and pharmaceutically acceptable salts and solvates thereof may be used to bind to P2X 7 receptors in a subject or to treat a neuroinflammatory disorder or a neurodegenerative disorder in a subject in a similar manner to that described below for the compounds of formula (I).
  • the compounds of formula (Villa) and (IXa), and pharmaceutically acceptable salts and solvates thereof may be used to image P2X 7 receptors in a subject or to monitor the progression of a neuroinflammatory disorder or a neurodegenerative disorder in a subject in a similar manner to that described below for the compounds of formula (I) radiolabelled with 18 F.
  • Figure I P2X7 Receptor Functional Assay: representative images of: i) negative control, ii) positive control, iii) test ligand 1 and iv) test ligand 2.
  • FIG. 1 P2X 7 Receptor Functional Assay: summary of the % relative dye uptake for: negative control, positive control, test ligand 1 and test ligand 2.
  • halo refers to fluoro, chloro, bromo or iodo.
  • alkyl used either alone or in a compound word such as “arylalkyl”, refers to a straight chain, branched or mono- or polycyclic alkyl.
  • the alkyl is a C1-C 2 0 alkyl, e.g. alkyl or Ci-C 3 alkyl.
  • straight chain and branched alkyl examples include methyl, ethyl, w-propyl, isopropyl, butyl, iso-batyl, .sec-butyl, amyl, /s ⁇ -amyl, .vec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyL 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1 , 1 ,2-trimethylpropyl.
  • cyclic alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • arylalkyl refers to an alkyl substituted with an aryl group.
  • An example of arylalkyl is benzyl.
  • cycloalkyl refers to a monocyclic or polycyclic alkyl having 3 to 12 carbons.
  • alkenyl refers to a straight chain, branched or cyclic alkenyl with one or more double bonds.
  • the alkenyl is a C 2 -C 2O alkenyl, e.g C 2 -CO alkenyl.
  • alkenyl include vinyl, ally!, l-methylvinyl, butenyl, iso- butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclope ⁇ tenyl,
  • alkynyl refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds.
  • the alkynyl is a C2-C 2 0 alkynyl, e.g. C 2 -C 6 alkynyl.
  • aryl used either alone or in compound words such as “arylalkyl”, refers to a radical of a single, polynuclear, conjugated or fused aromatic hydrocarbon or aromatic heterocyclic ring system.
  • aryl include phenyl, naphthyl, pyridyl, furanyl, thiophenyl and pyrazolyl.
  • the aromatic heterocyclic ring system may contain 1 to 4 heteroatoms each independently selected from N, O and S and may contain up to 8 carbon atoms in the ring.
  • optionally substituted alkyl refers Io an alkyl group which may be substituted by one or more substituents (for example, one, two or three substituents).
  • the optional substituents can be any group and may, for example, be an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g.
  • phosphine alkyl phosphine, phosphate or phosphoramide
  • a silicon containing group e.g. trialkylsilyl or trialkylsilyloxy
  • a selenium containing group e.g. alkylselenyl
  • optionally substituted alkenyl refers to an alkenyl group which may be substituted by one or more substituents (for example, one, two or three substituents).
  • the optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imi ⁇ o, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g.
  • phosphine alkyl phosphine, phosphate or phosphoramide
  • a silicon containing group e.g. trialkylsilyl or trialkylsilyloxy
  • a selenium containing group e.g. alkylselenyl
  • optionally substituted alkynyl refers to an alkynyl group which may be substituted by one or more substituents (for example, one, two or three substituents).
  • the optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g.
  • phosphine alkyl phosphine, phosphate or phosphoramide
  • a silicon containing group e.g. trialkylsilyl or trialkylsilyloxy
  • a selenium containing group e.g. alkylselenyl
  • optionally substituted aryl refers to an aryl group which may be substituted by one or more substituents (for example, one, two or three substituents).
  • the optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g.
  • phosphine alkyl phosphine, phosphate or phosphoramide
  • a silicon containing group e.g. trialkylsilyl or trialkylsilyloxy
  • a selenium containing group e.g. alkylselenyl
  • alkoxy refers to a group of the formula -Oalkyl. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
  • the present invention provides a compound of formula (1)
  • V ⁇ is a carboaromatic or heteroaromatic ring having one or more substituents; R 6 is
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated; or a salt or solvate thereof.
  • the present inventors have surprisingly found that the compounds of formula (I) bind theP2X 7 receptor with high affinity and can be radiolabelled for use in in vivo studies of the P2X 7 receptor. Accordingly, the present invention further provides a compound of formula (I) as defined above radiolab led with a radioisotope.
  • the radioisotope can be selected from any suitable radioisotope known to the skilled addressee and include for example radioisotopes listed in the Handbook of Radiopharmaceuticals, Radiochemistry Applications. Ed. Michael Welsch and Carol S. Redvanly, John Wiley & Sons Ltd 2003; and PET Chemistry, The Driving Force for Molecular Imaging. Ed. P.A. Schubiger, L. Lehmann, M Friebe. Springer 2007. Radioisotopes include although are not limited to 18 F, 123 1, 76 Br, 124 1, 75 Br and ' 1 C, or a salt or solvate thereof.
  • the present inventors have surprisingly found that compounds of formula (I) radio labelled with a radioisotope selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and 11 C can be used to image P2X 7 and therefore microglial activation in a subject.
  • the compounds of formula (I) radiolabeled with a radioisotope can be used to study events in a number of disorder consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, septic shock, atherosclerosis, neuropathic pain, chronic inflammatory pain, inflammation, depression, neurodegeneration, neuro inflammation, epilepsy, pancreatitis, diabetes, tuberculosis, uterine cancer, cervical cancer, thyroid cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, lupus renal cyst formation disorder.
  • the compounds of formula (I) radio labelled with a radioisotope can be used to study neuropathological events in a number of neuroinflammatory and neurodegenerative disorders, and can be used as a tool for diagnosing or monitoring the progression of such disorders.
  • the radioisotope is selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and 11 C.
  • radiolabelling is not limited to these radioisotopes.
  • the salts of the compounds of formula (I), and the compounds of formula (1) radiolabelled with a radioisotope selected from 18 F, 123 1, 76 Br, 124 1, 7S Br and 1 1 C, are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention.
  • Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, as
  • solvates of the compounds of formula (I), or the radiolabelled compounds of formula (I) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable solvates also fall within the scope of the present invention.
  • Ring v&) in formula (I) can be any carboaromatic or heteroaromatic ring, such as, for example, benzene, pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, 1,3,5-triazene, ftiran, benzofuran, imidazole, oxazole, isoxazole, thiazole, isothiazole, thiophene, benzothiophene, carbazole, purine, indole, naphthalene, anthracene, phenanthre ⁇ e, quinoline, isoquinoline, or triphenylene.
  • ring vJ> is benzene or pyridine.
  • the compound of formula (I) is a compound of formula (II), formula (III) or formula (IV):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a monovalent radical;
  • n is 0, 1 or an integer greater than 1 and wherein when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated.
  • n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8.
  • n is 0, 1, 2, or 3. More preferably n is 0, l or 2.
  • R 6 is
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -OR a , -SR a , -SeR a , -OCOR b , -OCONR b 2 , -NR b 2 , -NR b COOR b , -NR b CONR b 2 , -POR b 2 , -POR ⁇ OR 6 ) or -PO(OR b ); wherein R a is selected from optionally substituted aflcyl, optionally substituted aryl and -SiR c 3 , wherein each R° is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl;
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR ⁇ -SR a , -SeR 3 , -OCOR b , -OCONR b 2, -NR b 2 , -NR b COOR b , or -NR e CONR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiRS, wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR a , -SR a , -S
  • R 1 , R 3 , and R 5 are each independently H, halo, optionally substituted alkyl, -OR a , -SR a , or -NR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR c 3 , wherein each R c is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R b is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R 2 and R 4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR a , -SR a , or -NR b 2 ; wherein R a is selected from optionally substituted alkyl, optionally substituted aryl and -SiR c 3, wherein each R c is independently selected from optionally substituted alkyl and optionally substituted ary
  • R 1 and R 3 are each independently H or halogen.
  • R 4 is preferably H or -OR", wherein R a is optionally substituted alkyl.
  • R 1 and R 3 are each independently H, F or Cl;
  • R 2 and R 5 are each H; and
  • R 4 is H or methoxy.
  • the compound of formula (II) is selected from
  • the compounds of formula (I), (II), (III) and (IV) may be prepared using processes known in the art. Synthetic procedures for the preparation of examples of compounds of formula (I), (II), (III) and (IV) are set out in the Examples described below.
  • a compound of formula (I) can be radiolabelled with 18 F, 123 I, 76 Br, 124 I, 75 Br or 11 C by standard techniques known in organic chemistry for modifying an organic compound to replace a hydrogen, halo or carbon group in the compound with 18 F, 123 1, 76 Br, 124 I, 75 Br or 11 C.
  • compounds of formula (I) radiolabelled with a radioisotope selected from 18 F, 123 1, 76 Br, 124 1, 75 Br and 1 1 C may be prepared by incorporating 18 F, 123 [, 76 Br, 124 I, 75 Br or ' 1 C as a substituent in one of the starting materials or in an intermediate used in the synthesis of the compound of formula (I).
  • a compound of formula (II), (IH) or (IV) radiolab led with 18 F, u % 76 Br, u ⁇ 75 Br or 11 C may, for example, be prepared by preparing a compound having the formula (II), (III) or (IV) defined above, wherein one of R 1 , R 2 , R 3 , R 4 and R 5 is substituted with a leaving group, such as tosylate, mesylate, Br or I, that allows an aliphatic nucleophilic substitution reaction to occur at the leaving group, and then subjecting the compound to conditions under which an aliphatic nucleophilic substitution reaction occurs to replace the leaving group with a group containing 18 F, 123 1, 76 Br, 124 I, 75 Br or ' 1 C.
  • a compound of formula (H), (III) or (IV) may be modified by reactions known in organic chemistry to introduce a leaving group as a substituent on one of R 1 , R 2 , R 3 , R 4 and R s .
  • a compound of formula (I) radiolabelled with "C may, for example, be prepared from a compound of formula (I) having an alkoxy substituent on the carboaromatic or heteroaromatic ring.
  • the compound of formula (I) with the alkoxy substituent on the carboaromatic or heteroaromatic ring can undergo dealkylation of the alkoxy group leaving a hydroxyl substituent.
  • the resulting hydroxy-substituted compound can be alkylated with a reagent labelled with 11 C (e.g. an alkyl halide labelled with 11 C).
  • the compound of formula (I) may be radiolabelled with 18 F (half-life 1 10 minutes), 123 I (half-life 13.2 hours), 76 Br (half-life 16.2 hours), 124 I (half-life 4.2 days), 75 Br (half-life 1.6 hours) or 1 1 C (half-life 20 minutes).
  • the compound of formula (1) is radio labelled with 18 F.
  • Examples of compounds of formula (I) radio labelled with 18 F or ' 1 C include:
  • Compounds of formula (I) may be radio labelled with a suitable radtioisotope known to the skilled address.
  • radiolabelled compounds include:
  • the compounds of formula (I) radiolabelled with 18 F, 123 1, 76 Br, 124 I, 75 Br or 1 1 C can be used to study neuroinflammatory and neurodegenerative disorders and can be used to monitor the progression of neuroinflammatory and neurodegenerative disorders.
  • Neuroinflammatory and neurodegenerative disorders that can be studied or monitored using these compounds include Alzheimer's disease, multiple sclerosis, Parkinson's disease, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumours and neuropathic pain. Each of these disorders is associated with neuronal injury or infection.
  • a compound of formula (I) radiolabelled with a radioisotope selected from 18 F, 123 I, 76 Br, 124 I, 75 Br and ' 1 C, or a pharmaceutically acceptable salt or solvate thereof is administered to the subject.
  • the compound of formula (1) is radiolabeled with 18 F, 76 Br, 124 1, 75 Br or 11 C
  • the image of the location of the radioisotope in the subject, and therefore the location of P2X 7 in the subject may be obtained by positron emission tomography (PET) imaging using conventional techniques known the art.
  • PET positron emission tomography
  • the compound of formula (I) is radiolabeled with 123 I
  • the image of the location of the radioisotope in the subject may be obtained by single photo emission computer tomography (SPECT) imaging using conventional techniques known the art.
  • SPECT single photo emission computer tomography
  • the data is acquired using conventional dynamic or list mode acquisition techniques, commencing immediately after administration of the compound of formula (I) radiolabeled with 18 F, 123 1, 76 Br, 124 I, 75 Br or 11 C, or pharmaceutically acceptable salt or solvate thereof, and continuing for about 40 minutes or longer.
  • the data is typically processed to provide a time-series of 3D reconstructions, each depicting the distribution of the radioisotope in the body at a particular point in time.
  • the compound of formula (I) radiolabeled with 18 F, 123 I, 76 Br, 124 I, 75 Br or 11 C, or pharmaceutically acceptable salt or solvate thereof is administered parenterally.
  • the compound of formula (I) radiolabeled with 18 F, 123 1, 76 Br, 124 I, 75 Br or 1 1 C, or pharmaceutically acceptable salt or solvate thereof is administered parenterally by intravenous injection or infusion.
  • the compound of formula (1) radiolabeled with 18 F, 123 1, 76 Br, 124 1, 75 Br or 1 1 C, or pharmaceutically acceptable salt or solvate thereof is administered by administering a pharmaceutical composition comprising the compound of formula (I) radiolabeled 18 F, 123 1, 76 Br, 124 1, 75 Br or 11 C, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • Preparations for parenteral administration typically include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water and alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution.
  • the compounds of formula (I) radiolabelled with a radioisotope selected from 18 F, 123 I, 76 Br, 124 1, 75 Br and 11 C may be used to monitor the progression of a neuroinflammatory disorder or neurodegenerative disorder in a subject.
  • the method comprises administering to the subject a compound of formula (I) radiolabelled with a radioisotope selected from 18 F, 123 1, 76 Br, 124 1, 75 Br and 1 1 C, or a pharmaceutically acceptable salt or solvate thereof, and obtaining an image of the location of the radioisotope in the subject to assess the extent of P2X 7 binding of the compound or salt or solvate thereof in the brain of the subject.
  • the compounds of formula (I) bind the P2X ⁇ receptor with high affinity and may be used to treat a neuroinflammatory disorder or neurodegenerative disorder in a subject.
  • the method of treatment comprises administering a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, to the subject.
  • the compound of formula (1), or pharmaceutically acceptable salt or solvate thereof may be administered orally, topically or parenterally (e.g. by subcutaneous injection, by aerosol administration to the lungs or nasal cavity, or by intravenous, intramuscular, intrathecal or intracranial injection or infusion techniques) in a dosage unit formulation containing conventional non-toxic pharmaceutically acceptable carriers.
  • the compound of formula (I), or pharmaceutically acceptable salt or solvate thereof may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergree ⁇ , cherry, orange or raspberry flavouring.
  • Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water and alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution. Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, growth factors, inert gases, and the like.
  • the term "subject" as used herein refers to any animal.
  • the subject may be a mammal, e.g. a human.
  • the subject is a companion animal such as a dog or cat, a domestic animal such as a horse, pony, donkey, mule, llama, alpaca, pig, cow or sheep, or a zoo animal such as a primate, felid, canid, bovid or ungulate.
  • the term "therapeutically effective amount” refers to an amount of a compound effective to yield a desired therapeutic response.
  • the specific “therapeutically effective amount” will vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulation employed, and the attending clinician will be able to determine an appropriate therapeutically effective amount.
  • a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering a compound to a subject.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • the carrier is "pharmaceutically acceptable” in the sense of being not biologically or otherwise undesirable, Le. the carrier may be administered to a subject along with the active ingredient without causing any or a substantial adverse reaction.
  • the terms “treating”, “treatment” and the like are used herein to mean affecting a subject to obtain a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or disorder or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure of a disease or disorder.
  • Treating covers any treatment of, or prevention of, disease or disorder in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the disease or disorder from occurring in a subject that may be predisposed to the disease or disorder, but has not yet been diagnosed as having the disease or disorder; (b) inhibiting the disease or disorder, i.e., arresting the development of the disease or disorder; or (c) relieving or ameliorating the effects of the disease or disorder, i.e. causing regression of the effects of the disease or disorder.
  • Oxalyl chloride (6.8 g, 4.7 mL, 54 mmol) was added slowly to a magnetically stirred suspension of ester-acid 6 (3.7 g, 18 mmol) in CH2CI2 (20 mL) at room temperature. After stirring for 30 min, the clear solution was concentrated under reduced pressure with minimal heating. The solid residue was further dried in vacuo for 10 min and dissolved in benzene (20 mL).
  • a cubane having two carboxylic substituents can be synthesised by the following synthetic routes.
  • Powdered LiAlH 4 (3 g, 80 mmol) was added to a solution of the 1 -cubanecarboxamide in THF (120 mL) at 0 0 C with stirring. After warming to room temperature, the suspension was heated at reflux for 16 h, cooled to room temperature, and saturated aq. NaOH (ca. 20 mL) was added dropwise at 0 0 C with vigorous stirring. After stirring for 1 h at room temperature, the white mixture was filtered and the residue was washed with CH 2 Cl 2 (60 mL). The combined organic portions were dried (Na 2 SO ⁇ ) and evaporated in vacuo to give the crude amine 9 (4.1 g, 60%) as a colourless oil with some solid impurities.
  • Methyl iodide (1.6 mL, 26 mmol) was added to a stirred suspension of 2-chloro-5- hydroxybenzoic acid 10 (0.80 g, 4.6 mmol) and K 2 CO 3 (2.85 g, 20 mmol) in DMF (40 mL). The reaction mixture was heated at 40 0 C for 5 h, followed by another addition of methyl iodide (1.2 mL, 19 mmol). After 16 h of stirring at 40 0 C, the reaction mixture was cooled to room temperature and H 2 O (100 mL) was added, followed by extraction with Et 2 O (2 x 60 mL, 1 x 30 mL). The organic layers were washed sequentially with aq.
  • Cookson diketone was converted to the title compound in 4 steps following procedure reported by Eaton, et al. (J. Chem. Soc. Chem. Comm., 1974, 978). Zinc-acetic acid reduction afforded the cleavage of the strained cyclobutane ring. Subsequent reaction with sodium borohydride produced an internal hemiacetal, which upon bromination with HBr-acetic acid yielded the bromoketone. Finally, hydrogen abstraction using potassium /er/-butoxide afforded the desired ketone 20.
  • the reaction can be illustrated, by way of example, with 1-Cubanemethylamine (8), which can be synthesised from 1-Cubanecarboxylic acid (7).
  • R 2-F, 4-F, 2-Cl-5-OMe Si) LiAIH 4 iv) ArCOCI NEt 3 , MeCN
  • Oxalyl chloride (0.55mL, 6 mmol) was added to a solution of 2-chloro-5- methoxybe ⁇ zoic acid 12 (0.38 g, 2.1 mmol) in THF (20 mL) at 0 0 C. After warming to room temperature, the reaction was gently refluxed for 2 h. The solution was then concentrated under reduced pressure, THF (20 mL) was added and concentrated again under reduced pressure. The residue was dissolved in MeCN (15 mL) and added to a solution of 1-adamantanemethylamine (0.32 g, 1.9 mmol) and NEt 3 (0.20 g, 2.0 mmol) in MeCN (15 mL). After 2 days of stirring at room temperature, the reaction mixture was concentrated under reduced pressure.
  • Ci 6 H 14 ONF [M + H] + : 256.1 132, found: 256.1 127; m/z (+ES1) 278 ([M + Na] + , 95), 256 ([M + H] + , 100); Anal. (C 16 H 14 ONF): calc, C 75.28, H 5.53, N 5.49; found, C 74.83, H 5.54, N 5.23.
  • Oxalyl chloride (0.65 mL, 7.5 mmol) was added to a solution of 2-chloro-5- methoxybenzoic acid 12 (0.47 g, 2.5 mmol) in THF (25 mL) at 0 0 C. After warming to room temperature, the reaction mixture was gently refluxed for 2 h. The reaction mixture was then concentrated under reduced pressure, THF (20 mL) was added, and concentrated again under reduced pressure. The residue was dissolved in MeCN
  • the log P 7 . 4 ⁇ f benzamides 1 to 5 and (Z) were measured by employing reverse-phase HPLC method.
  • Phosphate buffer 50 mM was prepared by dissolving weighed amounts of KH 2 PO 4 in Alpha-Q water and the pH was adjusted to 7.4 with NaOH solution (0.1 M).
  • the lipophilicity of each compound was estimated by comparison of its retention time to that of standards having known log P values.
  • the standards used to generate a general calibration equation were aniline, benzene, toluene, cumene, triphenylamine, and hexachlorobenzene dissolved in mobile phase. All sample injections were performed in triplicates and the results averaged to yield the final values.
  • the exponential equation of the trendline function from the calibration graph and Excel TM allowed the log P values for the unknowns to be calculated.
  • test ligands were screened using a variety of assays.
  • the assays were performed on cultured rat spinal cord microglia cells.
  • the P2X 7 receptor functional assay was based upon the ability of P2X 7 receptor to form a non-selective pore upon activation with an agonist, thereby allowing the fluorescent dye propidium iodide to permeate the cells.
  • the experimental design consisted of: i) Negative control (cells + dye); ii) Positive control (cells + dye + ⁇ BzATP- a strong agonist of P2X 7 receptor); and iii) Ligand evaluation (cells + dye + BzATP + test ligand).
  • Results are presented as % relative dye uptake. compared to the positive control, 1 ⁇ M of test ligand was added to the cultured cells. A decrease in the % relative dye uptake indicates that the tested ligand is a P2X 7 receptor antagonist. An increase in the % relative dye uptake indicates that the tested ligand is a P2X 7 receptor agonist.
  • the functional assay was performed using a confocal, inverted microscope equipped with Sutter DG-4 Wavelength Switcher, MetaMorph and MetaFluor software for fluorescence image acquisition. For each set of experiment, at least 4 different views were taken from the same culture and both light and fluorescence images were taken for each. The light images were used to count the total cells in one view and the fluorescence images were used to count the number of cells that took up the dye ( Figure 1). Average reading from 4 replicates and the standard errors for all the experiments are represented in Figure 2.
  • the decrease in fluorescence observed in the tested ligand treatments demonstrates that the tested ligands are antagonists of the P2X 7 receptor.
  • test ligands were submitted to Psychoactive Drug Screening Program (PDSP), Case Western Reserve University, USA for binding assays to many types of neuroreceptors as shown in Table 1.
  • PDSP Psychoactive Drug Screening Program
  • K inhibition constant
  • PDSP G-protein coupled P2 receptors
  • P2Y receptors G-protein coupled P2 receptors
  • This assay was performed on adhesive cells and measured the ability of each of the tested ligands to stimulate or inhibit the influx or efflux of Ca 2+ ions. Similar to the P2X 7 receptor functional assay, these measurements were made by fluorescence imaging and measured as relative fluorescence units (RPU). These results indicate that the tested ligands are highly P2X 7 receptor selective.
  • the Novelty Suppressed Feeding Test assesses stress-induced anxiety by measuring an animals feeding in an adverse environment. These times differentially regulated by antidepressants.
  • Elevated Plus Maze Test is widely used as an anxiety paradigm and is based on unconditioned responses of animals to a potentially dangerous environment. A combination of maze height, luminosity and open space induce fear or anxiety- with the time spent in different parts of the maze reflecting anxiety levels.
  • the Social Interaction Test measures the duration of social interaction between two animals meeting each other for the first time.
  • the test is conducted in a square black Perspex box (52 x 52 x 40 cm) dimly lit with red light (40 W).
  • a miniature video camera is positioned in the box and the footage recorded for analysis. The experimenter remains outside the room during testing. Rats are split into pairs of approximately equal weight and are placed together for 10 minutes. Behaviours such as sniffing, adjacent lying, following, crawling under/over and mutual grooming are indicators of social interaction. Anxious animals spend less time interacting socially.
  • the anxiolytic data obtained using these tests will be correlated with the data obtained from the antidepressant tests.
  • the above assays were conducted on: i) wild type (WT) mice without test ligand administration; ii) WT mice receiving 20 mg/kg or 40 mg/kg of test ligand; iii) P2X 7 receptor knockout (KO) mice without test ligand administration; and iv) P2X 7 receptor KO mice receiving 20mg/kg or 40 mg/kg of test ligand.
  • the assay can also be used to determine whether the ligand is an agonist, or has no effect. No adverse effects were observed at either dose.

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Abstract

Cette invention concerne des composés de formule (I), dans laquelle A est un cycle carboaromatique ou hétéroaromatique ayant un ou plusieurs substituants; R6 est éventuellement substitué par un ou plusieurs substituants; et n est 0, 1 ou un nombre entier supérieur à 1 et lorsque n est supérieur ou égal à 1, la ou les liaisons entre les atomes de carbone peuvent être saturées ou insaturées, lesdits composés se liant au récepteur P2X7 avec une affinité élevée. Cette invention concerne également des procédés pour le diagnostic, le traitement ou le suivi de troubles dans lesquels le récepteur P2X7 est impliqué, en particulier pour le diagnostic, le traitement ou le suivi de troubles neuroinflammatoires ou neurodégénératifs ou de la progression de ceux-ci chez un sujet.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009106564A2 (fr) * 2008-02-29 2009-09-03 Ge Healthcare Limited Imagerie du système nerveux central
WO2010115881A1 (fr) 2009-04-09 2010-10-14 Ge Healthcare Limited Imagerie du système nerveux central à l'aide d'agents de liaison aux récepteurs p2x7 purinergiques
WO2014001247A1 (fr) 2012-06-26 2014-01-03 Bayer Pharma Aktiengesellschaft N-[4-(quinolin-4-yloxy)cyclohexyl(méthyl)](hétéro)arylcarboxamides utilisables en tant qu'antagonistes des récepteurs aux androgènes, leur production et leur utilisation en tant que médicaments
WO2019170543A1 (fr) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs d'erk5
WO2020037350A1 (fr) * 2018-08-24 2020-02-27 The University Of Sydney Composés benzamide substitués par adamantanyle et leur utilisation en tant qu'antagonistes du récepteur p2x7
WO2020234103A1 (fr) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs de kras
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070155738A1 (en) * 2005-05-20 2007-07-05 Alantos Pharmaceuticals, Inc. Heterobicyclic metalloprotease inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070155738A1 (en) * 2005-05-20 2007-07-05 Alantos Pharmaceuticals, Inc. Heterobicyclic metalloprotease inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KALINDJIAN S.B. ET AL.: "The Synthesis of a Radioligand with High Potency and Selectivity for CCKb/Gastrin Receptors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 10, 1996, pages 1171 - 1174, XP004134891, DOI: doi:10.1016/0960-894X(96)00192-8 *
MAHKAM M. ET AL.: "Synthesis and characterization of cubane polyamides", POLYMER INTERNATIONAL, vol. 49, 2000, pages 260 - 264 *
MORTON M.F. ET AL.: "Pharmacological comparison of the alternatively spliced short and long CCK2 receptors", BRITISH JOURNAL OF PHARMACOLOGY, vol. 140, 2003, pages 218 - 224 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009106564A2 (fr) * 2008-02-29 2009-09-03 Ge Healthcare Limited Imagerie du système nerveux central
WO2009106564A3 (fr) * 2008-02-29 2010-03-25 Ge Healthcare Limited Imagerie du système nerveux central
WO2010115881A1 (fr) 2009-04-09 2010-10-14 Ge Healthcare Limited Imagerie du système nerveux central à l'aide d'agents de liaison aux récepteurs p2x7 purinergiques
WO2014001247A1 (fr) 2012-06-26 2014-01-03 Bayer Pharma Aktiengesellschaft N-[4-(quinolin-4-yloxy)cyclohexyl(méthyl)](hétéro)arylcarboxamides utilisables en tant qu'antagonistes des récepteurs aux androgènes, leur production et leur utilisation en tant que médicaments
US9428460B2 (en) 2012-06-26 2016-08-30 Bayer Pharma Aktiengesellschaft N-[4-(quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products
WO2019170543A1 (fr) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs d'erk5
WO2020037350A1 (fr) * 2018-08-24 2020-02-27 The University Of Sydney Composés benzamide substitués par adamantanyle et leur utilisation en tant qu'antagonistes du récepteur p2x7
WO2020234103A1 (fr) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs de kras
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

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