[go: up one dir, main page]

WO2008064432A1 - Polycyclic molecular compounds - Google Patents

Polycyclic molecular compounds Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
formula
solvate
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2007/001857
Other languages
French (fr)
Inventor
Michael Kassiou
Mark Coster
Hendra Gunosewoyo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Sydney
Original Assignee
University of Sydney
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2006906739A external-priority patent/AU2006906739A0/en
Application filed by University of Sydney filed Critical University of Sydney
Publication of WO2008064432A1 publication Critical patent/WO2008064432A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to compounds of Formula (I), wherein A is a carboaromatic or heteroaromatic ring having one or more substituents; R6 Formula (A) is optionally substituted with one or more substituents; and n is 0, 1 or an integer greater than 1 and when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated, which bind the P2X7 receptor with high affinity. This invention also relates to methods for the diagnosis, treatment or monitoring of disorders in which the P2X7 receptor is implicated, in particular the diagnosis, treatment or monitoring of (the progression of) neuroinflammatory and neurodegenerative disorders in a subject.

Description

POLYCYCLIC MOLECULAR COMPOUNDS
TECHNICAL FIELD
This invention relates to compounds that bind the P2X7 receptor with high affinity. This invention also relates to methods for the diagnosis, treatment or monitoring of disorders in which the P2X7 receptor is implicated. In particular, the invention relates to methods for the diagnosis, treatment or monitoring of (the progression of) neuro inflammatory and neurodegenerative disorders in a subject.
BACKGROUND ART
Any reference to the prior art in the present specification should not be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the relevant technical field.
The P2X7 receptor is a non-desensitising cation selective ion channel directly gated by extracellular ATP.
The P2X7 receptor functions both as a channel permeable to small cations and also as a cytolytic pore. The P2X7 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 et al 2005 Pain 114:386-96); inflammation (US20070259920, Lister et al 2007 J Inflamm (Lond) 4:5, WO99/29686); depression (US20070259920, Bennett 2007 Aust NZ J Psychiatry 41 :563-71); neurodegeneration (US20070259920, Sperlagh et al 2006 Prog Neurobiol 7S-.327-46, Melani et al 2006 J Cereb Blood Flow Metab 26:974-82); rieuroinflammation (Choi et al 2007 J Neurosci 27:4957-68, Yiangou et al 2006 BMC Neurol 6: 12); Epilepsy (Rappold et al 2006 Brain Res 1089:171-8); pancreatitis (Yuan et al 2007 Expert Opin Ther Targets 1 1 :1261-71); diabetes (Coutinho-Silva et al 2007 40:108-16); chlamydia (Darville et al 2007 J Immunol 176:3707-14); tuberculosis (Britton et al 2007 Novartis Found Symp 281:79-89; Fernando et al 2007 Am J Respir Crit Care Med 175:360-6); cancer (including uterine cancer (Li et al 2007 Gynecol Oncol 106:233-43, Li et al 2006 Cancer Epidemiol Biomarkers Prev 15:1906-13; US20040142342), cervical cancer (Ying Hong et al 2006 J Biol Chem.; US20040142342), and thyroid cancer (Solini et al 2007 Endocrinology Epub)); neuroblastoma (Raffaghello et al 2006 Cancer Research 66:907-914); Crohn's disease (Haas et al 2007 Scand J Immunol 65; 166-70); irritable bowel syndrome (US20040142342); lupus (Elliott et al 2005 Arthritis Res Ther 7:R468-75) and renal cyst formation (Hillman et al 2004 Biochem Biophys Res Commun 332:434-9). It is widely acknowledged that ligands that bind the P2X7 receptor with high affinity may be of benefit in the treatment of such disorders.
To date, the few classes of compounds known to interact with the P2X7 receptors, including the natural agonist adenosine triphosphate (ATP) and its analogues, have large molecular weights (>700).and are very lipophilic (clogP>6). As such, for example, they are not suitable for in vivo brain studies. The analogue BzATP is the most potent agonist for P2X7 receptor described in the art.
Figure imgf000003_0001
It would be advantageous to identify alternative compounds that can bind the P2X7 receptor with high affinity. In particular, it would be useful to identify compounds that could be used, for example, to image P2X7 expression in vivo. If such compounds could be designed in a manner that would allow them to traverse the blood brain barrier, they could be utilised, for example, to study the cascade of biochemical events involved in the initial stages of several neuro inflammatory and neurodegenerative disorders.
It would also be advantageous to identify alternative compounds active at the P2X7 receptor as such compounds have potential to serve as therapeutic tools for a number of disorders including, for example, 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 (including uterine cancer, cervical cancer or thyroid cancer), neuroblastoma, Crohn's disease, irritable bowel syndrome, lupus renal cyst formation and, in particular, neuroinflammatory and neurodegenerative disorders.
SUMMARY OF THE INVENTION The inventors have developed a series of compounds which bind the P2X7 receptor with high affinity. It is clear that such compounds could be useful in the diagnosis, treatment and/or monitoring of progression of disorders in which the P2X7 receptor is involved.
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 P2X7 receptor, e.g. using positron emission tomography (PET).
In addition, 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.
According to the first aspect of the invention there is provided a compound of formula (I)
Figure imgf000005_0001
(D
wherein is a carboaromatic or heteroaromatic ring having one or more substituents;
R6 is
Figure imgf000005_0002
optionally substituted with one or more substituents; and 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.
Preferably v-V is not 3,5 difluorophenyl. Preferably ^Q is unsubstituted or substituted phenyl or pyridyl. Preferably ^o) is substituted 2-pyridyl, 3-pyridyl, or 4-pyridyl.
Preferably the compound of formula (I) is a compound of formula (II), formula (III) or formula (IV):
Figure imgf000005_0003
(H) (IH) (IV) wherein:
R1, R2, R3, R4, and R5 are each independently a monovalent radical;
R6 is
Figure imgf000006_0001
optionally substituted with one or more substituents; and 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. Preferably R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -OR\ -SR", -SeRa, -OCORb, -OCONRb 2j -NRh 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -POR^OR6) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeR8, -OCORb, -OCONRb 2, -NRb 2,
-NRbCOORb, -NRbCONRb 2, -PORb 2, -POR6COR*1) or -PO(OR*1); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRc 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
More preferably R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -0Ra, -SRa, -SeR8, -OCORb, -OCONRb 2, -NRb 2, -NRbC00Rb, or -NReCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro. bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR", -SRa, -SeRa, -0C0Rb, -OCONRb2, -NRb 2, -NRbCOORb, or -NRbCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
Even more preferably R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, -OR*, -SRa, or -NRb2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR*, -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiR°3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
R1 and R3 are preferably each independently H or halogen. R4 is preferably H or -OR\ wherein R1 is optionally substituted alkyl. Preferably R1 and R3 are each independently H, F or Cl; R2 and R5 are each H; and R4 is H or methoxy. The compound is preferably selected from
Figure imgf000008_0001
Figure imgf000008_0005
or a salt or solvate thereof.
Preferably the compound .is a compound of formula
Figure imgf000008_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000008_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000008_0004
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000009_0001
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000009_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000009_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000009_0004
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000010_0001
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000010_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000010_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000010_0004
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000011_0001
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000011_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000011_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000011_0004
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000012_0001
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000012_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000012_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000012_0004
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000013_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000013_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000013_0003
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000013_0004
or a salt or solvate thereof. According to a second aspect the current invention provides a compound of formula (Ia)
Figure imgf000014_0001
(Ia) wherein ^V is a carboaromatic or heteroaromatic ring having one or more substituents;
R6 is
Figure imgf000014_0002
optionally substituted with one or more substituents; and 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.
Preferably the radioisotope is selected from 18F, 123I1 76Br, 124I, 75Br and 11C.
Preferably ^ is not 3,5- difluorophenyl. Preferably^ is substituted phenyl or substituted pyridyl. Preferably Α* 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):
Figure imgf000015_0001
(Ha) (HIa) (IVa)
wherein:
R1, R2, R3, R4 and R5 are each independently a monovalent radical;
R6 is
Figure imgf000015_0002
optionally substituted with one or more substitueπts; and 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.
Preferably 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.
Preferably R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyζ optionally substituted alkynyl, optionally substituted aryl, -OH, -OR", -SR8, -SeR", -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, k>do, optionally substituted alkyl, optionally substituted aflcenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SR", -SeRa, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRcj, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
More preferably R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SR", -SeRB, -OCORb 7 -OCONRb 2, -NRb 2, -NRbCOORb, or -NRbCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SR", -SeR*, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, or -NRbCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiR0 J, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl. Preferably R1, R3, and R5 are each independently H, halo, optionally substituted alky I, -OR', -SR*, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR", -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and — SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
R1 and R3 are preferably each independently H or halo. R4 is preferably H or -ORa, wherein R' is optionally substituted alkyl.
Preferably R1 and R3 are each independently H, F or Cl; R2 and R5 are each
4 - independently H; and R is H or methoxy.
Preferably the compound is selected from
Figure imgf000017_0001
Figure imgf000017_0002
or a salt or solvate thereof.
According to the second aspect the compound is preferably a compound of formula
Figure imgf000018_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000018_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000018_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000018_0004
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000019_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000019_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000019_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000019_0004
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000020_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000020_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000020_0003
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000020_0004
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000021_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000021_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000021_0003
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000021_0004
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000022_0001
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000022_0002
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000022_0003
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000022_0004
or a salt or solvate thereof.
Preferably the compound is a compound of formula
Figure imgf000023_0001
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000023_0002
or a salt or solvate thereof. Preferably the compound is a compound of formula
Figure imgf000023_0003
or a salt or solvate thereof.
According to a third aspect 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
R6^ NH2 (V)
wherein R6 is
Figure imgf000024_0001
optionally substituted with one or more substituents; and
n is 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
Figure imgf000024_0002
wherein VcV is defined according to the first aspect and L is a leaving group; and optionally forming a salt or solvate thereof.
Preferably the leaving group is a halogen, or an alcohol.
According to a fourth aspect the current invention provides a radio labelled compound of formula (Ia) as defined in the second aspect comprising reacting a compound of general formula
R6 ^ NH2 (Va)
wherein R6 is
Figure imgf000025_0001
optionally substituted with one or more substituents; and
n is 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
Figure imgf000025_0002
wherein vtV is defined according to the second aspect and L is a leaving group; and optionally forming a salt or solvate thereof. Preferably the leaving group is a halogen, or an alcohol.
According to a fifth aspect the current invention provides a compound of formula (I) according to the first aspect when made by the process according to the third aspect.
According to a sixth 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. According to a seventh 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.
According to an eight aspect the current invention provides 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.
Preferably the isotope is selected from 18F, 123I, 76Br, 1241, 75Br and ' 1C, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
According to a ninth aspect the current invention provides a method of binding a P2X7 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.
According to a tenth aspect 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.
Preferably the compound administered to the subject is a compound according to the first aspect.
According to an eleventh aspect the current invention provides a method of imaging P2X7 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.
Preferably the radioisotope is selected from 18F, 123I, 76Br, 124I, 75Br and 11C. According to a twelfth aspect the current invention provides .method of imaging P2X7 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.
Preferably the radioisotope is selected from 18F, 123I, 76Br, 124I, 75Br and 11C. The compound of formula (Ia), (Ha), (UIa) or (IVa) is preferably radiolabeled with a radioisotope selected from 18F, 1231, 76Br, 124I and 75Br. More preferably the compound of formula (Ia), (Ha), (HIa) or (IVa) is radiolabelled with 18F.
Preferably the compound administered to the subject is a radiolabelled compound according to the second aspect.
According to a thirteenth 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
According to a fourteenth aspect the current invention provides a method for diagnosing or monitoring the progression of a disorder in which the P2X7 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
Preferably 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
Preferably the cancer is selected from the group including uterine cancer, cervical cancer and thyroid cancer.
According to a fifteenth aspect 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 P2Xγ binding of the compound or salt or solvate thereof in the brain of the subject.
Preferably the radioisotope is selected from 18F, 123I, 76Br, 124I, 75Br and 11C.
According to a sixteenth aspect 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 P2X7 binding of the compound or salt or solvate thereof in the brain o f the subject.
Preferably the radioisotope is selected from 18F, 123I, 76Br, 1241, 75Br and 11C. 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.
Preferably the neuroinflammatory disorder or neurodegenerative disorder is
Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumour or neuropathic pain. According to a seventeenth aspect 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.
According to an eighteenth aspect the current invention provides a method for treating a disorder in which the P2X7 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.
Preferably 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.
Preferably the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
According to a nineteenth aspect 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.
According to a twentieth aspect 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.
Preferably the compound of formula (II), (III), (IV) or pharmaceutically acceptable salt or solvate thereof is a compound according to the first aspect. Preferably 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.
According to a twenty-first aspect 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 P2X7 receptor with high affinity a subject.
Preferably the binding is antagonistic.
According to a twenty-second aspect 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 P2X7 receptor with high affinity in a subject.
Preferably the binding is antagonistic.
According to a twenty-third aspect 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 P2X7 receptors in a subject.
According to a twenty-fourth aspect 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 P2X7 receptors in a subject, and obtaining an image of the location of the radioisotope in the subject.
According to a twenty-fifth aspect 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.
According to a twenty-sixth aspect 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 P2X7 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
Preferably 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.
Preferably the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
According to a twenty-seventh aspect 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject. According to a twenty-eight aspect 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
According to a twenty-ninth aspect 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.
According to a thirtieth aspect 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.
Preferably 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, πeurodegeneratioπ, neuroinflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation.
Preferably the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
According to a thirty-first aspect 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. According to a thirty-second aspect 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.
According to a thirty-second aspect 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
Figure imgf000033_0001
wherein R is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amine, or oxygen.
Preferably the compound is selected from
Figure imgf000033_0002
According to a thirthy-third aspect 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
Figure imgf000033_0003
wherein each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted amine. Preferably the compound is selected from
Figure imgf000034_0001
In another aspect, the present invention provides a compound of formula:
Figure imgf000034_0002
(VHI) (IX) wherein R1, Rz, R3, R4 and R5 are each independently a monovalent radical, provided that R2 and R4 are not fluoro; or a salt or solvate thereof.
R1, R2, R3, R4 and R5 may be any of the monovalent radicals described below for R1, R2, R3, R4 and R5 in formula (II), provided that R2 and R4 are not fluoro. - Jt -
In some embodiments, the compound of formula (VIII) is
Figure imgf000035_0001
In some embodiments, the compound of formula (IX) is
Figure imgf000035_0002
In another aspect, the present invention provides a radiolabeled compound of formula (Villa) or (IXa):
Figure imgf000035_0003
(VIITa) (IXa) wherein R1, R^, R\ R4 and R3 are each independently a monovalent radical, provided that R2 and R4 are not fluoro; or a salt or solvate thereof. In some embodiments, the compound of formula (Villa) is
Figure imgf000036_0001
In some embodiments, the compound of formula (IXa) is
Figure imgf000036_0002
The compounds of formula (VIII) and (IX), and salts and solvates thereof, bind the P2X7 receptor with hight affinity. The compounds of formula (VIII) and (IX), and pharmaceutically acceptable salts and solvates thereof, may be used to bind to P2X7 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). Similarly, the compounds of formula (Villa) and (IXa), and pharmaceutically acceptable salts and solvates thereof, may be used to image P2X7 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 18F.
In this specification, by reference to a compound "radiolabelled" with 18F, 123I, 76Br, 124I, 7sBr or 1 1C, it is meant that the compound contains 18F, 1231, 76Br, 124I, 75Br or 1 1C respectively. Typically, in a compound of formula (II), (III) or (IV) radiolabelled with 18F, 123I, 76Br, 124I, 75Br or 1 1C, one of R1, R2 , R3, R4 and R3 is substituted with 18F, 123I, 76Br, 1241, 75Br or ' 1C or one of R1, R2 , R3, R4 and Rs is 18F, 123I, 76Br, 1241, 75Br or 11C. In the claims and the description of the invention which follow, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, Le. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure I : P2X7 Receptor Functional Assay: representative images of: i) negative control, ii) positive control, iii) test ligand 1 and iv) test ligand 2.
Figure 2: P2X7 Receptor Functional Assay: summary of the % relative dye uptake for: negative control, positive control, test ligand 1 and test ligand 2.
DETAILED DESCRIPTION OF THE INVENTION
In this specification, the term "halo" refers to fluoro, chloro, bromo or iodo.
In this specification, the term "alkyl" used either alone or in a compound word such as "arylalkyl", refers to a straight chain, branched or mono- or polycyclic alkyl. Typically, the alkyl is a C1-C20 alkyl, e.g.
Figure imgf000037_0001
alkyl or Ci-C3 alkyl. Examples of straight chain and branched alkyl include methyl, ethyl, w-propyl, isopropyl, butyl, iso-batyl, .sec-butyl,
Figure imgf000037_0002
amyl, /sσ-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. Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In this specification, the term "arylalkyl" refers to an alkyl substituted with an aryl group. An example of arylalkyl is benzyl.
In this specification, the term "cycloalkyl" refers to a monocyclic or polycyclic alkyl having 3 to 12 carbons. In this specification, the term "alkenyl" refers to a straight chain, branched or cyclic alkenyl with one or more double bonds. Typically, the alkenyl is a C2-C2O alkenyl, e.g C2-CO alkenyl. Examples of alkenyl include vinyl, ally!, l-methylvinyl, butenyl, iso- butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopeπtenyl,
1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1 -octenyl, cyclooctenyl, 1-nonenyl, 2-noπenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1 ,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
In this specification, the term "alkynyl" refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds. Typically, the alkynyl is a C2-C20 alkynyl, e.g. C2-C6 alkynyl.
In this specification, the term "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. Examples of aryl include phenyl, naphthyl, pyridyl, furanyl, thiophenyl and pyrazolyl. When the aryl comprises a heterocyclic aromatic ring system, 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.
In this specification, the term "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) or a selenium containing group (e.g. alkylselenyl).
In this specification, the term "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, imiπo, 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) or a selenium containing group (e.g. alkylselenyl).
In this specification, the term "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) or a selenium containing group (e.g. alkylselenyl).
In this specification, the term "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) or a selenium containing group (e.g. alkylselenyl).
In this specification, the term "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)
Figure imgf000040_0001
(I)
wherein
V^ is a carboaromatic or heteroaromatic ring having one or more substituents; R6 is
Figure imgf000040_0002
optionally substituted with one or more substituents; and 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 theP2X7 receptor with high affinity and can be radiolabelled for use in in vivo studies of the P2X7 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 18F, 1231, 76Br, 1241, 75Br and ' 1C, or a salt or solvate thereof.
The present inventors have surprisingly found that compounds of formula (I) radio labelled with a radioisotope selected from 18F, 123I, 76Br, 124I, 75Br and 11C can be used to image P2X7 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. In particular 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. Preferably the radioisotope is selected from 18F, 123I, 76Br, 124I, 75Br and 11C. However, the person skilled in the art would appreciate that radiolabelling is not limited to these radioisotopes.
The compounds of formula (I), and the compounds of formula (I) radiolabeled with a radioisotope selected from 18F, '23I, 76Br, 124I, 75Br and ' 1C, form salts and solvates, and salts and solvates of such compounds are encompassed by the present invention. The salts of the compounds of formula (I), and the compounds of formula (1) radiolabelled with a radioisotope selected from 18F, 1231, 76Br, 1241, 7SBr and 1 1C, 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, ascorbic and valeric acids. *
The solvates of the compounds of formula (I), or the radiolabelled compounds of formula (I) (wherein one or more solvent molecules are associated with each molecule of the compound of formula (I) or radiolabelled compound 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, phenanthreπe, quinoline, isoquinoline, or triphenylene. In some embodiments, ring vJ> is benzene or pyridine.
In one embodiment, the compound of formula (I) is a compound of formula (II), formula (III) or formula (IV):
Figure imgf000043_0001
(") (IU) (IV) wherein: R1, R2, R3, R4, and R5 are each independently a monovalent radical;
R6 is
Figure imgf000043_0002
optionally substituted with one or more substituents; and 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.
In some embodiments of formula (II), formula (III) or formula (IV), n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8. For example, in some embodiments, n is 0, 1, 2, or 3. More preferably n is 0, l or 2.
In some embodiments, R6 is
Figure imgf000043_0003
In some embodiments R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -POR^OR6) or -PO(ORb); wherein Ra is selected from optionally substituted aflcyl, optionally substituted aryl and -SiRc 3, wherein each R° is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeR8, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
In some embodiments R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -OR\ -SRa, -SeR3, -OCORb, -OCONRb2, -NRb 2, -NRbCOORb, or -NReCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRS, wherein each Rc 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 R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeR\ -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, or -NRbCONRb 2; wherein R" is selected from optionally substituted alkyl, optionally substituted aryl and — SiR°3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
In some embodiments R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, -ORa, -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRc 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -ORa, -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRc3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
In some embodiments R1 and R3 are each independently H or halogen. R4 is preferably H or -OR", wherein Ra is optionally substituted alkyl. Preferably R1 and R3 are each independently H, F or Cl; R2 and R5 are each H; and R4 is H or methoxy. In some embodiments, the compound of formula (II) is selected from
Figure imgf000045_0001
or a salt or solvate thereof.
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 18F, 123I, 76Br, 124I, 75Br or 11C by standard techniques known in organic chemistry for modifying an organic compound to replace a hydrogen, halo or carbon group in the compound with 18F, 1231, 76Br, 124I, 75Br or 11C. Alternatively, compounds of formula (I) radiolabelled with a radioisotope selected from 18F, 1231, 76Br, 1241, 75Br and 1 1C may be prepared by incorporating 18F, 123[, 76Br, 124I, 75Br or ' 1C 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 18F, u% 76Br, u\ 75Br or 11C may, for example, be prepared by preparing a compound having the formula (II), (III) or (IV) defined above, wherein one of R1, R2, R3, R4 and R5 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 18F, 1231, 76Br, 124I, 75Br or ' 1C. 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 R1, R2, R3, R4 and Rs.
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. In this case, using suitable reagents and conditions, 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 11C (e.g. an alkyl halide labelled with 11C).
For example, the following compound can be radiolabelled with 11C by the method described in Scheme 1 :
Figure imgf000046_0001
Scheme 1
The compound of formula (I) may be radiolabelled with 18F (half-life 1 10 minutes), 123I (half-life 13.2 hours), 76Br (half-life 16.2 hours), 124I (half-life 4.2 days), 75Br (half-life 1.6 hours) or 1 1C (half-life 20 minutes). Typically, the compound of formula (1) is radio labelled with 18F.
Examples of compounds of formula (I) radio labelled with 18F or ' 1C include:
Figure imgf000047_0001
Figure imgf000047_0003
Figure imgf000047_0004
Figure imgf000047_0005
Compounds of formula (I) may be radio labelled with a suitable radtioisotope known to the skilled address. Examples of radiolabelled compounds include:
Figure imgf000047_0006
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000049_0003
Figure imgf000049_0002
Compounds of formula (I) radiolabeled with 18F, 1231, 76Br, 124I, or 75Br are more practical in a clinical sense for imaging than compounds radio label led with radioisotopes having a significantly shorter half-life, as multiple scans can be performed on one day. In addition, hospitals/organisations that do not have a cyclotron on site can use such radioligands, as the radioligands can be prepared offsite and transported to the hospital/organisation with no significant loss of activity during transportation. In addition, longer scans (e.g. 180 minutes) can be undertaken with compounds labelled with '8F, 123I, 76Br, 124I or 75Br making them more appropriate for the study of most biological processes.
Compounds of formula (I) radiolabelled with 18F, 1231, 76Br, 124I, 75Br or 11C have affinity and selectivity for P2X7, and can be used for imaging P2X7 in a subject. Accordingly, compounds of formula (I) radiolabelled with 18F, 123I, 76Br, '24I, 75Br or 11C can be used to study P2X7 in a subject.
In a subject having a neuroinflammatory or neurodegenerative disorder, P2X7 expression in the brain is increased compared to a subject not having a neuroinflammatory or neurodegenerative disorder. Accordingly, the compounds of formula (I) radiolabelled with 18F, 1231, 76Br, 124I, 75Br or 1 1C 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.
In accordance with the method of the present invention for imaging P2X7 receptor in a subject, a compound of formula (I) radiolabelled with a radioisotope selected from 18F, 123I, 76Br, 124I, 75Br and ' 1C, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject. When the compound of formula (1) is radiolabeled with 18F, 76Br, 1241, 75Br or 11C, the image of the location of the radioisotope in the subject, and therefore the location of P2X7 in the subject, may be obtained by positron emission tomography (PET) imaging using conventional techniques known the art. When the compound of formula (I) is radiolabeled with 123I, 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.
Typically for both PET and SPECT imaging, the data is acquired using conventional dynamic or list mode acquisition techniques, commencing immediately after administration of the compound of formula (I) radiolabeled with 18F, 1231, 76Br, 124I, 75Br or 11C, or pharmaceutically acceptable salt or solvate thereof, and continuing for about 40 minutes or longer. At the completion of data acquisition, 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.
Typically, the compound of formula (I) radiolabeled with 18F, 123I, 76Br, 124I, 75Br or 11C, or pharmaceutically acceptable salt or solvate thereof, is administered parenterally. Typically, the compound of formula (I) radiolabeled with 18F, 1231, 76Br, 124I, 75Br or 1 1C, or pharmaceutically acceptable salt or solvate thereof is administered parenterally by intravenous injection or infusion.
Typically, the compound of formula (1) radiolabeled with 18F, 1231, 76Br, 1241, 75Br or 1 1C, or pharmaceutically acceptable salt or solvate thereof, is administered by administering a pharmaceutical composition comprising the compound of formula (I) radiolabeled 18F, 1231, 76Br, 1241, 75Br or 11C, 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. Examples of 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 18F, 123I, 76Br, 1241, 75Br and 11C 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 18F, 1231, 76Br, 1241, 75Br and 1 1C, 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
The compounds of formula (I) bind the P2Xη 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 wintergreeπ, 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. Examples of 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. In some embodiments, 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.
As used herein, 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.
As used herein, 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.
Generally, 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" as used herein 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.
Specific embodiments of the present invention will now be described by way of example only. The examples should be interpreted as limiting the invention to the particulars described.
EXAMPLES
1.1 Preparation of reagents
4-MethoxycarbonyIcubane carboxylic acid (6)
Figure imgf000054_0001
6
A solution of methanolic NaOH (8.5 mL, 2.5 M, 21 mrool) was added dropwise to a solution of dimethyl 1,4-cubanedicarboxylate (4.5 g, 20 mmol) in THF (140 mL) at room temperature. The mixture was stirred overnight and then concentrated under reduced pressure with minimal heating. The solid residue was diluted with H2O (50 mL) and washed with CHCl3 (3 x 25 mL). The aqueous layer was acidified to pH 3 with dropwise addition of cone. HCl (ca. 2.5 mL) and extracted with CHCI3 (1 x 80 mL; 2 x 40 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo for 3 h to yield the ester-acid 6 (3.7 g, 88 %) as a colourless solid; m.p. 184-186 0C; 1H NMR (200 MHz, CDCl3) δ 4.27 (6H, m, cubyl H), 3.72 (3H, s, CH3).
l-Cubanecarboxylic acid (7)
Figure imgf000055_0001
7
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). The solution was added dropwise over about 20 min to a magnetically stirred, refluxing suspension of N-hydroxypyridine-2-thione sodium salt (2.9 g, 20 mmol), 4-(N,/V-dimethylamino)pyridine (46 mg, 0.38 mmol), and distilled f-butyl thiol (3.9 mL, 3.1 g, 35 mmol) in benzene (56 mL), under irradiation from a 500 watt tungsten filament lamp, placed ca. 2 cm from the reaction vessel. After an additional 1 h of reflux, the mixture was cooled (ice-water bath) and a saturated solution of aq. Ca(OCl)2 (15 mL) was added with vigorous stirring. The mixture was then diluted with Et2O (50 mL) and washed with H2O (3 x 50 mL). The aq. layer was back extracted with Et2O (50 mL). The combined organic extracts were dried (Na2SO4) and the solution was concentrated under reduced pressure to ca. 25 mL. Methanolic NaOH (40 mL, 1.25 M, 50 mmol) was added, and the solution was refluxed for 1 h, cooled, and concentrated to near dryness under reduced pressure. Benzene (40 mL) was added and the solution was reconcentrated to near dryness. H2O (60 mL) was added and the mixture was extracted with CH2CI2 (3 x 25 mL). The aq. layer was acidified slowly to pH 1 with vigorous stirring by the addition of cone. HCl (ca. 5 mL). The yellow mixture was extracted with CH2Cl2 (1 x 60 mL, 2 x 20 mL) and the combined organic extracts were dried (Na2SO4) and evaporated to give the acid 7 (2.12 g, 80%) as a yellow solid; 1H NMR (200 MHz, CDCI3) δ 4.30 (3H, m, 2-CH, 6-CH, 8-CH), 4.03 (4H, m, 3-CH, 4-CH, 5-CH, 7-CH). A portion of the acid was recrystallised to give analytically pure 7; m.p. 126-128 0C.
Figure imgf000056_0001
ii) 'BuSH hv Hi) NaOH, McOH. THF
Figure imgf000056_0002
A cubane having two carboxylic substituents can be synthesised by the following synthetic routes.
Figure imgf000056_0003
Figure imgf000056_0004
iv) PhI(OAc)2, 12 v) n-BuLi, then MeOH vi) Mg, AcOH
Figure imgf000057_0001
iv) n-BuLi, then MeOH V) HNO3
1-Cubanemethylamine (S)
H1 ^NH,
8 The acid 7 (0.45 g, 3.0 mmol) was dissolved in oxalyl chloride (2.5 mL) and stirred at room temperature for 45 min. Excess oxalyl chloride was removed under reduced pressure and the residue was dissolved in CH2Cb (20 mL) in a three-neck round bottom flask equipped with a cold finger filled with dry ice/acetone. NH3 gas was condensed into the flask (ca. 3 mL) and the suspension was stirred for 30 min. After warming to room temperature, the excess NH3 was allowed to evaporate. H2O (40 mL) was added, followed by extraction with CHCI3 (2 x 60 mL, 1 x 30 mL). The combined organic extracts were dried (Na2SO.*) and evaporated in vacuo for 2.5 h to give 1-cubanecarboxamide (0.37 g) as a white solid. Powdered LiAlH<i (0.45 g, 12 mmol) was added to a solution of the amide in THF (60 mL) at 0 0C with stirring. After warming to room temperature, the suspension was refluxed for 16 h before cooling down to 0 0C with ice- water bath. Saturated aq. NaOH (ca. 2 mL) was added dropwise with vigorous stirring to quench the excess L1AIH4 after which the mixture was stirred at room temperature for 1 h. The granular precipitate was filtered off and washed with CH2CI2 (70 mL). The combined organic portions were dried (Na2SO^) and evaporated under reduced pressure. The crude product was purified by flash chromatography (90: 10:0.5 v/v CH2Cl2:Me0H:aq. NH3) to yield the amine 8 (287 mg, 70%) as a light brown oil; Rf 0.14 (90:10:0.5 v/v CH2Cl2:Me0H:NH3); 1H NMR (200MHz, CDCl3) δ 4.03 (I H, m, 4-CH), 3.85 (6H, m, cubyl H), 2.83 (2H, s, T-CH2); 13C NMR (75.5 MHz, CDCl3) δ 59.7 (1-C), 48.8 (4-CH), 46.9 (CH), 44.4 (CH)1 44.2 (1 '-CH2).
1-Adamantanemεthylamine (9)
Figure imgf000058_0001
9 1-Adamantanecarboxylic acid (7.4 g, 41 mmol) was heated to reflux with thionyl chloride (15 mL) and DMF (2 drops) for 3 h. The excess thionyl chloride was distilled off under reduced pressure, and the residual traces were removed in vacuo for 15 min. The residue was dissolved in THF (20 mL) and added to aq. NH3 (100 mL, 30%) with ice cooling and stirring. After stirring for 1 h at room temperature, the precipitate was filtered off, H2O (ca. 1 L) added, followed by CH2Cl2 (ca. 200 mL) until the entire solid dissolved. The organic layer was collected, dried (Na2SO^) and evaporated in vacuo for 5 h to give 1-adamantanecarboxamide (5.15 g) as a colourless solid; 1H NMR (200 MHz, CDCl3) S 5.75 (br), 2.05 (3H, br s), 1.89-1.88 (6H, m), 1.80-1.63 (6H, m).
Powdered LiAlH4 (3 g, 80 mmol) was added to a solution of the 1 -cubanecarboxamide in THF (120 mL) at 00C 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 0C with vigorous stirring. After stirring for 1 h at room temperature, the white mixture was filtered and the residue was washed with CH2Cl2 (60 mL). The combined organic portions were dried (Na2SO<ι) and evaporated in vacuo to give the crude amine 9 (4.1 g, 60%) as a colourless oil with some solid impurities. The crude was then purified by flash chromatography (90:10:0.5 v/v CH2Cl2:Me0H:aq. NH3) to give the pure amine 9 as a colourless oil; Rr 0.13 (90: 10:0.5 v/v CH2Cl2: MeOH:aq.NH3); 1H NMR (200 MHz, CDCl3) δ 2.31 (2H, s, T-CH2), 1.98 (3H, br s), 1.76-1.60 (6H, m), 1.46-1.45 (6H, m). The spectroscopic data matched that reported by Sigma Aldrich. 2-Chloro-5-hydroxyben2oic acid (10)
Figure imgf000059_0001
10
5-Amino-2-chlorobenzoic acid (2.6 g, 15 mmol) was suspended in dilute H2SO4
(240 mL, 1.25 %) and cooled to ca. 5 0C in an ice- water bath. A solution of NaNCb
(1.5 g, 22 mmol) in H2O (45 mL) was then added via a dropping funnel over a period of 15 min, maintaining the temperature between 0-5 °C. Following the addition, the mixture was stirred for 1 h until the solution became clear, at which point it was poured into hot H∑O (450 mL, ca. 60 0C). Decolourising charcoal (2 g) was added and the mixture was refluxed for 30 min. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with EtOAc (3 x 250 mL). The combined organic extracts were dried (Na2SO-O and evaporated in vacuo for 3 h to give the acid 10
(1.78 g, 70 %) as a light brown solid; m.p. 186- 189 0C, Rr 0.43 (5:1 EtOAcrhexane + 1 drop acetic acid); IR (KBr disc) 3408 (O-H), 3315, 3312, 3070-2552 (br, COOH), 1713, 1678, 1645 (C=O), 1601, 1574, 1423, 1418, 1308, 1269, 1252, 1238, 121 1, 1 126, 1049, 935, 879, 825, 785, 771, 667, 569 cm 1; 1H NMR (300 MHz, DMSO-d6) δ 13.25 (I H, s, COOH), 9.98 (I H, s, OH), 7.30 (IH, d, J = 8.7 Hz, 3-CH), 7.14 (IH, d, J = 3.0 Hz, 6-CH), 6.90 (1 H, dd, J= 8.7, 3.0 Hz, 4-CH); 13C NMR (75.5 MHz, DMSO-d6) δ 167.5, 157.0, 132,9, 132.4 (CH), 121.8, 120.4 (CH), 1 18.0 (CH); HRMS (Ei) CaIc. for C7H5 35ClO3 [M]+:. 171.9927, found: 171.9925; m/z (-ESI) 345, 343 ([2M - 2H]2-, 20, 27), 173, 171 ([M - H]", 34, 100).
Methyl (2-chloro-5-methoxy)benzoate (11)
Figure imgf000059_0002
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 K2CO3 (2.85 g, 20 mmol) in DMF (40 mL). The reaction mixture was heated at 40 0C for 5 h, followed by another addition of methyl iodide (1.2 mL, 19 mmol). After 16 h of stirring at 40 0C, the reaction mixture was cooled to room temperature and H2O (100 mL) was added, followed by extraction with Et2O (2 x 60 mL, 1 x 30 mL). The organic layers were washed sequentially with aq. NaOH (0.1 M, 100 mL) and H2O (2 x 80 mL), dried (Na2SO-O, and concentrated- under reduced pressure to give the benzoate 11 (0.81 g, 94 %) as a yellow oil; 1H NMR (200 MHz, DMSO-d6) δ 7.49 (I H, d, J = 8.9 Hz, 3-CH), 7.32 (IH, d, J= 3.1 Hz, 6-CH), 7.16 (1 H, dd, J= 8.9, 3.1 Hz, 4-CH), 3.86 (3 H, s, CH3), 3.81 (3H1 S5 CH3).
2-Chlorα-5-methoxybenzoic acid (12)
Figure imgf000060_0001
12
A solution of methyl (2-chloro-5-methoxy)benzoate 11 (0.81 g, 4.3 mmol) in THF/H2O (1 : 1 v/v, 20 mL) was added to a solution of LiORH2O (0.85 g, 20 mmol) in THF/H2O (1 :1 v/v, 20 mL). After heating for 5 h at reflux, the reaction mixture was cooled to room temperature and stirred for a further 16 h. The reaction was concentrated under reduced pressure (until ca. 10 mL liquid remained) and HCI (2.2 M5 10 mL) was added dropwise until pH = 1. The mixture was extracted with CH2CI2 (2 χ 100 mL, 1 x 50 mL) and the organic layers were dried (Na2SO-O and concentrated in vacuo to give the acid 12 (0.66 g, 87%) as a light brown solid; m.p. 178-181 0C, Rf 0.46 (5:1 EtOAc:hexane + 1 drop acetic acid); IR (thin film) 3020, 2978, 2945, 2880, 2814, 2658, 2586, 2478, 2395, 1674 (C=O), 1312, 1267, 1234, 675 cm'1; 1H NMR (300 MHz7 DMSO-d6) δ 13.42 (I H, s, COOH), 7.43 (IH, d, J= 8.8 Hz, 3-CH), 7.28 (I H, d, J= 3.1 Hz, 6-CH), 7.10 (IH, dd, J= 8.8, 3.2 Hz, 4-CH), 3.79 (3H, s, CHj); IJC NMR (75.5 MHz, DMSO-d6) δ 176.0, 167.3, 141.8, 141.0 (CH), 132.1, 127.8 (CH), 125.0 (CH), 65.2 (CH3); HRMS (-ESI) CaIc. for C8H7ClO3 [M - H]": 185.0012, found: 185.0007; m/z (-ESI) 187, 185 ([M - H]\ 37, 100), 157 (1 1).
Racemic />j-trishomocubanone
Commercially available 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.
Figure imgf000061_0001
20
12 General procedure for the formation of an amide from an acid chloride and an amine
A solution of the acyl chloride (1.0 mmol) in MeCN (10 mL) was added dropwise to a solution of the amine (1.0 mmol) and NEt3 (0.10 g, 1.0 mmol) in MeCN (10 mL) at 0 0C. After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. H2O (35 mL) was added, followed by extraction with CH2Ch (3 x 35 mL). The organic layers were washed sequentially with NaHCOj (40 mL) and H∑O (40 mL), dried (Na2SO4), and concentrated in vacuo to give the crude amide, • which was then purified by flash chromatography (80:20 v/v cyclohexane.EtOAc).
The reaction can be illustrated, by way of example, with 1-Cubanemethylamine (8), which can be synthesised from 1-Cubanecarboxylic acid (7).
Figure imgf000062_0001
R=2-F, 4-F, 2-Cl-5-OMe Si) LiAIH4 iv) ArCOCI NEt3, MeCN
The reaction can also be illustrated, by way of example, with 1- Adamantanemethylamine (9)
Figure imgf000062_0002
R=2-F, 4-F, 2-CI-S-OMe
/V-adamantan-1 ylmethyl-2-fluoro-benzaπiide (1)
Figure imgf000062_0003
1
Following the general procedure, the crude benzamide 1 (275 rag, 96%) was obtained as a colourless solid; m.p. 121-125 0C, Rr 0.44 (80:20 v/v hexane: EtOAc); IR (thin film) 3394, 2924, 2899, 2847, 1647 (C-O), 1537, 1450, 617, 509 cm"1; 1H NMR (300 MHz, CD3OD) δ 7.70-7.65 (1 H, overlapping dd, 6-CH), 7.55-7.47 (IH, m, 4-CH), 7.29-7.17 (2H, m, 3-CH, 5-CH), 3.10 (2H, s, CH2-NH), 1.99 (3H, s),
1.80-1.67 (6H1 m), 1.61-1.60 (6H, m); 13C NMR (75.5 MHz, CD3OD) δ 167.5, 161.5 (1Jc-P = 248.7 Hz), 134.0 (CH, 3Jc-F = 8.7 Hz), 131.6 (CH, VC-F = 2.5 Hz), 125.9 (CH, 3J = 3.5 Hz), 125.3 (CH, 2Jc-F = 14.2 Hz), 1 17.4 (2Jc-F = 23.0 Hz), 52.7 (CH2), 41.7 (CH2), 38.4 (CH2), 35.9, 30.1 (CH); HRMS (+ESI) CaIc. for C18H22ONF [M + H]+: 288.1758, found: 288.1749; m/z (+ESI) 288 ([M + H]+, 100), 242 (12); Anal. (Ci8H22ONF): calc, C 75.23, H 7.72, N 4.87; found, C 74.91, H 7.59, N 4.85.
/V-adamantan-l-ylmethyI-4-fluoro-benzamide (2)
Figure imgf000063_0001
2
Following the general procedure, the crude benzamide 2 (265 mg, 92%) was obtained as a colourless solid; m.p. 156-1600C, Rf 0.38 (80:20 v/v hexane: EtOAc); IR (thin film) 3281 (N-H), 3097, 3063, 2957, 2924, 2899, 2847, 2793, 2752, 2673, 1639 (C=O), 1504, 1312, 1290, 1229, 1 159, 852, 735, 631, 600 cπf1; 1H NMR (300 MHz, CD3OD) δ 7.86 (2H, m, 2-CH, 6-CH), 7.19 (2H, m, 3-CH, 5-CH), 3.08 (2H, s, CH2-NH), 1.98 (3H, s), 1.79-1.67 (6H, m), 1.60-1.59 (6H, m); 13C NMR (75.5 MHz, CD3OD) δ 170.0, 166.5 (1Jc-F = 250.0 Hz), 132.9, 131.3 (CH, VC-F = 8.9 Hz), 116.7 (CH, 2Jc-F = 22.1 Hz), 52.8 (CH2), 41.9 (CH2), 38.5 (CH2), 36.3, 30.3 (CH);
HRMS (+ESI) Calc. for Ci8H22ONF [M + H]+: 288.1758, found: 288.1760; m/z (+ESI) 597 ([2M + Na]+, 100), 342 (69), 288 ([M + H]+, 72); Anal. (C18H22ONF): calc, C 75.23, H 7.72, N 4.87; found, C 74.97, H 7.44, N 4.91.
/V-adamantan-l-ylmethyI-(2-chloro-5-methoxy)-benzamide (Z)
Figure imgf000063_0002
Oxalyl chloride (0.55mL, 6 mmol) was added to a solution of 2-chloro-5- methoxybeπzoic acid 12 (0.38 g, 2.1 mmol) in THF (20 mL) at 0 0C. 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 NEt3 (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. H2O (75 mL) was added, followed by extraction with CH2Cb (3 x 75 mL). The organic layers were washed sequentially with NaHCO3 (140 mL) and H2O (140 mL), dried (Na2SO4), and evaporated in vacuo. The crude material was purified by flash chromatography (80:20 v/v cyclohexane:EtOAc) to give the benzamide (Z) (0.46 g, 72%) as a colourless solid; m.p. 115-118 0C, Rr 0.25 (80:20 v/v hexane:EtOAc); IR (thin film) 3447, 3288 (N-H), 3076, 2901, 2847, 2270, 1645 (C=O), 1599, 1574, 1531, 1472, 1450, 1312, 1292, 1234, 1026, 808, 719, 677, 617 cm"1; 1H NMR (300 MHz, CD3OD) δ 7.36-7.33 (I H, m, CH), 7.00-6.97 (2H, m, CH), 3.81 (3 H, s, CH3), 3.05 (2H, s, CH2), 1.99 (3H, s), 1.80-1.67 (6H, m), 1.63-1.63 (6H, m); 13C NMR (75.5 MHz, CD3OD) δ 170.5, 160.3, 139.2, 132.3 (CH), 123.2, 1 17.9 (CH), 1 15.7 (CH), 56.6 (CH3), 53.0 (CH2), 41.9 (CH2), 38.5 (CH2), 36.1, 30.3 (CH); HRMS (+ESI) CaIc. for Ci9H24O2N35Cl [M + H]+: 334.1571, found: 334.1562; m/z (+ESI) 691, 689 ([2M + Na]+, 66, 100), 334.1 ([M], 26);
Anal. (C19H24O2NCI): calc, C 68.35, H 7.25, N 4.20; found, C 68.47, H 7.24, N 4.26.
/V-cuban-l-ylmethyl-2-fluoro-benzamide (4)
Figure imgf000064_0001
Following the general procedure, a solution of 1 -cubanemethyl amine (73 mg, 0.55 mmol) and NEt3 (56 mg, 0.55 mmol) in MeCN (5 mL) was treated with a solution of 2-fluoro benzoyl chloride (88 mg, 0.55 mmol) in MeCN (5 mL). Following the standard workup, the crude material was purified by flash chromatography (80:20 v/v cyclohexane:EtOAc) to give the benzamide 4 (100 mg, 71%) as a light cream coloured solid; m.p. 71-75 0C, Rf 0.34 (80:20 v/v hexane: EtOAc); IR (thin film) 3369 (N-H), 3275, 2978, 2962, 2907, 2853, 1639 (C=O), 1614, 1543, 1296, 1213, 756, 629 cm'1; 1H NMR (300 MHz, CD3OD) δ 7.68-7.63 (IH, m, 6-CH), 7.53-7.50 (I H, m, 4-CH), 7.29-7.16 (2H, m, 3-CH, 5-CH), 4.08-4.04 (I H, m, cubyl H), 3.95-3.92 (6H, m, cubyl H), 3.61 (2H, s, CH2); 13C NMR (75:5 MHz, CDjOD) δ 167.8, 161.6 (1Jc-F = 248.9 Hz), 134.2 (CH, 3Jc-F= 8.5 Hz), 131.7 (CH, 4Jc-F = 2.4 Hz), 126.0 (CH, 3Jc-K = 3.5 Hz), 125.2 (CH, 2Jc-F = 14.2 Hz), 1 17.5 (CH, 2Jc-F = 22.9 Hz), 59.3, 50.4 (CH), 49.4 (CH), 45.8 (CH), 43.4 (CH2); HRMS (+ESI) CaIc. for Ci6H14ONF [M + H]+: 256.1 132, found: 256.1 127; m/z (+ES1) 278 ([M + Na]+, 95), 256 ([M + H]+, 100); Anal. (C16H14ONF): calc, C 75.28, H 5.53, N 5.49; found, C 74.83, H 5.54, N 5.23.
N-cu ban- 1 -y hnethyl-4-fluo ro-benza m ide (5)
Figure imgf000065_0001
Following the genera! procedure, a mixture of 1 -cubanemethyl amine (0.20 g,
1.5 mmol) and NEt3 (0.15 g, 1.5 mmol) in MeCN (15 mL) was treated with a solution of 4-fluoro benzoyl chloride (0.24 g, 1.5 mmol) in MeCN (15 mL). Following the standard workup, the crude material was purified by flash chromatography (80:20 v/v cyclohexane:EtOAc) to give the benzamide 5 (250 mg, 65%) as a light cream coloured solid; m.p. 176-178 0C, Rr 0.37 (80:20 v/v cycJohexane.ΕtOAc); IR (thin film)
3380 (N-H), 3227, 3070, 3043, 2976, 2961, 2922, 2814, 1636 (C=O), 1545, 1504, 1275, 1 159, 627, 600 cm'1; 1H NMR (300 MHz, CD3OD) δ 7.85 (2H, m, 2-CH, 6-CH), 7.18 (2H, m, 3-CH, 5-CH), 4.06-4.03 (IH, m, cubyl H), 3.92-3.90 (6H, m, cubyl H), 3.59 (2H, s, CH2); 13C NMR (75.5 MHz, CD3OD) δ 170.0, 166.5 (1JcF = 249.9 Hz), 132.7, 131.3 (CH, 3JC_F = 8.9 Hz), 1 16.7 (CH, 2Jc-K= 22.0 Hz), 59.5, 50.3 (CH), 49.4 (CH), 45.7 (CH), 43.4 (CH2); HRMS (+ESI) CaIc. for C16H14ONF [M + H]+: 256.1 132, found: 256.1 129; m/z (+ESI) 256 ([M + H]+, 96); Anal. (C16H14ONF): calc, C 75.28, H 5.53, N 5.49; found, C 75.14, H 5.53, N 5.48.
N-cuban-l-ylmethyl-(2-chloro-5-methoxy)-benzamide (3)
Figure imgf000066_0001
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 0C. 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
(25 mL) and added to a solution of 1 -cubanemethyl amine (0.27 g, 2.0 mmol) and NEt3 (0.25 g, 2.5 mmol) in MeCN (20 mL). After 16 h of stirring at room temperature, the reaction mixture was concentrated under reduced pressure. H2O (90 mL) was added, followed by extraction with CH2CI2 (3 x 90 mL). The organic layers were washed sequentially with NaHCO3 (140 mL) and H2O (140 mL), dried (Na2SO4), and evaporated in vacuo. The crude material was purified by flash chromatography (80:20 v/v cyclohexane: EtOAc) to give the benzamide 3 (0.35 g, 58%) as a light cream coloured solid; m.p. 160-161 0C, Rf 0.28 (80:20 v/v cyclohexane:EtOAc); IR (thin film) 3313 (N-H), 3192, 3074, 3065, 2986, 2966, 2924, 2851, 2835, 2733, 2696, 2258, 2231, 2193, 2131, 1638 (C=O), 1605, 1545, 1298, 1 136, 1024, 818, 519, 509 cm"1; 1H NMR (300 MHz, CD3OD) δ 7.36-7.33 (I H, m, CH), 7.00-6.94 (2H, m, CH), 4.08-4.05 ( I H1 m, cubyl H), 3.94-3.93 (6H, m, cubyl H), 3.81 (3H, s, CH3), 3.57 (2H, s, CH2); 13C NMR (75.5 MHz, CD3OD) δ 170.6, 160.3, 139.1, 132.2 (CH), 123.2, 1 18.0 (CH), 115.6 (CH), 59.4, 56.6 (CH3), 50.3 (CH), 49.5 (CH), 45.8 (CH), 43.3 (CH2); HRMS (+ESI) Calc. for C17H16O2N35Cl [M + Na]+: 324.0764, found: 324.0756; m/z (+ESI) 627, 625 ([2M + Na]+, 84, 100), 324 ([M + Na]+, 95), 302 ([M + H]+, 30); AnaL (C17Hi6O2NCl): calc, C 67.66, H 5.34, N 4.64; found, C 67.89, H 5.48, N 4.49. Synthesis of substituted compounds
Figure imgf000067_0002
THF
Figure imgf000067_0001
M AiCOCl
NEt3, MeCN v) fiuorration
1 J Demethylation of the methyl aryl ethers yV-adaniantan-l-yIraethyi-(2-chloro-5-hydroxy)-benzamide (13)
Figure imgf000067_0003
13
To a solution of iV-adamantan-l -ylmethyl-(2-chloro-5-methoxy)-benzamide (Z) (75 mg, 5 0.23 mmol) in CH2Cl2 (4 mL) at O 0C was added BBr3 (1 M in CH2Ch, 350 μL, 0.35 mmol). The reaction mixture was stirred at room temperature for 5 h before another portion Of BBr3 (1 M in CH2CI2, 350 μL, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 days, after which time complete reaction was confirmed by t.l.c. The excess BBr3 was quenched with MeOH (1.5 mL) O and the reaction mixture was concentrated under reduced pressure. EtOAc (50 mL) was added followed by washing with H2O (4 x 40 mL). The organic layer was dried (Na∑SO-t) and concentrated in vacuo to give the crude material which was purified by flash chromatography (95:5 v/v CH2CbIMeOH) to give the hydroxy-benzamide 13 (60 mg, 84%) as a light brown solid; m.p. 248-250 0C, Rf 0.28 (95:5 v/v 5 CH2Cl2:Me0H); 1H NMR (300 MHz, CDjOD) δ 7.25-7.22 (1 H, m, CH), 6.85-6.80 (2H, m, CH), 3.04 (2H, s, CH2), 1.99 (3H, s), 1.80-1.67 (6H, m), 1.63- 1.62 (6H, m); 13C NMR (75.5 MHz5 CDjOD) δ 170.8, 158.1, 139.2, 132.2 (CH), 121.7, 1 19.3 (CH), 116.9 (CH), 52.9 (CH2), 41.8 (CH2), 38.5 (CH2), 36.1, 30.3 (CH); HRMS (+ESI) CaIc. for C18H22O2N35Cl [M + Na]+: 342.1234, found: 324.1232; m/z (+ESI) 663,
661 ([2M + Na]", 73, 100), 342 ([M + NaJ+, 16), 320 ([M + H]+, 9);
Anal. (C18H22O2NCl) C, H, N: calc, 67.60, 6.93, 4.38; found, 67.78, 7.04, 4.1 1.
Λ?-cuban-l-ylmethyl-(2-chIoro-5-hydro)-y)-benzamide (14)
Figure imgf000068_0001
14
To a solution of N-cuban-l -ylmethyl-(2-chloro-5-methoxy)-benzamide 3 (65 mg, 0.22 mmol) in CH2Cl2 (4 mL) at 0 0C was added BBr3 (1 M in CH2Cl2, 350 μL, 0.35 mmol). The reaction mixture was stirred at room temperature for 5 h before another portion Of BBr3 (1 M in CH2Cl2, 350 μL, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 days, after which time complete reaction was confirmed by t.Lc. The excess BBr3 was quenched with MeOH (1.5 mL) and the reaction mixture was concentrated under reduced pressure. EtOAc (50 mL) was added followed by washing with H2O (4 x 40 mL). The organic layer was dried (Na2SO.*) and concentrated in vacuo to give the crude material which was purified by flash chromatography (95:5 v/v CH2Cb:MeOH) to give the hydroxy-benzamide 14 (63 mg, 100%) as a fine, light brown solid; m.p. 140-1420C, Rf 0.20 (95:5 v/v CH2CI2-MeOH); 1H NMR (300 MHz, CD3OD) δ 7.24-7.21 (I H, m, CH), 6.83-6.80 (2H, m, CH), 4.08-4.04 (1 H, m, cubyl H), 3.94-3.93 (6H, m, cubyl H), 3.55 (2H, s, CH2); 13C NMR (75.5 MHz, CD3OD) δ 170.8, 158.1, 139.0, 132.2 (CH), 121.7, 119.4 (CH), 1 16.9 (CH), 59.4, 50.3 (CH), 49.5 (CH), 45.8 (CH), 43.3 (CH2); HRMS (-ESI) CaIc. for CI6HI4O2N35CI [M + Na]+: 310.0608, found: 310.0606; m/z (-ES1) 575, 573 ([2M - 2Hf, 100, 92), 289, 287 ([M - Hf, 30, 80). Preparation of ZVtrishomocubylamides
Reaction of ZVtrishomocubanone with hydrochloric acid salt of hydroxy lamine produced an oxime, which was then reduced using lithium aluminium hydride and subsequently reacted with hydrogen chloride to make the amine salt. The hydrochloric acid salt of the amine was then reacted with different aromatic acids under standard peptide coupling condition using EDCHCl and HOBt as the coupling reagent and N- methylmorpholine as a base. Purification by column chromatography yielded the desired amides.
Figure imgf000069_0001
Si) HCI, ether
Figure imgf000069_0002
20 21
22 X=C, R'=F, R2=H, R3=H
23 X=C, R'=H, R2 =F, R3=H
24 X=C, R'=C1, R2=H, R3=0Me
25 X=N, R'=F, R2=H, R3=H
Figure imgf000069_0003
Preparation of ZVtrishomocubylmethylamides
Reaction of D3-trishomocubanone with p-tosylmethylisocyanide produced the nitrile, which was then reduced using lithium aluminium hydride to afford the desired amine. The amine was then reacted with different aromatic acids under standard peptide coupling condition using EDCHCl and HOBt as the coupling reagent and N- methylmorpholine as a base. Purification by column chromatography yielded the desired amides.
Figure imgf000070_0001
29 X=C, R'=H, R1 =F, RJ=H
Figure imgf000070_0002
31 X=N, R'=F, R2=H, R3=H
32 X=N, R'=H, R2=F, R3=H
Preparation of /Vtrishomocubylethylamides (saturated or unsaturated)
Wittig reaction of D3-trishomocubanone with (cyanomethyl)triphenylphosphonium chloride produced the unsaturated nitrile. LiAIH4 reduction afforded the unsaturated amine, which could then be hydrogenated using palladium-charcoal. The unsaturated and saturated amines were then reacted with different aromatic acids under standard peptide coupling condition using EDCHCl and HOBt as the coupling reagent and N- methylmorpholine as a base. Purification by column chromatography yielded the desired amides.
Figure imgf000070_0003
20 33
U
Figure imgf000070_0004
, 35 X=C, R'=H, R2 -F, R3=H
36 X=C, R'=C1, R2=H, R3OMe
37 X=N, R'=F, R2=H, R3=H
38 X=N, R'=H, R2=F, R3=H
Figure imgf000071_0001
20 33
39 X=C, R'=F, R2=H, R3=H
40 X=C, R'=H, R2 =F, R3=H
41 X=C, R'=C1, R2=H, R3=OMe
42 X=N, R'=F, R^H, RJ=H
Figure imgf000071_0002
2. Lipophilicity Measurements
The log P7.4θf 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 KH2PO4 in Alpha-Q water and the pH was adjusted to 7.4 with NaOH solution (0.1 M). Samples were analysed using a Waters XTerra MS Cl 8 column, with 5 μm particle size, 2.1 x 150 mm in dimension, and a mobile phase of MeOH and phosphate buffer (65:35 v/v, pH = 7.5) with a flow rate of 0.3 mL/min. 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. A calibration curve of log P vs. retention time was produced which resulted in an experimental calibration equation (Y = 0.8346 e°-8084x) with r2 of 0.9967. The exponential equation of the trendline function from the calibration graph and Excel ™ allowed the log P values for the unknowns to be calculated.
The lipophilicity at physiological pH (log P-7.4) of these compounds was found to be around 2.5.
3. P2X7 Receptor Functional Assays To obtain qualitative information about the binding and activity of P2X7 receptor ligands, test ligands were screened using a variety of assays.
In vitro P2X7 Receptor Functional Assay
A functional assay performed in collaboration with Dr Guo Jun Liu, Neurobiology Research Laboratory, University of Sydney.
The assays were performed on cultured rat spinal cord microglia cells.
The P2X7 receptor functional assay was based upon the ability of P2X7 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 P2X7 receptor); and iii) Ligand evaluation (cells + dye + BzATP + test ligand).
Results are presented as % relative dye uptake. compared to the positive control, 1 μM of test ligand was added to the cultured cells. A decrease in the % relative dye uptake indicates that the tested ligand is a P2X7 receptor antagonist. An increase in the % relative dye uptake indicates that the tested ligand is a P2X7 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 P2X7 receptor.
Figure imgf000073_0001
Neuroreceptor and Transporter Binding Assays
Extensive screening for binding to the other biological targets was undertaken to ensure the specificity and selectivity of the test ligands to P2X7 receptor. The 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.
Figure imgf000074_0001
Table 1. The receptors classes and their subtypes tested in the PDSP binding assay
Where significant inhibition was achieved (> 50 % inhibition at 10 μM ligand concentration), secondary binding assays were performed, whereby K, (inhibition constant) determinations were made (Table 2). Kj is the concentration of a drug needed to inhibit a known, usually tritium-labelled, drug. A Ki value greater than 3,000 nM represents very weak binding.
The results of the binding assay by PDSP indicated that hone of the tested ligands exhibited extensive binding to the neuroreceptor subtypes tested. In addition, PDSP also conducted a functional assay on G-protein coupled P2 receptors (P2Y receptors), which indicated that none of the tested ligands displayed any P2Y activity. 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 Ca2+ ions. Similar to the P2X7 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 P2X7 receptor selective.
Figure imgf000075_0001
Table 2. The Ki determinations in the PDSP secondary binding assays for tested ligands.
In vivo assays
To determine the antidepressant properties of the test ligands, experiments were performed on rodents using the Forced Swim Test and Novelty Suppressed Feeding Test. These are well known assays for the measurement of antidepressant activity.
In the Forced Swim Test animals are forced to swim in a cylinder filled with water from which they cannot escape. A first trial of 15 minutes durations followed by a second trial of 5 minutes duration 24 hours later. The time that the test animal spends without moving in the second trial is measured. This immobility time is decreased by antidepressants.
The Novelty Suppressed Feeding Test assesses stress-induced anxiety by measuring an animals feeding in an adverse environment. These times differentially regulated by antidepressants.
To determine the anxiolytic properties of the test ligands, experiments were performed on rodents using the Elevated Plus Maze Test and Social Interaction Test.
The 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.
C- 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) P2X7 receptor knockout (KO) mice without test ligand administration; and iv) P2X7 receptor KO mice receiving 20mg/kg or 40 mg/kg of test ligand.
The results of one of the in vivo assays demonstrated that both P2X7 receptor KO mice without test ligand administration and WT animals receiving the test ligand showed anxious behaviour when compared to WT mice without ligand administration (as indicated by reduced activity, higher emergence times and increased hide box times). P2X7 receptor KO mice receiving the test ligand showed increased anxious behaviours compared to WT mice without test ligand administration.
The above results demonstrated that the tested ligand is- a P2X7 receptor antagonist.
However, 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.
While the present invention has been described in terms of the preferred embodiments, it is understood that variations and modifications will occur to those skilled in the art.
Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the invention as claimed.

Claims

CLAIMS:
A compound of formula (I)
Figure imgf000078_0001
(1)
wherein vjV is a carboaromatic or heteroaromatic ring having one or more substituents; R6 is
Figure imgf000078_0002
optionally substituted with one or more substituents; and n is 0, 1 or an integer greater than 1 and wherein when n is I or greater the bond or bonds between the carbon atoms may be saturated or unsaturated; or a salt or solvate thereof.
2. A compound according to claim 1 wherein vβ' is not 3,5 difluorophenyl.
3. A compound according to claim 2 wherein ^V is unsubstituted or substituted phenyl or pyridyl.
4. A compound according to claim 3 wherein (&) is substituted 2-pyridyl, 3- pyridyl, or 4-pyridyl.
5. A compound according to any one of the preceding claims wherein the compound of formula (I) is a compound of formula (II), formula (III) or formula (IV):
Figure imgf000079_0001
(H) (IH) (IV) wherein:
R , 1 , D R2 , n R3 , R , and R are each independently a monovalent radical;
R6 is
Figure imgf000079_0002
optionally substituted with one or more substituents; and 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.
6. A compound according to any one of the preceding claims wherein n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
7. A compound according to any one of the preceding claims wherein n is 0, 1, 2, or 3.
8. A compound according to any one of claims 5 to 7 wherein R , R , and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeR", -OCOR", -OCONRb2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyi, optionally substituted alkenyl, optionally substituted alkyπyl, optionally substituted aryl, -OH, -OR\ -SR1, -SeRa, -OCORh, -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
9. A compound according to claim 8 wherein R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, or -NReCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyJ, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, or -NRbCONRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
10. A compound according to claim 9 wherein R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, -ORa, -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRcj, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -ORa, -SRa, or -NRbi; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
1 1. A compound according to any one of claims 5 to 7 wherein R1 and R3 are each independently H or halogen.
12. A compound according to any one of claims 5 to 7 wherein R4 is H or -OR", wherein Ra is optionally substituted alkyl.
13. A compound according to any one of claims 5 to 7 wherein R1 and R3 are each independently H, F or Cl; R2 and R5 are each H; and R4 is H or methoxy.
14. A compound selected from
Figure imgf000081_0001
or a salt or solvate thereof.
15. A compound of formula
Figure imgf000081_0002
or a salt or solvate thereof.
16. A compound of formula
Figure imgf000082_0001
or a salt or solvate thereof.
17. A compound of formula
Figure imgf000082_0002
or a salt or solvate thereof.
18. A compound of formula
Figure imgf000082_0003
or a salt or solvate thereof.
19. A compound of formula
Figure imgf000082_0004
or a salt or solvate thereof.
20. A compound of formula
Figure imgf000083_0001
or a salt or solvate thereof.
21. A compound of formula
Figure imgf000083_0002
or a salt or solvate thereof.
22. A compound of formula
Figure imgf000083_0003
23. A compound of formula
Figure imgf000083_0004
or a salt or solvate thereof.
24. A compound of formula
Figure imgf000084_0001
or a salt or solvate thereof.
25. A compound of formula
Figure imgf000084_0002
or a salt or solvate thereof.
26. A compound of formula
Figure imgf000084_0003
or a salt or solvate thereof.
27. A compound of formula
Figure imgf000084_0004
or a salt or solvate thereof.
28. A compound of formula
Figure imgf000085_0001
or a salt or solvate thereof.
29. A compound of formula
Figure imgf000085_0002
or a salt or solvate thereof.
30. A compound of formula
Figure imgf000085_0003
or a salt or solvate thereof.
31. A compound of formula
Figure imgf000085_0004
or a salt or solvate thereof.
32. A compound of formula
Figure imgf000086_0001
or a salt or solvate thereof.
33. A compound of formula
Figure imgf000086_0002
or a salt or solvate thereof.
34. A compound of formula
Figure imgf000086_0003
or a salt or solvate thereof.
35. A compound of formula
Figure imgf000086_0004
or a salt or solvate thereof.
36. A compound of formula
Figure imgf000087_0001
or a salt or solvate thereof.
37. A compound of formula
Figure imgf000087_0002
or a salt or solvate thereof.
38. A compound of formula (Ia)
Figure imgf000087_0003
(Ia) wherein
<o) is a carboaromatic or heteroaromatic ring having one or more substituents;
R6 is
Figure imgf000087_0004
optionally substituted with one or more substituents; and 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 radiolabelled with a radioisotope; or a salt or solvate thereof.
39. A compound according to claim 38 wherein said radioisotope is selected from 18F, 123I7 76Br, 1241, 75Br and 11C
40. A compound according to claim 38 or 39 wherein vft' is not 3,5- difluorophenyl.
41. A compound according to claim 40 wherein Vc/ is substituted phenyl or substituted pyridyl.
42. A compound according to claim any one of claims 38 to 41 wherein ^c) is 2- pyridyl, 3-pyridyl, or 4-pyridyl.
43. A compound according to any one of claims 38 to 42 wherein the compound of formula (Ia) is a compound of formula (Ha), formula (HIa) or formula (IVa):
Figure imgf000088_0001
(Ih) (IHa) (IVa)
wherein:
R1, R2, R3, R4 and R5 are each independently a monovalent radical;
R6 Js
Figure imgf000088_0002
optionally substituted with one or more substituents; and 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.
44. A compound according to any one of claims 38 to 43 wherein n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
45. A compound according to any one of claims 38 to 44 wherein n is 0, 1 , 2 or 3.
46. A compound according to any one of claims 43 to 45 wherein R1, R3, and R5 are each independently H, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCOR", -OCONRb 2, -NRb 2, -NRbCOORb, -NRbCONRb 2, -PORb 2, -PORb(ORb) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, .OH, -ORa, -SR", -SeR", -OCORb, -OCONRb 2, -NRb 2,
-NRbCOORb, -NRbC0NRb 2, -PORb 2, -POR^OR6) or -PO(ORb); wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc 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.
47. A compound according to claim 46 wherein R1, R3, and Rs are each independently H, halo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCORb, -OCONRb 2, -NRb 2, -NRbCOORb, or -NRbC0NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRC 3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, optionally substituted aryl, -OH, -ORa, -SRa, -SeRa, -OCORb, -OCONRb 2, -NRbz, -NRbCOORb, or -NRbC0NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRS, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
48. A compound according to claim 47 wherein R1, R3, and Rs are each independently H5 halo, optionally substituted alkyl, -ORa, -SRa, or -NRb 2; wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiRcj, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted. alkyl and optionally substituted aryl; and R2 and R4 are each independently H, chloro, bromo, iodo, optionally substituted alkyl, -OR", -SR\ or -NR1Y, wherein Ra is selected from optionally substituted alkyl, optionally substituted aryl and -SiR°3, wherein each Rc is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each Rb is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.
49. A compound according to any one of claims 43 to 48 wherein R1 and R3 are each independently H or halo.
50. A compound according to any one of claims 43 to 49 wherein R4 is H or -ORa, wherein Ra is optionally substituted alkyl.
51 . A compound according to any one of claims 43 to 50 wherein R1 and R3 are each independently H, F or Cl; R2 and R5 are each independently H; and R4 is H or methoxy.
52. A compound selected from
Figure imgf000091_0001
Figure imgf000091_0005
or a salt or solvate thereof.
53. A compound according to claim 38 of formula
Figure imgf000091_0002
or a salt or solvate thereof.
54. A compound according to claim 38 of formula
Figure imgf000091_0003
or a salt or solvate thereof.
55. A compound according to claim 38 of formula
Figure imgf000091_0004
or a salt or solvate thereof.
56. A compound according to claim 38 of formula
Figure imgf000092_0001
or a salt or solvate thereof.
57. A compound according to claim 38 of formula
Figure imgf000092_0002
or a salt or solvate thereof.
58. A compound according to claim 38 of formula
Figure imgf000092_0003
or a salt or solvate thereof.
59. A compound according to claim 38 of formula
Figure imgf000092_0004
or a salt or solvate thereof.
60. A compound according to claim 38 of formula
Figure imgf000093_0001
or a salt or solvate thereof.
61. A compound according to claim 38 of formula
Figure imgf000093_0002
or a salt or solvate thereof.
62. A compound according to claim 38 of formula
Figure imgf000093_0003
or a salt or solvate thereof.
63. A compound according to claim 38 of formula
Figure imgf000093_0004
or a salt or solvate thereof.
64. A compound according to claim 38 of formula
Figure imgf000094_0001
or a salt or solvate thereof.
65. A compound according to claim 38 of formula
Figure imgf000094_0002
or a salt or solvate thereof.
66. A compound according to claim 38 of formula
Figure imgf000094_0003
or a salt or solvate thereof.
67. A compound according to claim 38 of formula
Figure imgf000094_0004
or a salt or solvate thereof.
68. A compound according to claim 38 of formula
Figure imgf000095_0001
or a salt or solvate thereof
69. A compound according to claim 38 of formula
Figure imgf000095_0002
or a salt or solvate thereof
70. A compound according to claim 38 of formula
Figure imgf000095_0003
or a salt or solvate thereof.
71. A compound according to claim 38 of formula
Figure imgf000095_0004
or a salt or solvate thereof.
72. A compound according to claim 38 of formula
Figure imgf000096_0001
or a salt or solvate thereof.
73. A compound according to claim 38 of formula
Figure imgf000096_0002
or a salt or solvate thereof.
74. A compound according to claim 38 of formula
Figure imgf000096_0005
Figure imgf000096_0003
or a salt or solvate thereof.
75. A compound according to claim 38 of formula
Figure imgf000096_0004
or a salt or solvate thereof.
76. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 5 comprising reacting a compound of general formula
R1 ,H N"H2 (V)
wherein R is
Figure imgf000097_0001
optionally substituted with one or more substituents; and
n is 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
Figure imgf000097_0002
wherein *<y is defined in any one of claims 1 to 5 and L is a leaving group; and optionally forming a salt or solvate thereof.
77. The process according to claim 76 wherein said leaving group is a halogen, or an alcohol.
78. A process for the preparation of a radiolabeled compound of formula (Ia) as defined in any one of claims 38 to 42 comprising reacting a compound of general formula
R6^ NH2 (Va)
wherein Rδ is
Figure imgf000098_0001
optionally substituted with one or more substituents; and
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, with a compound of general formula
Figure imgf000098_0002
wherein V-IV is defined in any one of claims 38 to 42 and L is a leaving group; and optionally forming a salt or solvate thereof.
79. The process according to claim 78 wherein said leaving group is a halogen, or an alcohol.
80. A compound of formula (I) as defined in any one of claims I to 5 when made by the process of claim 76 or claim 77.
81. A radiolabeled compound of formula (Ia) as defined in any one of claims 38 to 42 when made by the process of claim 78 or claim 79.
82. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
83. A pharmaceutical composition comprising a compound of formula (I) as defined in claim any one of claims 1 to 4 radio labelled with an isotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
84. A radiolabelled compound according to claim 83 wherein said isotope is selected from 18F, 123I, 76Br, 124I, 75Br and 1 1C, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
85. A method of binding a P2X7 receptor with high affinity in a subject, comprising administering to the subject a compound of formula (I) as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate thereof.
86. A method of binding a P2X7 receptor with high affinity in a subject, comprising administering to the subject a compound of formula (II), (III) or (IV) as defined in claim 5 or a pharmaceutically acceptable salt or solvate thereof.
87. The method of claim 85 wherein the compound administered to the subject is a compound as claimed in any one of claims 5 to 37.
88. A method of imaging P2X7 receptors in a subject, comprising administering to the subject a compound of formula (Ia) as defined in claim 38 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.
89. The method of claim 88 wherein said radioisotope is selected from 18F, 123I, 76Br, 124I, "Br and 1 1C.
90. A method of imaging P2X7 receptors in a subject, comprising administering to the subject a compound of formula (Ua), (HIa) or (IVa) as defined in claim 43 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.
91. The method according to claim 91 wherein said radioisotope is selected from 18F, 123I5 76Br, 124I, 75Br and 1 1C.
92. The method of claim 88 or 90 wherein the compound of formula (Ia), (Ha), (Ilia) or (IVa) is radiolabeled with a radioisotope selected from 18F, 123I, 76Br, 124I and 75Br.
93. The method of claim 92 wherein the compound of formula (Ia), (Ua), (UIa) or (IVa) is radiolabeled with ιaF.
94. The method of claim 90 wherein the compound administered to the subject is a radiolabeled compound as claimed in any one of claims 38 to 75.
95. 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), as claimed in claim 38 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
96. A method for diagnosing or monitoring the progression of a disorder in which the P2X7 receptor is implicated, the method comprising administering to the subject a compound of formula (Ia) as claimed in claim 38 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
97. The method according to claim 96, wherein 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.
98. The method according to claim 97, wherein the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
99. A method for diagnosing or monitoring the progression of a neuro inflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (Ia) as defined in claim 38 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
100. A method according to claim 99 wherein said radioisotope is selected from 18F, IZ31, 76Br, 1241, 75Br and 11C.
101. A 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), (Ilia) or (IVa) as defined in claim 43 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
102. A method according to claim 101 wherein said radioisotope is selected from 18F, 1231, 76Br, 124I, 75Br and 1 1C.
103. The method of claim 101 or 102 wherein the compound of formula (Ha), (Ilia) or (IVa) or pharmaceutically acceptable salt or solvate thereof is a radiolabeled compound as claimed in any one of claims 38 to 75.
104. The method of any one of claims 99 to 103 wherein 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.
105. A method for treating a disorder in which the P2X7 receptor is implicated in a subject, the method comprising administering to the subject a compound of formula (I) as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.
106. The method of claim 105 wherein 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, πeurodegeneration, neuroinflammation, epilepsy, pancreatitis, diabetes, tuberculosis, cancer, neuroblastoma, Crohn's disease, irritable bowel syndrome, and lupus renal cyst formation.
107. The method of claim 106 wherein the cancer is selected from the group consisting of uterine cancer, cervical cancer and thyroid cancer.
108. A method for treating a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (1) as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.
109. A method for treating a neuroinflammatory disorder or neurodegenerative disorder in a subject, the method comprising administering to the subject a compound of formula (H), (HI) or (IV) as defined in claim 5, or a pharmaceutically acceptable salt or solvate thereof.
1 10. The method of claim 109 wherein the compound of formula (II), (III), (IV) or pharmaceutically acceptable salt or solvate thereof is a compound as claimed in any one of claims 5 to 38.
1 1 1. The method of any one of claims 107 to 1 10 wherein the neuroinflammatory disorder or neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumour or neuropathic pain.
1 12. Use of a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for binding a P2X7 receptor with high affinity in a subject.
1 13. Use of claim 1 12, wherein the binding is antagonistic.
1 14. Use of a compound of formula (H), (IH), or (IV) as defined in claim 5, or a pharmaceutical acceptable salt or solvate thereof, for the manufacture of a medicament for binding a P2X7 receptor with high affinity in a subject.
1 15. Use of claim 1 14 wherein the binding is antagonistic.
1 16. Use a compound of formula (Ia) as defined in claim 38 radiolabeled with a radioisotope, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for imaging P2X7 receptors in a subject.
1 17. Use of a compound of formula (Ha), (IHa), or (IVa) as defined in claim 43, or a pharmaceutical acceptable salt or solvate thereof, for the manufacture of a medicament for imaging P2X7 receptors in a subject, and obtaining an image of the location of the radioisotope in the subject.
118. Use a compound of formula (Ia) as defined in claim 38 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.
119. Use of a compound of formula (Ia) as claimed in claim 38 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 P2X7 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 P2X7 binding of the compound or salt or solvate thereof in the subject.
120. Use of claim 1 19 wherein 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
121. Use of claim 20 wherein the cancer is selected from the group consisting of: uterine cancer, cervical cancer and thyroid cancer.
122. Use of a compound of formula (Ia) as defined in claim 38 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 neuroinflammatory 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
123. Use of a compound of formula (Ha), (HIa) or (IVa) as defined in claim 43 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 neuroinfiammatory 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 P2X7 binding of the compound or salt or solvate thereof in the brain of the subject.
124. Use of a compound of formula (1) as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a disorder in a subject.
125. Use of a compound of formula (1) as defined in any one of claims 1 to 5, 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.
126. Use of claim 125 wherein 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.
127. Use of claim 125 wherein the cancer is selected from the group consisting of: uterine cancer, cervical cancer and thyroid cancer,
128. Use of a compound of formula (I) as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a neuroinfiammatory disorder or neurodegenerative disorder in a subject.
129. Use of a compound of formula (II), (III) or (IV) as defined in claim 5, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a neuroinfiammatory disorder or neurodegenerative disorder in a subject.
130. A compound for use as an intermediate in the production of a compound of any one of claims 1 to 75 having the following structure
Figure imgf000106_0001
wherein R is halo, optionally substituted alky I, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amine, or oxygen.
131. An intermediate compound according to claim 130 wherein the compound is selected from
Figure imgf000106_0002
132. A compound for use as an intermediate in the production of a compound of any one of claims 1 to 75 having the following structure
Figure imgf000107_0001
wherein each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted amine.
133. An intermediate compound according to claim 132 wherein the compound is selected from
Figure imgf000107_0002
PCT/AU2007/001857 2006-12-01 2007-11-30 Polycyclic molecular compounds Ceased WO2008064432A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2006906739 2006-12-01
AU2006906739A AU2006906739A0 (en) 2006-12-01 Polycyclic molecular compounds

Publications (1)

Publication Number Publication Date
WO2008064432A1 true WO2008064432A1 (en) 2008-06-05

Family

ID=39467367

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2007/001857 Ceased WO2008064432A1 (en) 2006-12-01 2007-11-30 Polycyclic molecular compounds

Country Status (1)

Country Link
WO (1) WO2008064432A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009106564A3 (en) * 2008-02-29 2010-03-25 Ge Healthcare Limited Imaging the central nervous system
WO2010115881A1 (en) 2009-04-09 2010-10-14 Ge Healthcare Limited Imaging the central nervous system with purinergic p2x7 receptor binding agents
WO2014001247A1 (en) 2012-06-26 2014-01-03 Bayer Pharma Aktiengesellschaft N-[4-(Quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products
WO2019170543A1 (en) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification and use of erk5 inhibitors
WO2020037350A1 (en) * 2018-08-24 2020-02-27 The University Of Sydney Adamantanyl-substituted benzamide compounds and their use as p2x7 receptor antagonists
WO2020234103A1 (en) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification and use of kras inhibitors
WO2021152113A1 (en) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Substituted 2,3-benzodiazepines derivatives
WO2025155289A1 (en) * 2024-01-18 2025-07-24 The Trustees Of Princeton University Substituted cubanes and methods of making the same

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
WO2009106564A3 (en) * 2008-02-29 2010-03-25 Ge Healthcare Limited Imaging the central nervous system
WO2010115881A1 (en) 2009-04-09 2010-10-14 Ge Healthcare Limited Imaging the central nervous system with purinergic p2x7 receptor binding agents
WO2014001247A1 (en) 2012-06-26 2014-01-03 Bayer Pharma Aktiengesellschaft N-[4-(Quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products
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 (en) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification and use of erk5 inhibitors
WO2020037350A1 (en) * 2018-08-24 2020-02-27 The University Of Sydney Adamantanyl-substituted benzamide compounds and their use as p2x7 receptor antagonists
WO2020234103A1 (en) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification and use of kras inhibitors
WO2021152113A1 (en) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Substituted 2,3-benzodiazepines derivatives
WO2025155289A1 (en) * 2024-01-18 2025-07-24 The Trustees Of Princeton University Substituted cubanes and methods of making the same

Similar Documents

Publication Publication Date Title
US8492379B2 (en) Translocator protein ligands
WO2008064432A1 (en) Polycyclic molecular compounds
AU2009278279B2 (en) DAA-pyridine as peripheral benzodiazepine receptor ligand for diagnostic imaging and pharmaceutical treatment
JP2009537457A (en) 2-Arylpyrazolo [l, 5-α] pyrimidin-3-ylacetamide derivatives as ligands for transport proteins (18 kDa)
JP2008546783A (en) Stereoselective synthesis of amino acid analogs for tumor imaging
US20110142757A1 (en) Novel compounds and their uses in diagnosis
McConathy et al. Synthesis and biological evaluation of [11C] talopram and [11C] talsupram: candidate PET ligands for the norepinephrine transporter
Kumata et al. Synthesis and evaluation of 4-(2-fluoro-4-[11C] methoxyphenyl)-5-((2-methylpyridin-4-yl) methoxy) picolinamide for PET imaging of the metabotropic glutamate receptor 2 in the rat brain
Kawamura et al. Synthesis and in vivo evaluation of 18F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters
CA2911307C (en) Use of fluorinated derivatives of 4-aminopyridine in therapeutics and medical imaging
US20170174632A1 (en) 4-oxo-1, 4-dihydroquinoline-3-carboxamide as selective ligand for cannabinoid receptor 2 for diagnosis and therapy
CN102223900A (en) Imaging ligands
Fuchigami et al. Synthesis and characterization of [125I] 2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl) methyl] 3-trifluoromethyl-benzamide as novel imaging probe for glycine transporter 1
US20250340562A1 (en) Chromane imaging ligands
US20220118117A1 (en) Modulators of metabotropic glutamate receptor 4
JP2021522196A (en) Acetylated prodrug for delivery across the blood-brain barrier
JP2009541262A (en) Radiolabeled ligand of glycine 1 transporter
WO2024263515A2 (en) Stearoyl coa desaturase 1 (scd1) radiotracers
He Development of PET radioligands for imaging monoacylglycerol lipase and N-methyl D-aspartate receptor subtype 2A in the brain
Kumata et al. 3-(Cyclopropylmethyl)-7-((4-(4-[11C] methoxyphenyl) piperidin-1-yl) methyl)-8-(trifluoromethyl)-[1, 2, 4] triazolo [4, 3-a] pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2
EP2867200A1 (en) Compound and use of compound to prepare a radiolabelled compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07815657

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07815657

Country of ref document: EP

Kind code of ref document: A1