WO2010125103A1 - Dérivés de dicétopipérazine comme modulateurs de p2x7 - Google Patents

Dérivés de dicétopipérazine comme modulateurs de p2x7 Download PDF

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WO2010125103A1
WO2010125103A1 PCT/EP2010/055716 EP2010055716W WO2010125103A1 WO 2010125103 A1 WO2010125103 A1 WO 2010125103A1 EP 2010055716 W EP2010055716 W EP 2010055716W WO 2010125103 A1 WO2010125103 A1 WO 2010125103A1
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methyl
piperazinedione
chloro
fluorophenyl
phenyl
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PCT/EP2010/055716
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Laura Jane Chambers
David Kenneth Dean
Jorge Munoz-Muriedas
Jon Graham Anthony Steadman
Daryl Simon Walter
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to diketopiperazine derivatives which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor ("P2X7 receptor antagonists"); to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.
  • the P2X7 receptor is a ligand-gated ion-channel which is expressed in cells of the hematopoietic lineage, e.g. macrophages, microglia, mast cells, and lymphocytes (T and B) (see, for example, CoIIo, et al. Neuropharmacology, Vol.36, pp1277-1283 (1997)), and is activated by extracellular nucleotides, particularly adenosine triphosphate (ATP).
  • ATP adenosine triphosphate
  • Activation of P2X7 receptors has been implicated in giant cell formation, degranulation, cytolytic cell death, CD62L shedding, regulation of cell proliferation, and release of proinflammatory cytokines such as interleukin 1 beta (IL- 1 ⁇ ) (e.g.
  • P2X7 receptors are also located on antigen presenting cells, keratinocytes, parotid cells, hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.
  • the P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems and has been shown to mediate glutamate release in glial cells (Anderson, C. et al. Drug. Dev. Res., Vol.50, page 92 (2000)).
  • P2X7 receptor antagonists in the treatment of a wide range of diseases including pain and neurodegenerative disorders.
  • Recent preclinical in vivo studies have directly implicated the P2X7 receptor in both inflammatory and neuropathic pain (Dell'Antonio et al., Neurosci. Lett., Vol.327, pp87-90 (2002),. Chessell, IP., et al., Pain, Vol.114, pp386-396 (2005), Honore et al., J. Pharmacol. Exp.
  • WO 97/36889 (Merck & Co Inc) describes a series of 2,3-diketopiperazine farnesyl protein transferase inhibitors for the treatment of cancer.
  • WO 2006/086445, WO 2005/011656, WO 2005/01 1657 and WO 2005/01 1653 (all of Xenon Pharm Inc) describe a series of piperazine derivatives as stearoyl-CoA desaturase inhibitors for the treatment of a range of disorders.
  • the present invention provides compounds which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor ("P2X7 receptor antagonists").
  • A represents an aryl, heteroaryl or heterocyclyl group; and any ring or ring system of said aryl or heteroaryl is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of halogen, C 1-6 alkyl, -CF 3 , -OCF 3 , cyano, Ci -6 alkoxy, -NR 10 R 11 , -X-aryl, -X-heteroaryl and -X-heterocyclyl; R 1 , R 2 , R 3 , R 4 and R 5 independently represent hydrogen, fluorine, chlorine, -CF 3 , cyano or Ci -6 alkyl, such that at least one of R 1 , R 2 , R 3 , R 4 and R 5 is other than hydrogen;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen or Ci -6 alkyl;
  • X represents a linker selected from a bond, -(CH 2 ) n - and -O-(CH 2 ) n -; and
  • n represents an integer from 1 to 3.
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • Examples of alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, n-hexyl and i-hexyl.
  • 'halogen' is used herein to describe, unless otherwise stated, a group being fluorine, chlorine, bromine or iodine.
  • 'aryl' refers to a C 6- io monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthyl.
  • heteroaryl as used herein means a 5 to 6 membered monocyclic aromatic or a fused 8 to 10 membered bicyclic aromatic ring system containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur.
  • monocyclic aromatic rings include thienyl, furanyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
  • fused bicyclic aromatic ring systems include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, dihydrobenzodioxinyl, benzodioxinyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above.
  • heterocyclyl refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur.
  • Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like.
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1 /-/-3-benzazepine, tetrahydroisoquinolinyl, dihydrobenzodioxinyl, dihydrobenzooxazinyl and the like.
  • A represents an aryl or heteroaryl group; and any ring or ring system of said aryl or heteroaryl is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of halogen, Ci -6 alkyl, -CF 3 , cyano, Ci -6 alkoxy and -X-morpholinyl;
  • R 1 , R 2 , R 3 , R 4 and R 5 independently represent hydrogen, fluorine, chlorine, -CF 3 , cyano or C 1-6 alkyl, such that at least one of R 1 , R 2 , R 3 , R 4 and R 5 is other than hydrogen;
  • R 6 and R 7 independently represents hydrogen or C 1-6 alkyl
  • X represents a linker selected from a bond, -(CH 2 ) n - and -O-(CH 2 ) n -; and n represents an integer from 1 to 3.
  • the present invention covers and discloses all possible combinations of particular, preferred, suitable, or other embodiments of groups or features (e.g. of A, R 1 , R 2 , R3, R4, RS 1 R ⁇ , R7 ; R 8 ; R 9 ; RiO 1 RH 1 X, and/or n), e.g. covers and discloses all possible combinations of embodiments of different groups or features, which embodiments are described herein.
  • A represents a group other than pyridyl. In certain particular embodiments, A represents a group other than pyridazinyl.
  • A represents a C 6- io aryl group such as phenyl, naphthyl or tetrahydronaphthyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C 1-6 alkyl, -CF 3 , -OCF 3 , cyano, C- I-6 alkoxy, -NR 10 R 11 , -X-aryl, -X-heteroaryl and -X-heterocyclyl.
  • A represents a C 6- io aryl group such as phenyl, naphthyl or tetrahydronaphthyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen (e.g. chlorine, fluorine, bromine or iodine), Ci -6 alkyl (e.g. methyl, ethyl, isopropyl or t-butyl), -CF 3 , -OCF 3 , cyano, Ci -6 alkoxy (e.g. methoxy), -NR 10 R 11 (e.g. -NMe 2 Or -NEt 2 ), -X-aryl (e.g.
  • halogen e.g. chlorine, fluorine, bromine or iodine
  • Ci -6 alkyl e.g. methyl, ethyl, isopropyl or t-butyl
  • -CF 3 e.g. methyl
  • -phenyl e.g. -pyrrolyl or -imidazolyl
  • -X-heterocyclyl e.g. -piperidinyl, -pyrrolidinyl, -morpholinyl, -(CH 2 )-morpholinyl, -(CH 2 ) 2 -morpholinyl or -O-(CH 2 ) 2 -morpholinyl).
  • A represents a C 6-10 aryl group such as phenyl, naphthyl or tetrahydronaphthyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C 1-6 alkyl, -CF 3 , cyano, C 1-6 alkoxy and -X-morpholinyl.
  • A represents phenyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 alkyl (e.g. methyl, ethyl or isopropyl), -CF 3 , cyano, C 1-6 alkoxy (e.g. methoxy), and -X-morpholinyl (e.g. -morpholinyl, -(CH 2 )- morpholinyl or -(CH 2 ) 2 -morpholinyl).
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • C 1-6 alkyl e.g. methyl, ethyl or isopropyl
  • -CF 3 e.g. cyano, C 1-6 alkoxy (e.g. methoxy)
  • -X-morpholinyl e.g. -morpholinyl
  • A represents a 5 to 6 membered heteroaryl (e.g. pyridinyl or pyrimidinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C 1-6 alkyl (e.g. methyl), -CF 3 , cyano, C 1-6 alkoxy and -X-morpholinyl.
  • A represents a 5 to 6 membered heteroaryl (e.g. pyridinyl or pyrimidinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from C 1-6 alkyl (e.g. methyl).
  • A represents an 8 to 10 membered heteroaryl (e.g. indolyl, quinolinyl or isoquinolinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C 1-6 alkyl, -CF 3 , cyano, C 1-6 alkoxy and -X-morpholinyl.
  • substituents which may be the same or different, selected from halogen, C 1-6 alkyl, -CF 3 , cyano, C 1-6 alkoxy and -X-morpholinyl.
  • A represents an 8 to 10 membered heteroaryl (e.g. indolyl, quinolinyl or isoquinolinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from Ci -6 alkyl (e.g. methyl).
  • heteroaryl e.g. indolyl, quinolinyl or isoquinolinyl
  • 1 to 3 substituents which may be the same or different, selected from Ci -6 alkyl (e.g. methyl).
  • A represents an 8 to 10 membered heteroaryl (e.g. benzodioxinyl, quinolinyl or isoquinolinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C 1-6 alkyl, - CF 3 , cyano, Ci -6 alkoxy and -X-morpholinyl.
  • heteroaryl e.g. benzodioxinyl, quinolinyl or isoquinolinyl
  • A represents a heterocyclyl group (e.g. dihydrobenzodioxinyl or dihydrobenzooxazinyl) optionally substituted by 1 to 3 substituents, which may be the same or different, and which is or are C 1-6 alkyl (e.g. methyl).
  • A represents phenyl, naphthyl, tetrahydronaphthyl (e.g. 5,6,7,8-tetrahydronaphthalenyl), quinolinyl, pyridinyl or dihydrobenzodioxinyl (e.g.
  • 2,3-dihydro-1 ,4-benzodioxinyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from fluorine, chlorine, bromine, iodine, methyl, -CF 3 , cyano, methoxy, -morpholinyl, -(CH 2 )-morpholinyl, -(CH 2 ) 2 -morpholinyl, and -O-(CH 2 ) 2 -morpholinyl.
  • A represents phenyl optionally substituted by 1 to 3 substituents, which may be the same or different, selected from fluorine, chlorine, bromine, iodine, methyl, -CF 3 , cyano, methoxy, -morpholinyl, -(CH 2 )-morpholinyl, - (CH 2 ) 2 -morpholinyl, and -O-(CH 2 ) 2 -morpholinyl.
  • R 1 represents hydrogen, fluorine, chlorine, cyano, -CF 3 or C 1-3 alkyl (e.g. methyl). In certain particular embodiments, R 1 represents hydrogen, fluorine, chlorine, -CF 3 or methyl.
  • R 1 represents chlorine.
  • R 2 represents hydrogen, fluorine, chlorine, -CF 3 or C 1-3 alkyl (e.g. methyl). In certain particular embodiments, R 2 represents hydrogen, fluorine, chlorine, or -CF 3 .
  • R 2 represents hydrogen or chlorine.
  • R 3 represents hydrogen, fluorine or chlorine.
  • R 4 represents hydrogen, fluorine, chlorine,, -CF 3 , or methyl.
  • R 4 represents hydrogen
  • R 5 represents hydrogen, fluorine, chlorine, -CF 3 , cyano or C 1-3 alkyl (e.g. methyl). In certain particular embodiments, R 5 represents hydrogen, fluorine, chlorine, -CF 3 or C 1-3 alkyl (e.g. methyl).
  • R 5 represents hydrogen
  • R 2 , R 4 and R 5 represent hydrogen, R 1 represents chlorine, and R 3 represents fluorine or chlorine.
  • one of R 6 and R 7 represents hydrogen and the other represents C 1-6 alkyl (e.g. methyl). In one embodiment, R 6 and R 7 both represent hydrogen.
  • one of R 8 and R 9 represents hydrogen and the ootthheerr rreepprreesseennttss CC 11--66 alkyl (e.g. methyl). In one embodiment, R 8 and R 9 both represent hydrogen.
  • Antagonists of P2X7 may be useful in the treatment (e.g. amelioration) or prophylaxis (in particular treatment) of a variety of pain states (e.g. neuropathic pain, chronic inflammatory pain, or visceral pain), inflammation (e.g. rheumatoid arthritis or osteoarthritis), or neurodegenerative diseases such as Alzheimer's disease.
  • P2X7 antagonists may constitute useful therapeutic agents in the management of rheumatoid arthritis or inflammatory bowel disease.
  • P2X7 receptor antagonists may be competitive antagonists, inverse agonists, or negative allosteric modulators of P2X7 receptor function.
  • Certain compounds of formula (I) may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) may be used as salts, in which case the salts should be pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • a pharmaceutically acceptable salt is formed from a pharmaceutically acceptable acid such as an inorganic or organic acid.
  • Such acids include acetic, p-aminobenzoic, ascorbic, aspartic, benzenesulfonic, benzoic, bismethylenesalicylic, camphorsulfonic, citric, cyclohexylsulfamic, ethanedisulfonic, ethanesulfonic, fumaric, gluconic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, itaconic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, palmitic, pamoic, pantothenic, phosphoric, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • the pharmaceutically acceptable salt is is formed from a pharmaceutically acceptable strong acid.
  • the pharmaceutically acceptable salt can be a benzenesulfonate, camphorsulfonate, ethanesulfonate, hydrobromide, hydrochloride, methanesulfonate, nitrate, phosphate, sulfate, or p- toluenesulfonate.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared in crystalline or non-crystalline form (e.g. in crystalline or amorphous solid form), and, in particular if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope solvates (e.g. hydrates) of compounds of formula (I) or pharmaceutically acceptable salts thereof, for example stoichiometric solvates (e.g. hydrates); as well as compounds or salts thereof containing variable amounts of solvent (e.g. water).
  • Stereoisomeric forms e.g. diastereomers and enantiomers
  • the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the stereochemical composition of the final product has been determined by chiral HPLC (more specifically by methods (A), (B), (C) or (D) as set out in the Examples), the corresponding stereospecific name and structure have been assigned to the final product where the enantiomeric excess of said product is greater than 70%. Assignment of absolute stereochemistry is based on the known chirality of the starting material.
  • the stereochemistry of the final product has not been indicated.
  • the chirality of the main component of the product mixture will be expected to reflect that of the starting material and the enatiomeric excess will depend on the synthetic method used and is likely to be similar to that measured for an analogous example (where such an example exists).
  • compounds shown in one chiral form are expected to be able to be prepared in the alternative chiral form using the appropriate starting material.
  • racemic starting materials it would be expected that a racemic product would be produced and the single enatiomers could be separated by the usual methods.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the invention therefore also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises step (a), (b), (c), (d), (e), (f), (g), or (h) as follows, and optionally converting the compound into a pharmaceutically acceptable salt thereof: (a) Preparation of a compound of formula (I) wherein R 6 , R 7 , R 8 and R 9 each represent hydrogen by condensation of a compound of general formula (6) with an aldehyde of general formula (7) (see Scheme 1 ) wherein A, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above. Compounds (6) and (7) are optionally protected.
  • Step (i) typically comprises treatment of compound (2) with a suitable reagent such as di-tertbutyldicarbonate, with a base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as between O 0 C and room temperature.
  • a suitable reagent such as di-tertbutyldicarbonate
  • a base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises treatment of compound (3) with compound (4) with a suitable base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as between O 0 C and room temperature.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (iii) typically comprises treatment of compound (5) with a suitable acid such as 4 Molar hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and at a suitable temperature such as room temperature.
  • a suitable acid such as 4 Molar hydrochloric acid
  • a suitable solvent such as 1 ,4-dioxane
  • Step (iv) typically comprises treatment of compound (6) with compound (7) with a suitable reducing agent such as sodium triacetoxyborohydride and with a suitable dehydrating agent such as 4A molecular sieves, in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature.
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • a suitable dehydrating agent such as 4A molecular sieves
  • Step (i) typically comprises treatment of compound (8) with compound (4), in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C or room temperature.
  • Step (ii) typically comprises treatment of compound (9) with a suitable alkylating agent such as allyl bromide, with a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide and at a suitable temperature such as room temperature.
  • a suitable alkylating agent such as allyl bromide
  • a suitable base such as sodium hydride
  • Step (iii) typically comprises treatment of compound (10) with a suitable oxidising agent such as ozone, in a suitable solvent such as dichloromethane, at a suitable temperature such as -78 0 C and worked up with a suitable reagent such as dimethylsulfide.
  • a suitable oxidising agent such as ozone
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises treatment of compound (11 ) with compound (12) with a suitable reducing agent such as sodium triacetoxyborohydride and with a suitable dehydrating agent such as 4A molecular sieves, an acid such as acetic acid, in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C or room temperature.
  • a suitable reducing agent such as sodium triacetoxyborohydride and with a suitable dehydrating agent such as 4A molecular sieves
  • an acid such as acetic acid
  • a suitable solvent such as dichloromethane
  • a suitable temperature such as O 0 C or room temperature
  • the reaction may be carried out with polymer-supported cyanoborohydride as the reducing agent, an acid such as acetic acid, in a suitable solvent such as methanol and at a suitable temperature such as room temperature.
  • Step (i) typically comprises treatment of compound (12) with a suitable reagent such as methyl chlorooxoacetate, with a suitable base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C.
  • a suitable reagent such as methyl chlorooxoacetate
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises treatment of compound (13) with a suitable alkylating agent such as allyl bromide, with a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide and at a suitable temperature such as room temperature.
  • a suitable alkylating agent such as allyl bromide
  • a suitable base such as sodium hydride
  • Step (iii) typically comprises treatment of compound (14) with a suitable oxidising agent such as ozone, in a suitable solvent such as dichloromethane, at a suitable temperature such as -78 0 C and worked up with a suitable reagent such as dimethylsulfide.
  • a suitable oxidising agent such as ozone
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises treatment of compound (15) with compound (8) with a suitable reducing agent such as sodium triacetoxyborohydride or polymer-supported cyanoborohydride, optionally with a suitable dehydrating agent such as 4A molecular sieves, with the optional use of an acid such as acetic acid in a suitable solvent such as dichloromethane or 1 ,2-dichloroethane and at a suitable temperature such as between 0 0 C and 80 0 C.
  • a suitable reducing agent such as sodium triacetoxyborohydride or polymer-supported cyanoborohydride
  • a suitable dehydrating agent such as 4A molecular sieves
  • an acid such as acetic acid
  • a suitable solvent such as dichloromethane or 1 ,2-dichloroethane
  • the reaction may be carried out with sodium borohydride as the reducing agent and acetic acid as the solvent at a suitable temperature, such as between 80 0 C and 105 0 C.
  • reaction may be carried out with polymer-supported cyanoborohydride as the reducing agent, using an acid such as acetic acid, in a suitable solvent such as methanol and at a suitable temperature such as room temperature.
  • reaction may be carried out with polymer-supported cyanoborohydride as the reducing agent, using an acid such as acetic acid, in a suitable solvent such as 1 ,2-dichloroethane and at a suitable temperature such as between room temperature and 80 0 C.
  • the mixture would then be filtered, concentrated and taken up in a suitable solvent such as 1-butanol and heated at a suitable temperature such as 160 0 C.
  • Step (v) comprises treatment of compound (15) with compound (8) with a suitable reducing agent such as polymer-supported cyanoborohydride, with the use of an acid such as acetic acid in a suitable solvent such as methanol and at a suitable temperature such as room temperature.
  • a suitable reducing agent such as polymer-supported cyanoborohydride
  • Step (vi) comprises heating of compound (16) in a suitable solvent such as methanol or 1-butanol at a suitable temperature such as between 130 0 C and 200 0 C.
  • a suitable solvent such as methanol or 1-butanol
  • Step (i) typically comprises treatment of compound (16) with a suitable base such as lithium hydroxide, in a suitable solvent such as tetrahydrofuran and water and at a suitable temperature such as room temperature.
  • a suitable base such as lithium hydroxide
  • a suitable solvent such as tetrahydrofuran and water
  • Step (ii) typically comprises treatment of compound (17) with a suitable reagent such as thionyl chloride at a suitable temperature such as 4O 0 C.
  • a suitable reagent such as thionyl chloride at a suitable temperature such as 4O 0 C.
  • Step (ii) typically comprises treatment of compound (18) with a suitable reagent such as imidazole in a suitable solvent such as acetonitrile at a suitable temperature such as room temperature.
  • a suitable solvent such as acetonitrile
  • the mixture would then be worked up and the residue dissolved in a suitable solvent such as 1-butanol at a suitable temperature such as 200 0 C.
  • Step (i) typically comprises treatment of compound (8) with compound (19) with a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C or room temperature.
  • a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises treatment of compound (3) with compound (4), with a suitable base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature.
  • a suitable base such as triethylamine
  • Step (iii) typically comprises treatment of compound (5) with a suitable acid such as 4 Molar hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and at a suitable temperature such as room temperature, followed by neutralisation with a suitable base such as triethylamine in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature.
  • a suitable acid such as 4 Molar hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and at a suitable temperature such as room temperature
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises treatment of compound (20) with compound (21 ) with a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide and at a suitable temperature such as 5O 0 C.
  • a suitable base such as sodium hydride
  • a suitable solvent such as dimethylformamide
  • Step (i) typically comprises treatment of compound (22) with a suitable reagent such as ethylene diamine in a suitable solvent such as 1-methyl-2-pyrrolidinone using microwave irradiation at a suitable temperature such as 22O 0 C and for a suitable time such as between 1 and 2 hours.
  • a suitable reagent such as ethylene diamine in a suitable solvent such as 1-methyl-2-pyrrolidinone
  • microwave irradiation at a suitable temperature such as 22O 0 C and for a suitable time such as between 1 and 2 hours.
  • Step (ii) typically comprises treatment of compound (2) with compound (7) with a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C or room temperature.
  • a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves
  • a suitable solvent such as dichloromethane
  • Step (iii) typically comprises treatment of compound (23) with a suitable reagent such as oxalyl chloride, with a suitable base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as O 0 C or room temperature.
  • a suitable reagent such as oxalyl chloride
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (i) typically comprises treatment of compound (12) with compound (24) with a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves, in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature.
  • a suitable reducing agent such as sodium triacetoxyborohydride and a suitable dehydrating agent such as 4A molecular sieves
  • Step (ii) typically comprises treatment of compound (25) with compound (4) with a suitable base such as triethylamine, in a suitable solvent such as dichloromethane and at a suitable temperature such as between O 0 C and room temperature.
  • a suitable base such as triethylamine
  • Step (iii) typically comprises treatment of compound (26) with a suitable acid such as 4 Molar hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and at a suitable temperature such as room temperature, followed by neutralisation with a suitable base such as triethylamine in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature.
  • a suitable acid such as 4 Molar hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and at a suitable temperature such as room temperature
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises treatment of compound (27) with compound (28) with a suitable catalyst such as copper (II) acetate, a suitable base such as pyridine, a suitable oxidant such as pyridine N-oxide, a suitable dehydrating agent such as 4A molecular sieves in a suitable solvent such as toluene and at a suitable temperature such as 9O 0 C.
  • a suitable catalyst such as copper (II) acetate
  • a suitable base such as pyridine
  • a suitable oxidant such as pyridine N-oxide
  • a suitable dehydrating agent such as 4A molecular sieves in a suitable solvent such as toluene and at a suitable temperature such as 9O 0 C.
  • Compounds of the general formulae (2), (4), (7), (8), (12), (19), (21 ), (22), (24) and (28) are typically either available from commercial sources or can be prepared by a person skilled in the art using methods described in the chemical literature (
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • P2X7 receptor antagonists are capable of antagonizing the effects of ATP at the P2X7 receptor
  • they may be useful in the treatment or prophylaxis (in particular treatment) of pain; such as acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache or cluster headaches, pain associated with functional bowel disorders, lower back and/or neck pain, pain associated with sprains and/or strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache, or dysmenorrhea.
  • the chronic articular pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis), gouty arthritis or juvenile arthritis.
  • the inflammatory pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis) or fibromyalgia.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be useful in the treatment or prophylaxis (in particular treatment) of pain (e.g. inflammatory pain) in arthritis, such as pain (e.g. inflammatory pain) in rheumatoid arthritis or osteoarthritis.
  • pain e.g. inflammatory pain
  • arthritis such as pain (e.g. inflammatory pain) in rheumatoid arthritis or osteoarthritis.
  • Pain associated with functional bowel disorders includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • the neuropathic pain condition can be: diabetic neuropathy (e.g. painful diabetic neuropathy), sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, or lumbar radiculopathy; or pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • diabetic neuropathy e.g. painful diabetic neuropathy
  • sciatica non-specific lower back pain
  • trigeminal neuralgia multiple sclerosis pain
  • fibromyalgia HIV-related neuropathy
  • post-herpetic neuralgia trigeminal neuralgia
  • lumbar radiculopathy or pain resulting from physical trauma, a
  • the neuropathic pain condition can be pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and/or dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, or mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia), or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non-painful sensations such as "pins and needles" (paraesthesias and/or dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, or mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia), or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the acute pain condition can be post-surgical pain or dysmenorrhea (e.g. primary dysmenorrhea).
  • dysmenorrhea e.g. primary dysmenorrhea
  • the compounds or pharmaceutically acceptable salts of the present invention may potentially be useful in the treatment or prophylaxis (e.g. prophylaxis, e.g. reduction, delay or prevention) of the development of tolerence to the analgesic action of an opioid analgesic (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol).
  • an opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol.
  • ⁇ conditions which could potentially be subject to treatment or prophylaxis (in particular treatment) using the compounds or salts of the present invention are: fever, inflammation, immunological diseases, abnormal platelet function diseases (e.g. occlusive vascular diseases), impotence or erectile dysfunction; bone disease characterised by abnormal bone metabolism or resorbtion; hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAI D's) such as cyclooxygenase-2 (COX- 2) inhibitors, cardiovascular diseases (e.g. atherosclerosis); neurodegenerative diseases and/or neurodegeneration; neurodegeneration following trauma; tinnitus; dependence on (e.g. addiction to) a dependence-inducing agent such as: an opioid analgesic (e.g.
  • morphine a CNS (central nervous system) depressant (e.g. ethanol), a psychostimulant (e.g. cocaine) or nicotine
  • diabetes such as Type 1 or Type 2 diabetes, complications of diabetes such as complications of Type I or Type 2 diabetes, kidney dysfunction, liver dysfunction (e.g. hepatitis, cirrhosis), gastrointestinal dysfunction (e.g. diarrhoea), gastric cancer, colon cancer, overactive bladder, or urge incontinence.
  • Depression and alcoholism could potentially also be subject to treatment or prophylaxis by compounds or salts of the present invention.
  • Inflammation and/or the inflammatory conditions associated with said inflammation can be: arthritis (in particular rheumatoid arthritis or osteoarthritis), skin conditions (e.g. sunburn, burns, eczema, dermatitis, allergic dermatitis, or psoriasis), meningitis, ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis or of acute injury to the eye tissue (e.g. conjunctivitis), an inflammatory lung disorder (e.g.
  • COPD chronic obstructive pulmonary disease
  • bronchitis and/or emphysema bronchitis and/or emphysema
  • allergic rhinitis rhinitis
  • respiratory distress syndrome pigeon fancier's disease
  • farmer's lung or airways hyperresponsiveness
  • a gastrointestinal tract disorder e.g.
  • vascular disease migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, polymyositis, tendinitis, bursitis, or Sjogren's syndrome.
  • the inflammation and/or an inflammatory condition associated with said inflammation can in particular be arthritis (e.g. rheumatoid arthritis or osteoarthritis).
  • Immunological diseases include autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • Bone diseases characterised by abnormal bone metabolism or resorbtion can be: osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gouty and/or ankylosing spondylitis, tendinitis or bursitis.
  • osteoporosis especially postmenopausal osteoporosis
  • hyper-calcemia especially hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis osteoarthritis
  • osteoarthritis ostealgia
  • Cardiovascular diseases include hypertension or myocardiac ischemia; atherosclerosis; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • Neurodegenerative diseases which could potentially be subject to treatment or prophylaxis (in particular treatment) using the compounds or salts of the present invention are: dementia, particularly degenerative dementia (such as Alzheimer's disease, senile dementia, dementia with Lewy bodies, temporal lobe dementia, Huntingdon's chorea, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, or Amyotrophic Lateral Sclerosis (ALS); in particular Alzheimer's disease); mild cognitive impairment (MCI) e.g. MCI associated with ageing, particularly age associated memory impairment; motor neuron disease; vascular dementia (including multi-infarct dementia and/or dementia associated with cerebral ischaemia); or a neurodegenerative disease (e.g.
  • dementia particularly degenerative dementia (such as Alzheimer's disease, senile dementia, dementia with Lewy bodies, temporal lobe dementia, Huntingdon's chorea, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, or Amyotrophic Lateral Sclerosis
  • dementia associated with: an intracranial space occupying lesion, head trauma, intracranial and/or cerebral infections or related conditions (such as HIV infection, viral or bacterial meningitis, or cerebral herpes virus infections such as shingles or herpes simplex virus), metabolism, toxins, anoxia, hypoxia or vitamin deficiency.
  • intracranial space occupying lesion
  • head trauma such as HIV infection, viral or bacterial meningitis, or cerebral herpes virus infections such as shingles or herpes simplex virus
  • cerebral herpes virus infections such as shingles or herpes simplex virus
  • the neurodegenerative disease e.g. to be subject to treatment or prophylaxis (in particular treatment) by the compound of formula (I) or salt thereof, can in particular be degenerative dementia (in particular Alzheimer's disease), Parkinson's diesase (in particular dementia in Parkinson's diesase), vascular dementia (in particular multi- infarct dementia), dementia with Lewy bodies, Huntingdon's chorea, or mild cognitive impairment (MCI) e.g. MCI associated with ageing such as age associated memory impairment.
  • MCI mild cognitive impairment
  • the neurodegenerative disease e.g.
  • the compound of formula (I) or salt thereof can in particular be degenerative dementia (in particular Alzheimer's disease), vascular dementia (in particular multi-infarct dementia), or mild cognitive impairment (MCI) e.g. MCI associated with ageing such as age associated memory impairment.
  • degenerative dementia in particular Alzheimer's disease
  • vascular dementia in particular multi-infarct dementia
  • MCI mild cognitive impairment
  • the compound of formula (I) or the salt thereof of the invention is used for treatment or prophylaxis (in particular treatment) of a neurodegenerative disease (such as degenerative dementia e.g. Alzheimer's disease, or vascular dementia, or mild cognitive impairment), by disease modification and/or by neuroprotection.
  • a neurodegenerative disease such as degenerative dementia e.g. Alzheimer's disease, or vascular dementia, or mild cognitive impairment
  • the compound of formula (I) or the salt thereof of the invention is used for treatment or prophylaxis (in particular treatment) of a neurodegenerative disease (such as degenerative dementia e.g. Alzheimer's disease, or vascular dementia, or mild cognitive impairment) by symptomatic treatment of cognitive impairment associated with the neurodegenerative disease.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be useful for neuroprotection and/or in the treatment or prophylaxis (e.g. treatment) of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the compounds or pharmaceutically acceptable salts of the present invention may also be useful in the treatment or prophylaxis (in particular treatment) of malignant cell growth and/or metastasis, or myoblastic leukaemia.
  • Complications of Type 1 diabetes can be: diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma, nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease or sarcoidosis.
  • Kidney dysfunction can be: nephritis, glomerulonephritis, particularly mesangial proliferative glomerulonephritis or nephritic syndrome.
  • the compounds or pharmaceutically acceptable salts of the present invention may potentially be useful in the treatment or prophylaxis (e.g. treatment) of epilepsy and/or seizures (i.e. as anticonvulsants), for example in a mammal such as a human.
  • the compounds or pharmaceutically acceptable salts of the present invention may potentially be useful in the treatment or prophylaxis (e.g. treatment) of a human epileptic syndrome, such as: partial and/or generalised seizures (e.g. tonic, tonic- clonic, or absence seizures), temporal lobe epilepsy, absence epilepsies (including childhood, juvenile, myoclonic, photo- or pattern-induced), severe epileptic encephalopathies (including hypoxia-related or Rasmussen's syndrome), febrile convulsions, epilepsy partialis continua, progressive myoclonus epilepsies (including Unverricht-Lundborg disease or Lafora's disease), post-traumatic seizures and/or epilepsy such as those related to head injury, simple reflex epilepsies (including photosensive, somatosensory, proprioceptive, audiogenic or vestibular), metabolic disorders commonly associated with epilepsy such as pyridoxine-dependent epilepsy, Menkes' kinky hair disease, Krab
  • cortical malformations associated with epilepsy e.g. double cortex syndrome or subcortical band heterotopia
  • chromosomal anomolies associated with seizures or epilepsy such as Partial monosomy (15Q / Angelman syndrome); in a human.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis (e.g. treatment) of a condition which is mediated by P2X7 receptors, for example a condition or disease disclosed herein (in particular pain, inflammation such as rheumatoid arthritis or osteoarthritis, or a neurodegenerative disease (e.g.
  • Alzheimer's disease or mild cognitive impairment or epilepsy and/or seizures (e.g. a human epileptic syndrome); more particularly pain such as inflammatory pain, neuropathic pain or visceral pain, or rheumatoid arthritis or osteoarthritis); e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a method of treatment or prophylaxis e.g. treatment of a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from a condition which is mediated by P2X7 receptors, for example a condition or disease disclosed herein (in particular pain, inflammation such as rheumatoid arthritis or osteoarthritis, or a neurodegenerative disease (e.g. Alzheimer's disease or mild cognitive impairment), or epilepsy and/or seizures (e.g.
  • a human epileptic syndrome more particularly pain such as inflammatory pain, neuropathic pain or visceral pain, or rheumatoid arthritis or osteoarthritis
  • pain such as inflammatory pain, neuropathic pain or visceral pain, or rheumatoid arthritis or osteoarthritis
  • administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treatment or prophylaxis e.g. treatment of a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from or susceptible to pain, inflammation (e.g. rheumatoid arthritis or osteoarthritis), or a neurodegenerative disease (e.g.
  • Alzheimer's disease or mild cognitive impairment or epilepsy and/or seizures (e.g. a human epileptic syndrome), (more particularly pain such as inflammatory pain, neuropathic pain or visceral pain, or rheumatoid arthritis or osteoarthritis), which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treatment or prophylaxis e.g. treatment of a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from or susceptible to inflammatory pain, neuropathic pain or visceral pain (e.g. pain, such as inflammatory pain, in arthritis (e.g. rheumatoid arthritis or osteoarthritis)) which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a human or animal e.g. rodent e.g. rat
  • neuropathic pain or visceral pain e.g. pain, such as inflammatory pain, in arthritis (e.g. rheumatoid arthritis or osteoarthritis)
  • arthritis e.g. rheumatoid arthritis or osteoarthritis
  • a method of treatment of a subject for example a human subject, suffering from Alzheimer's disease or mild cognitive impairment, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treatment or prophylaxis e.g. prophylaxis, e.g. reduction, delay or prevention
  • an opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol
  • an opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol
  • a subject suffering from or susceptible to the development of such opioid analgesic tolerance which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis (e.g. treatment) of a condition which is mediated by the action of P2X7 receptors, for example a condition or disease disclosed herein (in particular pain, inflammation such as rheumatoid arthritis or osteoarthritis, or a neurodegenerative disease (e.g. Alzheimer's disease or mild cognitive impairment), or epilepsy and/or seizures (e.g. a human epileptic syndrome); more particularly pain such as inflammatory pain, neuropathic pain or visceral pain); e.g. in a mammal such as a human or rodent e.g.
  • a condition or disease disclosed herein in particular pain, inflammation such as rheumatoid arthritis or osteoarthritis, or a neurodegenerative disease (e.g. Alzheimer's disease or mild cognitive impairment), or epilepsy and/or seizures (e.g. a human epileptic syndrome); more particularly pain
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis (e.g. treatment) of pain (e.g. inflammatory pain, neuropathic pain or visceral pain), inflammation (e.g. rheumatoid arthritis or osteoarthritis), or a neurodegenerative disease (e.g. Alzheimer's disease or mild cognitive impairment), or epilepsy and/or seizures (e.g. a human epileptic syndrome), (more particularly: pain such as inflammatory pain, neuropathic pain or visceral pain, or rheumatoid arthritis or osteoarthritis); e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • pain e.g. inflammatory pain, neuropathic pain or visceral pain
  • inflammation e.g. rheumatoid arthritis or osteoarthritis
  • a neurodegenerative disease e.g.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis (e.g. treatment) of inflammatory pain, neuropathic pain or visceral pain (in particular inflammatory pain or neuropathic pain; such as inflammatory pain in arthritis such as rheumatoid arthritis or osteoarthritis); e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis (e.g. treatment) of Alzheimer's disease or mild cognitive impairment; e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis (e.g. prophylaxis, e.g. reduction, delay or prevention) of the development of tolerence to the analgesic action of an opioid analgesic (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol).
  • an opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
  • a compounds of formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with pharmaceutical practice.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may be for use in a method of treatment or prophylaxis or in a use or in a treatment or prophylaxis, as described herein.
  • a pharmaceutical composition of the invention which may be prepared by admixture, for example at ambient temperature and/or atmospheric pressure, is usually adapted for oral, parenteral or rectal administration.
  • the pharmaceutical composition may be in the form of a tablet, a capsule, a oral liquid preparation, a powder, a granule, a lozenge, a reconstitutable powder, an injectable or infusable solution or suspension, or a suppository.
  • An orally administrable pharmaceutical composition is generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain one or more excipients, such as a binding agent (e.g. hydroxypropylmethylcellulose or povidone), a filler (e.g. lactose and/or microcrystalline cellulose), a lubricant e.g. a tabletting lubricant (e.g. magnesium stearate or calcium stearate), a disintegrant (e.g. a tablet disintegrant such as sodium starch glycolate or croscarmellose sodium), and/or an acceptable wetting agent.
  • a binding agent e.g. hydroxypropylmethylcellulose or povidone
  • a filler e.g. lactose and/or microcrystalline cellulose
  • a lubricant e.g. a tabletting lubricant (e.g. magnesium stearate or calcium stearate)
  • a disintegrant e.g. a tablet disintegrant such as sodium starch glycolate
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain additive(s) such as a suspending agent(s), an emulsifying agent(s), a non-aqueous vehicle(s) (such as an edible oil), and/or a preservative(s), and/or, if desired, a flavouring(s) or colourant(s).
  • fluid unit dosage forms are typically prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound or salt is either suspended or dissolved in the vehicle.
  • the compound or salt can e.g. be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • an adjuvant(s) such as a local anaesthetic, a preservative(s) and/or a buffering agent(s) is or are dissolved in the vehicle.
  • the composition can for example be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are typically prepared in substantially the same manner, except that the compound or salt is typically suspended in the vehicle instead of being dissolved, and sterilization is not usually accomplished by filtration.
  • the compound or salt can be sterilised, e.g. by exposure to ethylene oxide, before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition, e.g. to facilitate uniform distribution of the compound or salt of the invention.
  • the composition contains from 0.1% to 99% (by weight of the composition), in particular from 0.1 to 60% or 1 to 60% or 10 to 60% by weight, of the active material (the compound or pharmaceutically acceptable salt of the invention), e.g. depending on the method of administration.
  • the carrier(s) and/or excipient(s) contained in the composition can for example be present in from 1% to 99.9%, e.g. from 10% to 99%, by weight of the composition; and/or in an amount of from 20 mg to 2000 mg such as 50 mg to 1000 mg per unit dose of the composition.
  • the dose of the compound or pharmaceutically acceptable salt thereof may vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and/or other similar factors.
  • a unit dose of 0.05 to 2000 mg or 0.05 to 1000 mg, for example 0.05 to 200 mg, such as 20 to 40 mg, of the compound or pharmaceutically acceptable salt of the invention (measured as the compound) may be used, e.g. in a pharmaceutical composition.
  • such a unit dose is for administration once a day e.g.
  • Such a unit dose may be for administration more than once (e.g. twice or three times) a day e.g. to a mammal such as a human.
  • Such therapy may extend for a number of days, weeks, months or years.
  • Compounds of formula (I) or pharmaceutically acceptable salts thereof may be used in combination with other (further) therapeutic agent(s), for example medicaments claimed to be useful in the treatment or prophylaxis (e.g. treatment) of the above mentioned disorders.
  • Such further therapeutic agent(s) may include a ⁇ 2-agonist (also known as ⁇ 2 adrenoceptor agonists; e.g. formoterol) and/or a corticosteroid (e.g. budesonide, fluticasone (e.g. as propionate or furoate esters), mometasone (e.g. as furoate), beclomethasone (e.g. as 17-propionate or 17,21-dipropionate esters), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, rofleponide or butixocort (e.g. as propionate ester)), e.g. for the treatment of a respiratory disorder (such as asthma or chronic obstructive pulmonary disease (COPD)), e.g. as described in WO 2007/008155 and/or WO 2007/008157.
  • a respiratory disorder such as asthma or chronic obstruct
  • a further therapeutic agent may include a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) (e.g. for oral administration), e.g. for the treatment of a cardiovascular disorder (such as atherosclerosis), e.g. as described in WO 2006/083214.
  • HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • atorvastatin e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin
  • a cardiovascular disorder such as atherosclerosis
  • a further therapeutic agent may in particular include a non-steroid anti-inflammatory drug (NSAID; e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g.
  • NSAID non-steroid anti-inflammatory drug
  • celecoxib paracetamol, loxoprofen or aceclofenac; in particular celecoxib, paracetamol, ibuprofen or diclofenac) (e.g. for oral administration), e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain), e.g. as described in WO 2005/025571.
  • Celecoxib (a COX-2 inhibitor) can for example be administered orally at a dosage regimen of 100 mg or 200 mg (measured as the free base) once or twice daily.
  • a further therapeutic agent may in particular include a tumour necrosis factor ⁇ (TNF ⁇ ) inhibitor (e.g.
  • etanercept or an anti- TNF ⁇ antibody such as infliximab or adalimumab
  • parenteral administration such as subcutaneous or intravenous administration
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis
  • e.g. as described in WO 2004/105798 e.g. as described in WO 2004/105798.
  • a further therapeutic agent may in particular include an anti-CD20 monoclonal antibody (e.g. for parenteral such as intravenous administration), such as ofatumumab (HuMax-CD20 TM, developed in part by Genmab AS) (e.g. ofatumumab for intravenous administration), rituximab, PRO70769, AME-133 (Applied Molecular Evolution), or hA20 (Immunomedics, Inc.); in particular ofatumumab or rituximab.
  • This further therapeutic agent can e.g. be for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain).
  • a further therapeutic agent may include 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine), e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105797.
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis
  • a further therapeutic agent may in particular include N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid (methotrexate), e.g. for oral administration and/or e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105796.
  • metalhotrexate N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid
  • metalhotrexate N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid
  • metalhotrexate N-[4-[[(2, 4-di
  • methotrexate can be administered to the human at a dosage regimen of 7.5 mg orally once weekly, or using divided oral doses of 2.5 mg at 12 hour intervals for 3 doses (7.5 mg total) as a course once weekly; the schedule can optionally be adjusted gradually to achieve an optimal response, but typically does not exceed a total weekly oral dose of 20mg of methotrexate; once a response has been achieved, the methotrexate dose is typically reduced to the lowest possible effective dose.
  • a further therapeutic agent may include an inhibitor of pro TNF ⁇ convertase enzyme (TACE), e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/073704.
  • TACE pro TNF ⁇ convertase enzyme
  • a further therapeutic agent may include: a) sulfasalazine; b) a statin (e.g.
  • atorvastatin for oral administration
  • lovastatin pravastatin
  • simvastatin fluvastatin, cerivastatin, crilvastatin, dalvastatin, rosuvastatin, tenivastatin, fluindostatin, velostatin, dalvastatin, nisvastatin, bervastatin, pitavastatin, rivastatin, glenvastatin, eptastatin, tenivastatin, flurastatin, rosuvastatin or itavastatin; c) a glucocorticoid agent (e.g.
  • an inhibitor of p38 kinase e.g. for oral administration
  • an anti-IL-6-receptor antibody e.g. an anti-IL-6-receptor monoclonal antibody (e.g. for parenteral such as intravenous administration)
  • anakinra e.g. an anti-IL-1 (e.g. IL-1 ⁇ ) monoclonal antibody (e.g.
  • an inhibitor of JAK3 protein tyrosine kinase i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody
  • M-CSF anti-macrophage colony stimulation factor
  • an anti-CD20 monoclonal antibody e.g. for parenteral such as intravenous administration
  • rituximab, ofatumumab HuMax-CD20 TM, developed in part by Genmab AS) (e.g. ofatumumab for intravenous administration), PRO70769, AME- 133 (Applied Molecular Evolution), or hA20 (Immunomedics, Inc.); in particular rituximab or ofatumumab;
  • IL-1 e.g. IL-1 ⁇
  • IL-1 ⁇ IL-1 ⁇
  • IL-1 ⁇ IL-1 ⁇
  • inflammatory or neuropathic pain e.g. as described in WO 2006/003517.
  • the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating inflammatory pain, such as paracetamol and/or an opioid analgesic (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol).
  • This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s) can be for the treatment of inflammatory pain, e.g. in a mammal such as a human.
  • paracetamol can be administered at a human oral dosage regimen of 500 mg to 1000 mg (e.g.
  • the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating neuropathic pain, such as:
  • an opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol, most particularly morphine
  • opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol, most particularly morphine
  • a monoamine reuptake inhibitor such as duloxetine or amytriptyline
  • This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of neuropathic pain, e.g. in a mammal such as a human.
  • pregabalin can be administered orally e.g. for neuropathic pain; e.g. at a human oral dosage regimen of 150 mg to 600 mg total pregabalin per day (measured as the free base), split between two to three doses per day.
  • pregabalin can be administered at a starting oral dosage regimen of 150 mg total pregabalin per day (split between 2 or 3 doses per day), escalating (e.g. in about one week) to an oral dosage regimen of 300 mg pregabalin total per day, and optionally escalating up to a maximum oral dosage regimen of 600 mg total pregabalin per day.
  • an oral dosage regimen of 150 mg to 300 mg total pregabalin per day can be administered.
  • an oral dosage regimen of 150 mg to 450 mg (e.g. 300 or 450 mg) total pregabalin per day can be administered.
  • Pregabalin can e.g. be administered separately from the compound of formula (I) or the salt thereof.
  • gabapentin can be administered orally, e.g. for neuropathic pain.
  • Oral dosage units can e.g. contain 100 mg, 300 mg, 400 mg, 600 mg or 800 mg of gabapentin (measured as the free base/acid).
  • the gabapentin dosage regimen for neuropathic pain can e.g. be from 300 mg once, twice or three times per day up to a total dose of 3600 mg / day. Some gradual up-titration of the dosage regimen is usually performed.
  • Slower titration of gabapentin dosage may be appropriate for individual patients.
  • the minimum time to reach a total dose of 1800 mg / day is typically one week, to reach 2400 mg / day is typically a total of 2 weeks, and to reach 3600 mg / day is typically a total of 3 weeks.
  • Gabapentin can e.g. be administered separately from the compound of formula (I) or the salt thereof.
  • gabapentin enacarbil ( ⁇ )-1-([( ⁇ - isobutanoyloxyethoxy)carbonyl]-aminomethyl)-1-cyclohexane acetic acid, which is a prodrug of gabapentin) can be administered orally, e.g. to a human, e.g. separately from the compound of formula (I) or the salt thereof.
  • gabapentin enacarbil (XP13512) is for example administered orally, e.g. to a human such as a human adult, e.g.
  • a 600 mg dose of gabapentin enacarbil contains the molar equivalent of 312 mg of gabapentin. See also K. C. Cundy et al., "Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin", J. CHn.
  • the opioid analgesic such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol
  • the opioid analgesic and/or the combination comprising the opioid analgesic is for the treatment of pain, in particular inflammatory or neuropathic pain, e.g. in a mammal such as a human.
  • the compound or salt of the present invention is administered (e.g. to a human), e.g.
  • the opioid analgesic is administered at a reduced dosage compared to the dosage (e.g. human dosage) typically used for said opioid analgesic (i.e. the compound or salt of the invention might give an opioid-sparing effect); this might give adequate pain control and/or might result in a reduction of opioid-analgesic-induced adverse events.
  • the further therapeutic agent may be useful in the treatment or prophylaxis (in particular treatment) of a Neurodegenerative disease.
  • the further therapeutic agent may be useful in alleviating the sympthoms of a Neurodegenerative disase.
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents (e.g. as defined herein).
  • the individual components of the combination of the invention may be present as separate pharmaceutical formulations / compositions, or may be present as a combined pharmaceutical formulation / composition (e.g. may be together in a single combined oral dosage form, e.g. a single combined tablet or capsule).
  • the individual components of this combination can for example be administered either sequentially in separate pharmaceutical formulations / compositions (e.g. oral), or simultaneously in separate or combined pharmaceutical formulation(s) / composition(s) (e.g. oral); in a particular embodiment they are administered sequentially in separate pharmaceutical formulations / compositions (e.g. oral).
  • compositions comprising a combination as defined herein together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • reaction was then cooled in an ice/water bath before the addition of triethylamine (4.03 ml) and methyl chlorooxoacetate (1.86 ml) and the reaction stirred for a further 18 hours.
  • the reaction was then diluted with dichloromethane (100 ml) and washed with 1 N hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100ml), passed through a hydrophobic frit and reduced in vacuo to yield a pale brown oil.
  • the reaction was stirred at O 0 C under argon for 20 minutes before being warmed to room temperature and stirred for 40 hours.
  • the molecular sieves were filtered off and to the filtrate was added further dichloromethane and saturated aqueous sodium bicarbonate.
  • the product was extracted with dichloromethane (three washes) and the combined organic layers washed with water. The organic layer was dried over sodium sulfate and evaporated in vacuo to give 0.185 g of a yellow oil.
  • the crude material was purified by flash-silica gel chromatography, eluting with a 10-
  • the vessel was purged with argon for 5 minutes followed by oxygen for 5 minutes. Ozone was then bubbled through the reaction mixture until a blue colour persisted (approximately 1 hour). The reaction was then purged with oxygen for 5 minutes followed by argon for 20 minutes until the exhaust gases gave a negative response to wetted starch iodide paper. The solution was then warmed to room temperature and dimethyl sulfide (2.05 ml, 27.8 mmol) added. The mixture was stirred at room temperature for 5 hours and then left to stand overnight.
  • the 5,6,7,8-tetrahydro-1-naphthalenamine (0.038 g, 0.26 mmol) was added to a mixture of methyl [[(2-chloro-4-fluorophenyl)methyl](2-oxoethyl)amino](oxo)acetate (0.10 g, 0.26 mmol, prepared as described earlier), acetic acid (0.044 ml, 0.78 mmol) and 4A molecular sieves in dichloromethane (6 ml) and stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (0.083 g, 0.39 mmol) was added and the reaction stirred overnight at room temperature. Saturated aqueous sodium bicarbonate (approx.
  • reaction mixture was allowed to warm to room temperature and stirred overnight.
  • the reaction mixture was then partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50ml), washed with two portions of water, brine and then dried over anhydrous magnesium sulfate.
  • the residue was concentrated in vacuo and purified by mass-directed automated HPLC.
  • reaction was then allowed to warm to room temperature and stirred for 6 hours before being heated to 60 0 C overnight.
  • the reaction was cooled to room temperature and saturated aqueous sodium bicarbonate was added until the evolution of gas stopped.
  • the aqueous layer was separated and washed with dichloromethane, the organic layers separated using a hydrophobic frit and concentrated in vacuo.
  • reaction was then heated to 80 0 C for 5 hours, followed by stirring at 80 0 C overnight.
  • the reaction was allowed to cool to room temperature and saturated aqueous sodium bicarbonate was slowly added until gas evolution had stopped.
  • the organic layer was separated using a hydrophobic frit and concentrated in vacuo. The residue was purified by flash-silica gel chromatography, eluting with a 10-75% gradient of ethyl acetate in isohexane.
  • Sodium triacetoxyborohydride (0.49 g, 2.12 mmol) was added; the reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then heated to 80 °C with stirring overnight. The reaction mixture was allowed to cool and saturated aqueous sodium bicarbonate was added until gas evolution stopped. The organic layer was separated using a hydrophobic frit. The aqueous layer was extracted with dichloromethane and the organic layer separated.
  • the filtrate solution was concentrated in vacuo and purified by flash-silica gel chromatography, eluting with a 2-20% gradient of ethyl acetate in isohexane to yield 4-(2-methyl-6- nitrophenyl)morpholine (1.29 g) as a bright yellow solid.
  • the 5-methyl-2-(4-morpholinyl)aniline used in the method described above was prepared as follows:
  • the 5-Fluoro-2-(4-morpholinyl)aniline used in the method described above was prepared as follows:
  • N,N-dimethyl-1 ,2-benzenediamine used in the method described above was prepared as follows:
  • N,N-dimethyl-2-nitroaniline (4.99 g, 30 mmol) was hydrogenated at 1 atmosphere hydrogen over 10% palladium on carbon paste (0.64 g, 3.0 mmol) in ethanol (100 ml) for 48 hours.
  • the catalyst was filtered off and the filtrate concentrated in vacuo to yield N,N-dimethyl-1 ,2-benzenediamine (3.89 g) as an oil.
  • reaction mixture was allowed to cool, reduced in vacuo and partitioned between ethyl acetate and water.
  • the organic layer was washed with water and separated, then dried over sodium sulfate and reduced in vacuo.
  • the residue was purified by flash- silica gel chromatography, eluting with a 5-15% gradient of ethyl acetate in hexane to yield 4-[2-(methyloxy)-3-nitrophenyl]morpholine (0.64 g) as a bright yellow solid.
  • reaction mixture was then concentrated in vacuo and redissolved in 1-butanol (3 ml).
  • the solution was heated to 16O 0 C for 1 hour in the microwave.
  • the mixture was concentrated in vacuo and purified by flash-silica gel chromatography. The mixture was eluted with a 0-100% gradient of ethyl acetate in hexane followed by a flush of 5% methanol in DCM, then 10% methanol in DCM.
  • reaction mixture was then concentrated in vacuo and redissolved in 1-butanol (3 ml).
  • the solution was heated to 16O 0 C for 1 hour in the microwave.
  • the mixture was concentrated in vacuo and purified by flash-silica gel chromatography. The mixture was eluted with ethyl acetates followed by 5% methanol in dichloromethane and finally 10% methanol in dichloromethane.
  • Iron powder (3.63 g, 65.0 mmol) was suspended in acetic acid (50 ml) and warmed to 4O 0 C with mechanical stirring.
  • 2-Chloro-3-nitrophenyl methyl ether (2.44 g, 13.01 mmol) dissolved in acetic acid (25 ml) was added at such a rate as to maintain a temperature of 45-5O 0 C.
  • the mixture was heated at 80 0 C for 2 hours after the addition had been completed.
  • the mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% 0.880 ammonia solution.
  • the aqueous phase was extracted with ethyl acetate (x3).
  • the combined extracts were washed with water (x3), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a red oil.
  • the crude product was purified by flash-silica gel chromatography, eluting with a 0-100% gradient of ethyl acetate in isohexane to afford 4-methyl-5-nitro-3,4-dihydro-2H-1 ,4-benzoxazine (1.06 g).
  • the 1-(2,3-dichlorophenyl)-2,3-piperazinedione used in the method described above was prepared as follows:
  • N-Boc-2-aminoacetaldehyde (2.0 g, 12.6 mmol) was dissolved in dichloromethane (50 ml). 4A molecular sieves (0.3g) were added and the solution cooled to O 0 C. 2,3-dichloroaniline (2.14 g, 13.2 mmol) and sodium triacetoxyborohydride (3.99 g, 18.9 mmol) were added and the suspension warmed to room temperature. The reaction was stirred for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (30 ml) and stirred for 20 minutes. The organic layer was separated using a hydrophobic frit and concentrated in vacuo.
  • N-(3-methyl-4-pyridinyl)-1 ,2-ethanediamine (0.37 g, 2.43 mmol) was suspended in dichloromethane (50 ml).
  • 4A molecular sieves (0.20 g), 2-chloro-4- fluorobenzaldehyde (0.46 g, 2.92 mmol), sodium triacetoxyborohydride (0.77 g, 3.65 mmol) and acetic acid (0.42 ml, 7.30 mmol) were added and the reaction stirred at room temperature for 20 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (30 ml) and stirred for 10 minutes.
  • the reaction was quenched by adding saturated aqueous sodium bicarbonate (20 ml) and the mixture extracted with dichloromethane (50 ml). The organic layer was separated using a hydrophobic frit and concentrated in vacuo. The residue was purified by flash-silica gel chromatography, eluting with a 0-10% gradient of 2 Molar ammonia in methanol solution in dichloromethane. The product fractions were concentrated in vacuo. The solids were triturated with diethyl ether (2 x 50 ml) and pale pink solids were filtered off. This material was suspended in methanol (15 ml) and 2 Molar hydrochloric acid was added (approx 5 ml).
  • N-[(2-Chloro-4-fluorophenyl)methyl]-N'-(3,6-dimethyl-2-pyridinyl)-1 ,2-ethane- diamine used in the method described above was prepared in an analogous manner to the N-[(2-chloro-4-fluorophenyl)methyl]-N'-(3-methyl-4-pyridinyl)-1 ,2-ethane- diamine described in Example 120 above, by substituting the appropriate chloropyridine for the 4-chloro-3-methylpyridine used in the above procedure.
  • the organic layer was separated using a hydrophobic frit and concentrated in vacuo.
  • the residue was purified by flash-silica gel chromatography, eluting with a 0-10% gradient of 2 Molar ammonia in methanol solution in dichloromethane.
  • the product fractions were concentrated in vacuo and purified by mass-directed automated HPLC.
  • the product was then dissolved in methanol and passed through a pre-conditioned 1 O g aminopropyl cartridge. The column was washed with further methanol (40 ml) and the solution concentrated in vacuo.
  • N-[(2-chloro-4-fluorophenyl)methyl]-N'-(3-methyl-2-pyridinyl)-1 ,2-ethanediamine used in the method described above was prepared in an analogous manner to the N- [(2-chloro-4-fluorophenyl)methyl]-N'-(3-methyl-4-pyridinyl)-1 ,2-ethanediamine described in Example 120 above, by substituting the appropriate chloropyridine for the 4-chloro-3-methylpyridine used in the above procedure.
  • 1-(3-bromo-2-methylphenyl)-4-[(2-chloro-4-fluorophenyl)methyl]-2,3- piperazinedione (0.085 g, 0.200 mmol), imidazole (0.0204 g, 0.300 mmol), potassium carbonate (0.0552 g, 0.399 mmol), copper (I) iodide (0.0038 mg, 0.020 mmol) and trans-N,N'-dimethyl-cyclohexane-1 ,2-diamine (6.30 ⁇ l, 0.040 mmol) were suspended in N,N-dimethylformamide (2 ml) and heated at 180 0 C for 1 hour in a microwave reactor.
  • the dichloromethane layer was separated, washed with brine (-50 ml), and then filtered through a hydrophobic frit and evaporated to give a slightly opaque colourless oil.
  • the oil was purified by flash-silica gel chromatography, eluting with a 0-100% gradient of ethyl acetate in isohexane, to give 1 ,1-dimethylethyl ((1S)-2- ⁇ [(2,4- dichlorophenyl)methyl]amino ⁇ -1-methylethyl)carbamate (1.57 g) as a clear pale- yellow oil.
  • the (5R)-1-[(2,4-dichlorophenyl)methyl]-5-methyl-2,3-piperazinedione used in the method described above was prepared in an analogous manner to the (5S)-1-[(2,4- dichlorophenyl)methyl]-5-methyl-2,3-piperazinedione used in Example 125.
  • the columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm
  • the stationary phase particle size is
  • Aqueous solvent Water + 0.1% Formic Acid
  • Aqueous solvent Water + 0.05% Formic Acid
  • the generic method used has a 5 minute runtime.
  • the above method has a flow rate of 3ml/mins.
  • the injection volume for the generic method is 5ul.
  • the column temperature is 30deg.
  • the UV detection range is from 220 to 330nm.
  • NaCI assay buffer of the following composition: 14OmM NaCI, 10 mM HEPES [4-(2-hydroxyethyl)-1-piperazine-1-ethanesulfonic acid], 5 mM ⁇ /-methyl-D-glucamine, 5.6 mM KCI, 10 mM D-glucose, 0.5 mM CaCI 2 (PH 7.4).
  • Human Embryonic Kidney (HEK) 293 cells stably expressing human recombinant P2X7 receptors, were grown in poly-D-lysine pretreated 96 well plates for 18-24 hours.
  • the cloning of the human P2X7 receptor is described in US 6,133,434, e.g. see Example 3 therein).
  • the cells were washed twice with 350 ⁇ l of the assay buffer, before addition of 50 ⁇ l of the assay buffer containing the putative P2X7 receptor antagonist compound.
  • the cells were then incubated at room temperature (19-21 0 C) for 30 min before addition of ATP and ethidium (100 ⁇ M final assay concentration).
  • the ATP concentration was chosen to be close to the EC ⁇ o f° r the receptor type and was 1 mM for studies on the human P2X7 receptor. Incubations were continued for 8 or 16 min and were terminated by addition of 25 ⁇ l of 1.3M sucrose containing 4 mM of the P2X7 receptor antagonist Reactive Black 5 (Aldrich).
  • Human Embryonic Kidney (HEK) 293 cells stably expressing human recombinant P2X7 receptors, were grown in poly-D-lysine pretreated 384 well plates for 24hours at room temperature (for a time sufficient for growth of a homogeneous layer of cells at the bottom of the wells).
  • human osteosarcoma (U-2OS) cells commercially available
  • Baculovirus (BacMam) vector to deliver the gene coding for human P2X7 receptor (i.e. transiently expressing human recombinant P2X7 receptors)
  • BacMam Baculovirus
  • the solution of the putative P2X7 receptor antagonist compound was created by (i) dissolving the compound in dimethyl sulfoxide (DMSO) to create a stock solution in DMSO at 20Ox the final assay concentration, and (ii) mixing 1 ⁇ l of the stock solution of the compound in DMSO with 50 ⁇ l of the assay buffer to create a solution at about 4x the final assay concentration.
  • DMSO dimethyl sulfoxide
  • the cells were then incubated at room temperature for 30 mins before addition (online, by FLIPR384 or FLIPR3 instrument (Molecular Devices, 131 1 La Drive, Sunnyvale, CA 94089-1136, USA)) of 10 ⁇ l of the assay buffer containing benzoylbenzoyl-ATP (BzATP) such as to create a 60 ⁇ M final assay concentration of BzATP (BzATP was added at 5x this final concentration).
  • BzATP concentration was chosen to be close to the EC ⁇ o for the receptor type.
  • the compounds of Examples 1 , 3-9, 1 1 , 14, 18, 22-31 , 33, 35-41 , 43, 46-50, 52-53, 55-61 , 64-73, 75-80, 86-94, 96-100, 102-105, 107-115, 118, 121 and 123-126 were found to have plC50 values >6.5 in the Ethidium Accumulation Assay.

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Abstract

L'invention porte sur un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci (I) dans laquelle: A représente un groupe aryle, hétéroaryle ou hétérocyclyle ; et tout cycle ou système cyclique dudit aryle ou hétéroaryle est éventuellement substitué par 1 à 3 substituants, qui peuvent être peuvent être identiques ou différents, choisis dans le groupe constitué par halogène, alkyle en C1-6, -CF3, -OCF3, cyano, alcoxy en C1-6, -NR10R11, -X-aryle, -X-hétéroaryle et -X-hétérocyclyle ; R1, R2, R3, R4 et R5 représentent chacun indépendamment hydrogène, fluor, chlore, -CF3, cyano ou alkyle en C1-6, de façon à ce qu'au moins l'un parmi R1, R2, R3, R4 et R5 soit autre qu'hydrogène ; R6, R7, R8, R9, R10 et R11 représentent chacun indépendamment hydrogène ou alkyle en C1-6 ; X représente un groupe de liaison choisi parmi une liaison, -(CH2)n- et -O-(CH2)n- ; et n représente un entier de 1 à 3. Les composés ou sels modulent la fonction du récepteur P2X7 et sont aptes à s'opposer aux effets de l'ATP au niveau du récepteur P2X7 (« antagoniste du récepteur P2X7 »).
PCT/EP2010/055716 2009-04-29 2010-04-28 Dérivés de dicétopipérazine comme modulateurs de p2x7 WO2010125103A1 (fr)

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