WO2003042190A1 - N-alkyl-adamantyl derivatives as p2x7-receptor antagonists - Google Patents

N-alkyl-adamantyl derivatives as p2x7-receptor antagonists Download PDF

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WO2003042190A1
WO2003042190A1 PCT/IB2002/004043 IB0204043W WO03042190A1 WO 2003042190 A1 WO2003042190 A1 WO 2003042190A1 IB 0204043 W IB0204043 W IB 0204043W WO 03042190 A1 WO03042190 A1 WO 03042190A1
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alkyl
formula
compounds
hydrogen
fluoro
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PCT/IB2002/004043
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French (fr)
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Allen Jacob Duplantier
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Pfizer Products Inc.
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Definitions

  • the present invention relates to N-alkyl adamantyl triazinyl benzamide derivatives, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy.
  • the active compounds of the present invention are useful in the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
  • the active compounds are also antagonists of the P2X 7 receptor.
  • the P2X 7 receptor (previously known as P2Z receptor), which is ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B).
  • P2X 7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
  • APC antigen-presenting cells
  • keratinocytes salivary acinar cells
  • P2X 7 antagonists are known in the art, such as International Patent Publications WO 01/46200, WO 01/42194, WO 01/44213, WO99/29660, WO 00/61569, WO 99/29661 , WO 99/29686, WO 00/71529, and WO 01/44170.
  • R 2 is selected from the group of suitable substituents such as (i) hydrogen, (ii) halogen, (iii) cyano, (iv) (C C )alkyl optionally substituted by one to four chloro or fluoro, (v) (C 2 -C 4 )alkenyl; (vi) (C 2 -C 4 )alkynyl and (vii) (C C )alkyloxy optionally substituted by one to four chloro or fluoro;
  • suitable substituents such as (i) hydrogen, (ii) halogen, (iii) cyano, (iv) (C C C )alkyl optionally substituted by one to four chloro or fluoro, (v) (C 2 -C 4 )alkenyl; (vi) (C 2 -C 4 )alkynyl and (vii) (C C )alkyloxy optionally substituted by one to four chloro or fluoro;
  • R 3 , R 4 and R 5 are each independently selected from the group suitable substituents such as (i) hydrogen; (ii) halogen, (iii) cyano, (iv) nitro, (v) amino, (vi) hydroxyl, (vii) (C ⁇ -C 6 )alkyl optionally substituted by one to four chloro or fluoro, (viii) (C 3 -C 8 )cycloalkyl optionally substituted by one to four chloro or fluoro, (ix) (C C 6 )alkyloxy optionally substituted by one to four chloro or fluoro, and (x) (C 3 -C 8 )cycloalkyloxy optionally substituted by one to four chloro or fluoro;
  • substituents such as (i) hydrogen; (ii) halogen, (iii) cyano, (iv) nitro, (v) amino, (vi) hydroxyl, (vii) (C ⁇ -C 6 )alkyl optionally substituted by
  • R 6 is hydrogen or (C ⁇ -C 6 )alkyl, preferably methyl;
  • R 7 is hydrogen, (C C 6 )alkyl or (C 3 -C 8 )cycloalkyl;
  • R 8 is absent or is selected from the group suitable substituents such as hydrogen,
  • (C C 6 )alkyl optionally substituted with one to six fluoro, HO-(C 2 -C 6 )alkyl and (C 3 -C 8 )cycloalkyl;
  • R 9 is selected from the group suitable substituents such as hydrogen, halo, (Ci-CeJalkyl optionally substituted with one to six fluoro, -C0 2 H, HO-(C 2 -C 6 )alkyl, (CrC 6 )alkoxy optionally substituted with one to six fluoro, hydroxy, (C ⁇ -C 10 )heteroaryl and (C 3 -C 8 )cycloalkyl; each R 10 is independently selected from the group consisting of hydrogen or halo; or the pharmaceutically acceptable salts or solvates or prodrugs thereof.
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as the chloride
  • the invention also relates to base addition salts of formula I.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • compositions containing prodrugs of compounds of the formula I can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, omithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • This invention also encompasses compounds of formula I containing protective groups.
  • compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient.
  • the protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press. (1973) and “Protective Groups in Organic Synthesis", 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1991).
  • the compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
  • the compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
  • One example of a tautomeric structure is when R 1 is a group of the formula
  • the present invention also includes atropisomers of the present invention.
  • Atropisomers refer to compounds of formula I that can be separated into rotationally restricted isomers.
  • the compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
  • a "suitable substituent” is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art.
  • substituents include, but are not limited to halo groups, perflu
  • alkyl as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, /7-propyl, /sopropyl, n-butyl, /so-butyl, secondary-butyl, tert/a/y-butyl); optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C C ⁇ Jalkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C C ⁇ alkyl.
  • suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C C ⁇ Jalkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C C ⁇ alkyl.
  • each of said alkyl refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkylamino.
  • Preferred alkyls include (C 1 -C )alkyl, most preferably methyl and ethyl.
  • cycloalkyl refers to a mono, bicyclic or tricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC 6 )alkoxy, (C 6 -C 0 )aryloxy, trifluoromethoxy, difluoromethoxy or (C ⁇ -C 6 )alkyl.
  • suitable substituents as defined above such as fluoro, chloro, trifluoro
  • halogen includes fluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide.
  • halo-substituted alkyl refers to an alkyl radical as described above substituted with one or more halogens included, but not limited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C ⁇ -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C r C 6 )alkyl.
  • alkenyl means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl
  • (C 2 -C 6 )alkynyl is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (Ci-CeJalkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C C 6 )alkyl.
  • Alkylcarbonylamino refers to groups such as acetamide.
  • aryl means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC ⁇ )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C ⁇ -C 6 )alkyl.
  • the term "5 to 10 membered saturated heterocyclic ring” refers to a cyclic group containing 1-7 carbon atoms containing three to five nitrogen heteroatoms and zero to three additional heteroatoms independently selected from the group consisting of -O- and -S(0) ⁇ -and each of the bonds between ring members is a single bond and wherein said ring is optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (CrC 6 )alkyl.
  • rings examples include 1 ,2,3-triazolidine, 1,2,4-triazolidine, tetrazolidine, 1 ,2,3,4-oxatriazolidine, 1 ,2,3,5-oxatriazolidine, perhydro-1 ,2,3-triazine, perhydro-1 ,3,5-triazine, perhydro-1 ,2,4-triazine, perhydro-purine, perhydro-pyrazolopyridine, perhydro-triazolopyridine, dihydro-6-azauracil, perhydro-pteridine, 1 ,2,3,4-thiatriazolidine and 1,2,3,5-thiatriazolidine.
  • the term "5 to 10 membered unsaturated heterocyclic ring” refers to a cyclic group containing 1-7 carbon atoms containing three to five nitrogen heteroatoms and zero to three additional heteroatoms independently selected from the group consisting of -O- and -S(0) n - and at least two of the bonds between ring members are double bonds such that the ring is an aromatic ring.
  • Such rings include 1 ,2,3-triazole, 1 ,2,4-triazole, 1-H-pyrazolo[4,3-d]oxazole, 4H-imidazo[4,5-d]thiazole, imidazo[1 ,2-b][1 ,2,4]triazine, tetrazole, 1 ,2,3,4-oxatriazole, 1 ,2,3,5-oxatriazole, 1 ,2,3-triazine, 1 ,3,5-triazine, 1 ,2,4-triazine, purine, pyrazolopyridine, pyrazino[2,3-d]pyridazine, triazolopyridine, xanthine, pteridine,
  • the term "5 to 10 membered partially unsaturated heterocyclic ring” refers to a cyclic group containing 1-7 carbon atoms containing three to five nitrogen heteroatoms and zero to three additional heteroatoms independently selected from the group consisting of -O- and -S(0) n - and at least one of the bonds between ring members is a double bond.
  • rings examples include dihydro-1 ,2,3-triazole, dihydro-1 ,2,4-triazole, dihydro-tetrazole, dihydro-1 ,2,3,4-oxatriazole, dihydro-1 ,2,3,5-oxatriazole, dihydro-1 ,2,3-triazine, dihydro-1 ,3,5-triazine, dihydro-1 ,2,4-triazine, .
  • R 1 heterocycles include 6-azauracil.
  • heteroaryl refers to an aromatic heterocyclic group usually with one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring.
  • heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1 ,3-oxazolyl, 1 ,2-oxazolyl), thiazolyl (e.g., 1 ,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), oxadiazolyl (e.g., 1 ,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted by
  • “Embodiment” as used herein refers to specific groupings of compounds or uses into discrete subgenera. Such subgenera may be cognizable according to one particular substituent such as a specific R 1 or R 2 group. Other subgenera are cognizable according to combinations of various substituents, such as all compounds wherein R 2 is chloro and R 1 is optionally substituted 6-azauracil.
  • Another embodiment of the present invention are those compounds of formula I wherein one of R 3 , R 4 or R 5 is selected from the group consisting of (i) hydrogen (ii) halogen, (ii) cyano, (iii) nitro, (iv) amino, (v) hydroxyl, (vi) (d-CeJalkyl optionally substituted by one to four chloro or fluoro, (vii) (C 3 -C 8 )cycloalkyl optionally substituted by one to four chloro or fluoro, (viii) (Ci-C ⁇ jalkyloxy optionally substituted by one to four chloro or fluoro, and (ix) (C 3 -C 8 )cycloalkyloxy optionally substituted by one to four chloro or fluoro.
  • a more preferred embodiment of the invention are those compounds of formula I wherein one of R 3 , R 4 or R 5 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, (d-C ⁇ alky! optionally substituted by one to four chloro or fluoro, and (CrC 4 )alkyloxy optionally substituted by one to four chloro or fluoro.
  • An even more preferred embodiment of the invention are those compounds of formula I wherein one of R 3 , R 4 or R 5 is selected from the group consisting of hydrogen, fluoro, cyano, methyl, -CF 3 , methoxy and -OCF 3 . Most preferably each of R 3 , R 4 or R 5 is hydrogen.
  • Another embodiment of the present invention are those compounds of formula I wherein m is one.
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 5 membered saturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (Ci-C ⁇ Jal yl, more preferably hydrogen or (C C 4 )alkyl, more preferably hydrogen or
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 5 membered unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (Ci-CeJalkyl, more preferably hydrogen or (C C 4 )alkyl, more preferably hydrogen
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 5 membered partially unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C ⁇ -C 6 )alkyl, more preferably hydrogen or (C C 4 )alkyl, more
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 6 membered saturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C r C 6 )alkyl, more preferably hydrogen or (C 1 -C 4 )alkyl, more
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 6 membered unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C C ⁇ Jalkyl, more preferably hydrogen or (C 1 -C )alkyl, more preferably hydrogen
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 6 membered partially unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (CrC ⁇ alkyl, more preferably hydrogen or (C C 4 )alkyl, more preferably hydrogen or
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered monocyclic saturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C C 6 )alkyl, more preferably hydrogen or (C C 4 )alkyl, more preferably hydrogen
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered monocyclic unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or more preferably hydrogen or (C r C 4 )alkyl, more preferably hydrogen or methyl.
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered monocyclic partially unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or more preferably hydrogen or (C ⁇ -C 4 )alkyl, more preferably hydrogen or methyl.
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered bicyclic saturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C ⁇ -C 6 )alkyl, more preferably hydrogen or (CrC 4 )alkyl, more
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered bicyclic unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C ⁇ Jalkyl, more preferably hydrogen or (C ⁇ -C 4 )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 7 membered bicyclic partially unsaturated heterocyclic ring containing three to four nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C 1 -C 4 )al
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered monocyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C 4 )alkyl, more
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered monocyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C 1 -C 4 )alky
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered monocyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered bicyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C )alkyl, more preferably
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered bicyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C 4 )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 8 membered bicyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C 1 -C 4 )al
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered monocyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C C 4 )alkyl, more preferably
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered monocyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )aikyl, more preferably hydrogen or (C 1 -C 4 )al
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered monocyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C 4 )alkyl
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered bicyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C )alkyl, more preferably
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered bicyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C 1 -C 4 )alky
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 9 membered bicyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl, more preferably hydrogen or (C 1 -C 4
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered monocyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C r C 6 )alkyl, more preferably hydrogen or (C r C 4 )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered monocyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C 4 )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered monocyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C 4 )alkyl
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered bicyclic saturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (C C 6 )alkyl, more preferably hydrogen or (C C 4 )alkyl, more preferably hydrogen
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered bicyclic unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (d-C )alkyl, more
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is a 10 membered bicyclic partially unsaturated heterocyclic ring containing three to five nitrogen atoms; wherein one to three of said nitrogen atoms of said heterocycle able to support an additional substituent may also optionally be substituted by R 8 ; wherein any carbon atom of said heterocycle able to support an additional substituent may also optionally be substituted by one to four R 9 substituents per ring; more preferably wherein R 8 and R 9 are each independently hydrogen or (d-C 6 )alkyl, more preferably hydrogen or (C C 4 )alkyl,
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is selected from the group
  • R is selected from the group consisting of hydrogen, (d-C 6 )alkyl, HO-(C 2 -C 6 )alkyl and (C 3 -C 8 )cycloalkyl group; wherein R 9 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, HO-(C 2 -C 6 )hydroxyalkyl and (C 3 -C 8 )cycloalkyl group.
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is selected from the group
  • R 8 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, HO-(C 2 -C 6 )alkyl and (C 3 -C 8 )cycloalkyl group; wherein R 9 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, HO-(C 2 -C 6 )hydroxyalkyl and (C 3 -C 8 )cycloalkyl group.
  • Another embodiment of the present invention are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is selected from the group
  • R 8 is selected from the group consisting of hydrogen, CF 3 -, (d-C 6 )alkyl, HO-(C 2 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl group.
  • R 9 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, CF 3 -CH 2 -, HO-(C 2 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl group.
  • 6-azauracil compounds are those compounds of formula I (as well as the benzamide, nicotinamide, picolinamide, isonicotinamide, pyridazinamide, pyrimidinamide, pyrazinamide, formanilide, carboxaminopyridine, carboxaminopyridazine, carboxaminopyrimidine and carboxaminopyrazine groups of compounds) wherein R 1 is
  • R 8 is selected from the group consisting of hydrogen or (d-C 6 )alkyl.
  • Another preferred embodiment of the present invention are those compounds of formula I wherein W is a bond.
  • W is -0-, -(CH 2 ) 0 0-, -0(CH 2 ) p O-, -(CH 2 ) r O(CH 2 ) q O-, >NR 7 , -(CH 2 ) 0 NR 7 -, -O(CH 2 ) p NR 7 -, -(CH 2 ) r NR 7 (CH 2 ) q O-, -NR 7 (CH 2 ) p O-, -CONR 7 -, S(0) n -, -CH 2 S(0) n -, -S0 2 NR 7 -, or-NR 7 S0 2 -; n is 0, 1 or 2; o is an integer from 1 to 6; p is an integer from 2 to 6; q is an integer from 2 to 3; r is an integer from 1 to 3;
  • R 7 represents hydrogen or (C ⁇ -C 6 )alkyl, preferably methyl
  • R 6 is hydrogen, (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl; and R 7 represents hydrogen or (d-C ⁇ )alkyl, preferably methyl.
  • n is an integer from 1 to 2;
  • R 2 is fluoro or chloro
  • R 4 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, (C C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (d-C 3 )alkyloxy, -CF 3 , -OCF 3 and (C 3 -C 6 )cycloalkyloxy;
  • R 8 is a hydrogen atom or a (d-CeJalkyl, CF 3 -CH 2 -, HO-(C 2 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl group;
  • R 10 is hydrogen or fluoro; or a pharmaceutically acceptable salt or solvate thereof.
  • Examples of specific preferred compounds of the formula I are the following: N-Adamantan-1-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)- benzamide;
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent.
  • the compounds of Formula I or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cells, such as but not limited to monocytes and/or macrophages.
  • the present invention relates to a method for treating a P2X 7 mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I.
  • the present invention also relates to a method for treating a condition selected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening of artificial joint implants, atherosclerosis, aortic aneurysm,
  • the present invention relates to a pharmaceutical composition for the treatment of a P2X 7 mediated disease in a mammal which comprises an effective amount of a compound according to formula I and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration
  • the compounds of the invention are useful for the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the invention further provides a method of treating osteoarthritis which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
  • the invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
  • a method of effecting immunosuppression e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
  • the invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
  • an obstructive airways disease e.g. asthma or COPD
  • administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the daily dosage of the compound of formula (l)/salt/solvate (active ingredient) may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.
  • the present invention also encompasses sustained release compositions.
  • the present invention also relates to processes of preparing the compounds of formula I and intermediates used in such processes.
  • the compounds of the invention are useful in treating a diverse array of diseases.
  • One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
  • the compounds of the invention may be combined with agents such as TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D 2 E 7 ) and TNF receptor immunoglobulin molecules (such as Enbrel®), COX-2 inhibitors (such as meloxicam, celecoxib , rofecoxib, valdecoxib and etoricoxib) low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d- penicillamine, auranofin or parenteral or oral gold.
  • TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D 2 E 7 ) and TNF receptor immunoglobulin molecules (such as Enbrel®), COX-2 inhibitors (such as meloxicam, celecoxib , rofecoxib, valdecoxib and etoricoxib) low dose methotrexate
  • the present invention still further relates to the combination of a compound of the invention together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist selected from the group consisting of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761 ⁇ /-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-terf-butylphenol hydrazones methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoIine compounds such as L-746,530; indole and quinoline compounds such as MK-591, MK-886, and BAY x 1005.
  • the present invention still further relates to the combination of a compound of the invention together with a receptor antagonists for leukotrienes LTB 4 , LTC 4 , LTD , and LTE selected from the group consisting of the phenothiazin-3-ones such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast
  • the present invention still further relates to the combination of a compound of the invention together with a PDE4 inhibitor including inhibitors of the isoform PDE4D.
  • the present invention still further relates to the combination of a compound of the invention together with a antihistaminic i- ⁇ receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
  • a antihistaminic i- ⁇ receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
  • the present invention still further relates to the combination of a compound of the invention together with a gastroprotective H 2 receptor antagonist.
  • the present invention still further relates to the combination of a compound of the invention together with an ⁇ -i- and ⁇ 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agent, including propylhexedrine, phenylephrine, phenylpropa ⁇ olamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.
  • an ⁇ -i- and ⁇ 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agent including propylhexedrine, phenylephrine, phenylpropa ⁇ olamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xyl
  • the present invention still further relates to the combination of a compound of the invention together with anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.
  • anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.
  • the present invention still further relates to the combination of a compound of the invention together with a ⁇ t - to ⁇ 4 -adrenoceptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline and aminophylline; sodium cromoglycate; or muscarinic receptor (M1, M2, and M3) antagonist.
  • a ⁇ t - to ⁇ 4 -adrenoceptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol;
  • the present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.
  • IGF-1 insulin-like growth factor type I
  • the present invention still further relates to the combination of a compound of the invention together with an inhaled glucocorticoid with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate.
  • the present invention still further relates to the combination of a compound of the invention together with (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists; (c) interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors including VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6 phosphate dehydrogenase inhibitors; (i) kinin-B !
  • anti-gout agents e.g., colchicine
  • xanthine oxidase inhibitors e.g., allopurinol
  • I uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone
  • m growth hormone secretagogues
  • PDGF ⁇ platelet-derived growth factor
  • fibroblast growth factor e.g., basic fibroblast growth factor (bFGF
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream s
  • Tachykinin NK, and NK 3 receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D- 4418
  • elastase inhibitors selected from the group consisting of UT
  • the present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11).
  • MMPs matrix metalloproteases
  • Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
  • NSAID's standard non-steroidal anti-inflammatory agents
  • piroxicam such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprof
  • the compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VegF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine;.
  • antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antisepsis compounds such as Valant.
  • the compounds of the present invention may also be used in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
  • cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
  • the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
  • CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors,
  • the compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate;.
  • osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax
  • immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate
  • Scheme 1 refers to the preparation of compounds of formula I.
  • Suitable bases include an excess of compound of formula III as well as triethylamine, dimethylaminopyridine, sodium carbonate, pyridine, and H ⁇ nigs base, preferably triethylamine.
  • the aforesaid reaction may be performed neat or in the presence of a solvent.
  • Suitable solvents include methylene chloride, tetrahydrofuran, and toluene, preferably methylene chloride.
  • a coupling reagent such as 1-[3-(dimethyIamino)propyl]-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate
  • reaction may be run at a temperature from about 0°C to about 50°C, for a period from about 1 hour to about 16 hours (as illustrated in Comprehensive Organic Transformation, R.C. Larock, VCH Publisher, Inc. (1989) pp. 972-976).
  • the aforesaid reaction may be conducted in the presence of a suitable base. Suitable bases include an excess of compound of formula V as well as triethylamine, dimethylaminopyridine, sodium carbonate, pyridine, and H ⁇ nigs base, preferably triethylamine.
  • the aforesaid reaction may be performed neat or in the presence of a solvent at a temperature from about 0°C to about 50°C, for a period from about 10 minutes to about 16 hours. Suitable solvents include methylene chloride, tetrahydrofuran, and toluene, preferably methylene chloride.
  • -(CH 2 ) 0 NR 7 -, -0(CH 2 ) p NR 7 -, -CONR 7 - or -S0 2 NR 7 -; can be prepared from a compound of the formula II, wherein L is a leaving group such as a methoxy or ethoxy, by reaction with a saponification reagent such as with an aqueous base, such as sodium hydroxide in an alcoholic solvent such as methanol, ethanol or tert.-butanol.
  • the aforesaid reaction may be run at a temperature from about 0°C to about 100°C, for a period from about 1 hour to about 24 hours.
  • a compund of the formula IV can be prepared by the reaction of a compound of a compound of formula II with an acid such as hydrochloric acid in a solvent such as dioxane at a temperature between 25°C to about 80°C, for a period from about 10 minutes to about 6 hours.
  • a compound of the formula II, wherein L is a leaving group such as alkoxy, W is a bond and R 1 is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring can be prepared from a compound of the formula VII by reaction with a compound of the formula
  • the reductive amination is typically carried out with a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably at a pH of between 6 and 8.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • the reaction is normally performed in a protic solvent, such as methanol or ethanol, or in a mixture of solvents, such as dichloroethane/methanol, at temperature of about -78°C to about 40°C for a period from about 1 hour to about 24 hours.
  • a compound of the formula II wherein L is a leaving group such as alkoxy, and R 1 is is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring, can be prepared from the diazonium intermediate derived from a compound of the formula VII.
  • the diazonium intermediate is prepared by reaction of a compound of the formula VII with an acid such as hydrochloric acid followed by treatment with sodium nitrite in a solvent such as glacial acetic acid at a temperature from about 0°C to about 30°C, and the reaction is generally run for a period of about 30 min to about 3 hours.
  • the reaction is typically carried out with sodium acetate as base at a temperature from about 0°C to about 120°C, and the reaction is generally run for a period of about 1 hour to about 24 hours.
  • sodium acetate as base
  • the reaction is generally run for a period of about 1 hour to about 24 hours.
  • a compound of formula II wherein W is a bond and R 1 is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring can be prepared by standard synthetic methods from a compound of the formula VII, wherein L is a protecting group such as alkoxy, by reaction with a bidentate reagent wherein two different transformable groups exist, such as an alkylating and acylating group of the formula
  • L is a leaving group such as halo
  • L 2 is hydrogen, (C C 6 )alkyl or halo
  • a compound of formula II wherein R 1 is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring, wherein the bridgehead atom is nitrogen can be prepared by standard synthetic methods from a compound of the formula VII, wherein L is a protecting group such as alkoxy, by reaction with an anhydride reagent of the formula
  • d is 2 to 8 and wherein any of said -CH 2 - groups may be optionally substituted by one or two R 9 substituents, and wherein at least two of said -CH 2 - groups are replaced with -NR 10 - (up to five -NR 10 -) and may optionally additionally contain 0-3 heteroatoms independently selected from the group consisting of -O- and -S(0) n -, wherein n is an integer from zero to 2; or any single bond between any two CH 2 groups may optionally be a double bond; wherein any carbon atom of said -(CH 2 )d- may optionally contain an oxo group; or any single bond between any two CH 2 groups may optionally be a double bond.
  • Compounds of the formula VII can be prepared from compounds of the formula XI by reaction with an alcohol of the formula ROH, wherein R is optionally substituted (d-C 4 )alkyl or (C 6 -C 10 )aryl, in the presence of an acid (a so called Fischer esterification) or a coupling reagent, such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), and a base, such as diisopropylethylamine (DIEA) or triethylamine, in an aprotic solvent, such as methylene chloride.
  • ROH is optionally substituted (d-C 4 )alkyl or (C 6 -C 10 )aryl
  • an acid a so called Fischer esterification
  • a coupling reagent such as 1-[3-(
  • Suitable solvents include methylene chloride and dimethyl formamide, preferably methylene chloride.
  • the aforesaid reaction may be run at a temperature from about 0°C to about 50°C, for a period from about 1 hour to about 16 hours (as illustrated in Comprehensive Organic Transformation, R.C. Larock, VCH Publisher, Inc. (1989) pp. 972-976).
  • Scheme 3 refers to the preparation of the compounds of formula V which are intermediates useful in the preparation of compound of formula I, in Scheme 1. Referring to Scheme 3, a compound of formula V is prepared by reduction of a compound of the formula XII.
  • Reduction may be effected with hydrogen gas (H 2 ), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaS0 4 ), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in an appropriate solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 10°C to about 60°C, as described in Catalytic Hydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc., San Diego, 31-63 (1979).
  • Pd on carbon methanol at 25°C and 50 psi of hydrogen gas pressure.
  • R 1 contains a group incompatible with the above hydrogenation conditions (e.g., an olefin or halide group)
  • a dissolving metal reduction wherein the compound of formula XII is treated with a metal, such as zinc, tin or iron, in the presence of an acid such as hydrochloric or sulfuric acid.
  • the aforesaid reaction may be run at a temperature from about 0°C to about 100°C, for a period from about 1 hour to about 16 hours.
  • Compounds of the formula XII can be prepared from compounds of formula XIII by reaction with reagents of the formulae VIII, IX and X as described previously in Scheme 2 for the conversion of a compound of formula VII to II.
  • compounds of the formula I wherein R 1 is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring, can be prepared by an aryl palladium coupling reaction.
  • Aryl palladium coupling reactions are well known to those skilled in the art.
  • One well known coupling method so called Buchwald and Hartwig conditions, involves the coupling of a compound of formula XIV, wherein L 2 is Cl, Br, I or triflate (TfO), with a compound of the formula R 1 -H, wherein H is a hydrogen on a nitrogen ring atom, in the presence of a palladium (0) catalyst and a base.
  • Palladium (0) catalysts include tris(dibenzylidene acetone)dipalladium(O) (Pd 2 (dba) 3 ), di(dibenzylidene acetone) palladium(O) (Pd(dba) 2 ), palladium acetate (Pd(OAc) 2 , and a suitable ligand, such as a triaryl phosphine ligand, tri(f-butyl)phosphine, 1 ,1 -bis(diphenylphosphanyl)ferrocene (DPPF), 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl (BINAP), or PHANEPHOS, preferably tri(orf/70-tolyl)phosphine.
  • a suitable ligand such as a triaryl phosphine ligand, tri(f-butyl)phosphine, 1 ,1 -bis(dip
  • Suitable bases include K 2 C0 3 , K 2 P0 4 , CsC0 3 , LiN(TMS) 2 or an alkoxide base such as sodium methoxide, sodium ethoxide, potassium f-butoxide, preferably sodium ferf-butoxide.
  • Suitable solvents include toluene or an ethereal solvent, preferably dioxane. The aforesaid reaction may be run at a temperature of about 40°C to 110°C for about 1 to 48 hours. Such conditions are reviewed in Angew. Chem. Int. Ed. Engl., 1998, 37, 2046-2067 and are well known to those of ordinary skill in the art.
  • Preferred Buchwald conditions use palladium acetate (Pd(OAc) 2 ) or palladium tetra-triphenylphosphine (Pd(PPh 3 ) ) as the source of the palladium.
  • Suitable solvents include THF, toluene or ethereal solvents.
  • the aforesaid reaction may be run at a temperature of about 25°C to 110°C for about 1 to 4 hours, preferably 2 hours.
  • Nickel catalysts such as Ni(cod) (nickel 1 ,5-cyclooctadiene), are also well known.
  • compounds of formula I can be prepared according to a so called Ullmann reaction by reaction of a compound of the formula XIV, wherein L 2 is a halide, with a compound of the formula R 1 -H, wherein H is a hydrogen on a nitrogen ring atom, in the presence of a suitable base and a suitable catalyst.
  • Suitable bases include alkali metal carbonates or hydroxide bases, preferably potassium carbonate.
  • Suitable catalysts include copper (0) catalyst, preferably finely powdered copper bronze.
  • Suitable solvents for the aforesaid reaction include neat or polar aprotic solvents, such as dimethylformamide (DMF), N,N dimethylacetamide or N-methylpyrrolidinone (NMP).
  • Suitable bases include alkali metal carbonate or hydroxide base, preferably potassium carbonate.
  • Suitable catalysts include palladium acetate (Pd(OAc) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ) and dichlorobis(triphenylphosphine)palladium.
  • Suitable solvents for the aforesaid reaction include neat or polar aprotic solvents, such as dimethylformamide (DMF), tetrahydrofuran, 1 ,4-dioxane, benzene, toluene, dimethoxyethane, or N-methylpyrrolidinone (NMP), preferably tetrahydrofuran and 1,4-dioxane.
  • DMF dimethylformamide
  • NMP N-methylpyrrolidinone
  • the aforesaid reaction may be run at a temperature between about 20 to 160 °C, usually 20 to 130 °C for about 10 minutes to 5 days, usually 30 minutes to 15 hours. (See Stifle, J.K., Angew. Chem. Int. Ed. Eng., 1986, 25, 508-524).
  • compounds of formula I can be prepared according to a so called Negishi coupling by reaction of a compound of the formula XIV, wherein L 2 is a halide or triflate, with a compound of the formula R 1 -W-zinc halide.
  • the catalyst may be selected from those typically employed for the so-called reaction (for example, tetrakis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)nickel, dichIorobis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, / n-BuLi, dich!orobis(1 ,1-bis(diphenylphosphino)ferrocene)palladium and dichlorobis(1,4-bis(diphenylphosphino)butane)palladium).
  • reaction for example, tetrakis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)nickel, dichIorobis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, / n-BuLi, dich
  • Suitable solvents include tetrahydrofuran, diethylether and dimethoxyethane, preferably tetrahydrofuran.
  • the reaction is carried out at a temperature in the range from 20 to 160 °C, usually 20 to 130 °C for 10 minutes to 5 days, usually 30 minutes to 15 hours.
  • the reactive groups of the reagents can be reversed.
  • L 2 in the aforesaid reaction can be the zinc halide coupled to an R 1 W'-halide or triflate. (Knochel, P. And Singer, R.D. Chem. Rev., 1993, 93, 2117-2188).
  • coupling can be carried out by a so called Suzuki coupling reaction of said compound of formula XIV, wherein L 2 is I, Br, Cl, or triflate, with an R 1 -W-borate or R 1 -W-boronic acid, a catalyst, a base and a dehydrating agent.
  • Suitable borates include (HO) 2 B-, 9-BBN, and alkylboranes.
  • Suitable catalysts include copper or palladium, preferably copper (II) acetate or palladium acetate (Pd(OAc) 2 ), palladium triphenylphosphine or Pd(dppf)CI 2 .
  • Suitable dehydrating agents include 4 angstrom molecular sieves.
  • Suitable bases include tertiary amine bases, such as triethylamine or pyridine, Na 2 C0 3 , sodium ethoxide, and K 3 P0 4 .
  • Suitable solvents include methylene chloride, dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF).
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • the aforesaid reaction is typically performed under an atmosphere of oxygen gas at a temperature of about 10°C to 50°C, preferably about 23°C for about 6 to 72 hours. Palladium-catalyzed boronic acid couplings are described in Miyaura, N., Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513.
  • the Suzuki coupling may be carried out in cases where L 2 is B(OH) 2 and R 1 -W is substituted with I, Br, Cl, or triflate or H wherein H is a hydrogen on a nitrogen atom, using a copper or palladium catalyst, preferably copper (II) acetate or palladium acetate using methods analogous to those of the preceding paragraph.
  • compounds of formula I can also be prepared from compounds of formula XV or XVI via intermediates of the formula II and XII.
  • the intermediates of the formula II and XII can be converted to compounds of formula I according to the methods of Schemes 1 and 3 respectively.
  • the compounds of formulae II and XII can be prepared from compounds of the formulae XV and XVI, respectively, by coupling reactions analogous to those described above for the conversion of compounds of formula XIV to formula I.
  • Scheme 5 refers to an alternate preparation of compounds of formula I.
  • a compound of formula I is prepared from a compound of formula XVII by reduction with tin in the presence of an acid such as hydrochloric acid followed by a so called Sandmeyer reaction wherein a diazonium intermediate is prepared by treatment with sodium nitrite followed by a quench with a cuprous halide such as cuprous chloride or cuprous bromide.
  • Suitable solvents include alcohols such as methanol and ethanol.
  • the aforesaid reaction is conducted at a temperature from about -20°C to about 0°C, and the reaction is generally run for a period of about 1 to 48 hours.
  • R 1 -W- is a standard transformable group, such as R 1 -0-, R 1 -(CH 2 ) 0 0-, R 1 -0(CH 2 ) p O-, R 1 -(CH 2 ) r O(CH 2 ) q O-, R 1 -(NR 7 )-, R 1 -(CH 2 ) 0 NR 7 -, R 1 -0(CH 2 ) p NR 7 -, R 1 -(CH 2 ) r NR 7 (CH 2 ) q O-, R 1 -NR 7 (CH 2 ) q O-, R 1 -CONR 7 -, R 1 -S-, R 1 -CH 2 S-; or W is a bond and R 1 is a 5 to 10 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing an NH can be prepared from a compound of the formula XVIII by reaction with a nucle
  • compounds of formula I and II can be prepared from compounds of formula XX by analogous Sandmeyer methods as described above.
  • the compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,
  • Those compounds of the formula I which are also acidic in nature, e.g., where R 4 includes a 6-azauracil or barbituric acid moiety, are capable of forming base salts with various pharmacologically acceptable cations.
  • Such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These nontoxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
  • the activity of the compounds of the invention for the various disorders described above can be determined according to one or more of the following assays. All of the compounds of the invention, that were tested, had an IC 50 of less than 1 ⁇ M in the in vitro human monocyte assay described below.
  • PHARMACOLOGICAL ANALYSIS Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are known to be agonists of the P2X 7 receptor, effecting the formation of pores in the plasma membrane (Drug Development Research (1996), 37(3), p. 126). Consequently, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed.
  • the propidium dye YOPRO-1 can be substituted for ethidium bromide so as to detect uptake of the dye. The increase in fluorescence can be used as a measure of P2X 7 receptor activation and therefore to quantify the effect of a compound on the P2X 7 receptor.
  • test solution comprising 200 ⁇ l of a suspension of THP-1 cells (2.5 x 10 6 cells/ml, more preferably prestimulated as described in the literature with a combination of LPS and TNF to promote receptor expression) containing lO ⁇ M ethidium bromide, 25 ⁇ l of a high potassium, low sodium buffer solution (10mM Hepes, 150 mM KCI, 5 mM D-glucose and 1.0% FBS at pH 7.5) containing 10 " °M bbATM, and 25 ⁇ l of the high potassium buffer solution containing 3 x 10 '5 M test compound (more preferably 5 x lO ⁇ M, more preferably 1 x lO ⁇ M.more preferably 1 x 10 "3 M).
  • the plate is covered with a plastic sheet and incubated at 37°C for one hour.
  • the plate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm.
  • bbATP a P2X 7 receptor agonist
  • pyridoxal 5-phosphate a P2X 7 receptor antagonist
  • the compounds of the invention can be tested for antagonist activity at the P2X 7 receptor using the cytokine IL-1 ⁇ as the readout.
  • Blood collected from normal volunteers in the presence of heparin is fractionated using lymphocyte separation medium obtained from Organon Technica (Westchester, PA). The region of the resulting gradient containing banded mononuclear cells is harvested, diluted with 10 ml of Maintenance Medium (RPMI 1640, 5% FBS, 25 mM Hepes, pH 7.2, 1% penicillin/streptomycin), and cells are collected by centrifugation. The resulting cell pellet was suspended in 10 ml of Maintenance Medium and a cell count was performed.
  • Maintenance Medium RPMI 1640, 5% FBS, 25 mM Hepes, pH 7.2, 1% penicillin/streptomycin
  • the cultured monocytes can be activated with 10 ng/ml LPS (E. coli serotype 055:B5; Sigma Chemicals, St. Louis, MO). Following a 2-hour incubation, the activation medium is removed, the cells are rinsed twice with 0.1 ml of Chase Medium (RPMI 1640, 1 % FBS, 20 mM Hepes, 5 mM NaHC0 3 , pH 6.9), and then 0.1 ml of Chase Medium containing a test agent is added and the plate is incubated for 30 minutes; each test agent concentration can be evaluated in triplicate wells.
  • LPS E. coli serotype 055:B5
  • MO a 2-hour incubation
  • the activation medium is removed, the cells are rinsed twice with 0.1 ml of Chase Medium (RPMI 1640, 1 % FBS, 20 mM Hepes, 5 mM NaHC0 3 , pH 6.9), and then 0.1 ml of Chase Medium containing a test agent is added
  • ATP then is introduced (from a 100 mM stock solution, pH 7) to achieve a final concentration of 2 mM and the plate is incubated at 37°C for an additional 3 hours. Media were harvested and clarified by centrifugation, and their IL-1 ⁇ content was determined by ELISA (R&D Systems; Minneapolis, MN).
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), topical or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filters (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • filters e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium starch
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula I can also be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397, which are herein incorporated by reference in their entirety.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (inflammation) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • the compound of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff" of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • Aerosol combination formulations for treatment of the conditions referred to above (e.g., adult respiratory distress syndrome) in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 1 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg of the p38 kinase inhibitor. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time
  • compositions containing and methods of treating or preventing comprising administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • the mass spectrum of the major eluting component was then obtained in positive or negative ion mode scanning a molecular weight range from 165 AMU to 1100 AMU. Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification.
  • THF refers to tetrahydrofuran.
  • DMF refers to N,N-dimethylformamide.
  • Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25°C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used.
  • protecting groups may be required during preparation. After the target molecule is made, the protecting group can be removed by methods well known to those of ordinary skill in the art, such as described in Greene and Wuts, "Protective Groups in Organic Synthesis” (2 nd Ed, John Wiley & Sons
  • Examples 2-3 are presented in Table 1 and were prepared analogously to the synthesis outlined in Example 1C, coupling the appropriate amine to 2-chloro-5-(3,5-dioxo- 4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)-benzoic acid. Final products were analyzed by LC/MS using a Micromass ZMD LC/MS (ESI mode). The method used for the HPLC mobile phase gradient change was as follows:

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058270A1 (en) * 2002-12-31 2004-07-15 Pfizer Products Inc. 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases
WO2004092384A2 (en) * 2003-04-17 2004-10-28 Affectis Pharmaceuticals Ag Means and methods for diagnosing and treating affective disorders
WO2006003517A1 (en) * 2004-06-29 2006-01-12 Warner-Lambert Company Llc Combination therapies utilizing benzamide inhibitors of the p2x7 receptor
WO2006003500A1 (en) * 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h`1,2,4!triazin-2-yl!-benzamide derivatives by deprotecting the hydroxyl-protected precursers
WO2006025783A1 (en) * 2004-08-30 2006-03-09 Astrazeneca Ab Adamantyl derivates as p2x7 receptor antagonists
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US7408065B2 (en) 2003-06-02 2008-08-05 Astrazeneca Ab P2X7 receptor antagonists and their use
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US7964616B2 (en) 2007-03-22 2011-06-21 Astrazeneca Ab Compounds 679
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US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057
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US9221832B2 (en) 2011-07-22 2015-12-29 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
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Families Citing this family (37)

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EP2343282B1 (en) * 2004-03-05 2015-07-22 F. Hoffmann-La Roche AG Diaminopyrimidines as P2X3 and P2X2/3 antagonists
JPWO2005107804A1 (ja) * 2004-05-06 2008-03-21 小野薬品工業株式会社 呼吸器疾患治療剤
WO2006003513A1 (en) * 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-`1,2,4!-triazin-2-yl!benzamide derivatives with p2x7 inhibiting activity by reaction of the derivative unsubstituted in 4-position of the triazine with an oxiran in the presence of a lewis acid
WO2006035876A1 (ja) * 2004-09-29 2006-04-06 Kowa Co., Ltd. 関節リウマチの予防及び／又は治療薬
WO2006083214A1 (en) * 2005-02-02 2006-08-10 Astrazeneca Ab Pharmaceutical composition comprising a p2x7 receptor antagonist and a hmg-coa reductase inhibitor
JPWO2006104172A1 (ja) * 2005-03-29 2008-09-11 興和株式会社 関節リウマチの予防及び／又は治療薬
WO2007008157A1 (en) * 2005-07-11 2007-01-18 Astrazeneca Ab New combination 2
US20080207577A1 (en) * 2005-07-11 2008-08-28 Astrazeneca Ab Combination I
EP1924564B1 (en) 2005-09-01 2016-11-09 F.Hoffmann-La Roche Ag Diaminopyrimidines as p2x3 and p2x2/3 modulators
CN101300235B (zh) 2005-09-01 2011-12-07 弗·哈夫曼-拉罗切有限公司 作为p2x3和p2x2/3调节剂的二氨基嘧啶类化合物
MX2008002731A (es) 2005-09-01 2008-03-26 Hoffmann La Roche Diaminopirimidinas como moduladores de p2x3 y p3x2/3.
JPWO2007049732A1 (ja) * 2005-10-28 2009-04-30 興和株式会社 関節リウマチの予防及び／又は治療法
EP2033646A4 (en) * 2006-06-29 2009-11-18 Kowa Co PROPHYLACTIC AND / OR THERAPEUTIC AGENT FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
WO2009019503A2 (en) * 2007-08-03 2009-02-12 Astrazeneca Ab P2x7 antagonists for use in the treatment of mood disorders
CN101842359A (zh) * 2007-10-31 2010-09-22 日产化学工业株式会社 哒嗪酮化合物和p2x7受体抑制剂
WO2009108551A2 (en) * 2008-02-25 2009-09-03 H. Lundbeck A/S Heteroaryl amide analogues
JP5562716B2 (ja) * 2010-05-12 2014-07-30 花王株式会社 電位依存性カチオンチャネル抑制剤
CN103304498B (zh) * 2013-06-02 2015-03-04 张远强 一种抗糖尿病化合物、其制备方法和用途
CN103304500B (zh) * 2013-06-02 2015-03-04 张远强 新型抗糖尿病化合物、其制备方法和用途
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CN104447704B (zh) * 2015-01-13 2016-07-27 佛山市赛维斯医药科技有限公司 一种腈基金刚烷四氮唑化合物、其制备方法和用途
KR102035463B1 (ko) * 2018-02-14 2019-11-26 연세대학교 산학협력단 암 줄기세포의 치료용 약학 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3789072A (en) * 1970-04-22 1974-01-29 Squibb & Sons Inc Carboxamides
WO1999029660A1 (en) * 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO2000061569A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2001044213A1 (en) * 1999-12-17 2001-06-21 Astrazeneca Ab New p2x7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases
WO2001094338A1 (en) * 2000-06-07 2001-12-13 Astrazeneca Ab Admantane derivatives

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU196892B (en) * 1984-06-12 1989-02-28 Fmc Corp Herbicides containing as active substance derivatives of 2-phenil-1,2,4-triasine-3,5-dion and process for production of these derivatives
US4766233A (en) * 1984-06-12 1988-08-23 Fmc Corporation Herbicidal 2-aryl-1,2,4-triazine-3,5(2H,4H)-diones and sulfur analogs thereof
US5128351A (en) * 1990-05-04 1992-07-07 American Cyanamid Company Bis-aryl amide and urea antagonists of platelet activating factor
US5077409A (en) * 1990-05-04 1991-12-31 American Cyanamid Company Method of preparing bis-aryl amide and urea antagonists of platelet activating factor
BR9107169A (pt) 1990-12-17 1993-11-16 Shell Int Research Derivados de isoquinolina fungicidas
GB9119467D0 (en) 1991-09-12 1991-10-23 Smithkline Beecham Corp Chemical compounds
US5691376A (en) 1994-02-17 1997-11-25 American Home Products Corporation Substituted biphenyl derivatives
US5686061A (en) 1994-04-11 1997-11-11 The Board Of Regents Of The University Of Texas System Particulate contrast media derived from non-ionic water soluble contrast agents for CT enhancement of hepatic tumors
JP3144624B2 (ja) 1995-06-02 2001-03-12 杏林製薬株式会社 Ｎ−ベンジルジオキソチアゾリジルベンズアミド誘導体及びその製造法
JP3906935B2 (ja) 1995-12-18 2007-04-18 杏林製薬株式会社 Ｎ−置換ジオキソチアゾリジルベンズアミド誘導体及びその製造法
WO1997023212A1 (en) 1995-12-21 1997-07-03 The Du Pont Merck Pharmaceutical Company ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS
ATE204857T1 (de) * 1996-03-29 2001-09-15 Searle & Co Meta-substituierte phenylenderivate und ihre verwendung als alphavbeta3 intergrin-antagonisten oder inhibitoren
US6187797B1 (en) * 1996-12-23 2001-02-13 Dupont Pharmaceuticals Company Phenyl-isoxazoles as factor XA Inhibitors
US6020357A (en) * 1996-12-23 2000-02-01 Dupont Pharmaceuticals Company Nitrogen containing heteroaromatics as factor Xa inhibitors
WO1998028269A1 (en) 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
DE19701287A1 (de) * 1997-01-16 1998-07-23 Wernicke & Co Gmbh Verfahren zum Erhöhen der Gebrauchsdauer von Schleifscheiben
EP1019375A1 (en) 1997-03-25 2000-07-19 Astra Pharmaceuticals Limited Novel pyridine derivatives and pharmaceutical compositions containing them
WO1998043973A1 (de) 1997-03-27 1998-10-08 Novartis Ag Zwischenprodukte und verfahren zur herstellung von pyrimidinderivaten
DE19719621A1 (de) 1997-05-09 1998-11-12 Hoechst Ag Sulfonylaminocarbonsäuren
US6297239B1 (en) 1997-10-08 2001-10-02 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
SE9704272D0 (sv) * 1997-11-21 1997-11-21 Astra Pharma Prod Novel Compounds
SE9704546D0 (sv) 1997-12-05 1997-12-05 Astra Pharma Prod Novel compounds
SE9704544D0 (sv) 1997-12-05 1997-12-05 Astra Pharma Prod Novel compounds
JPH11318492A (ja) * 1998-03-09 1999-11-24 Aisin Seiki Co Ltd 蛍光発生性基質を含有する組成物
US6320078B1 (en) 1998-07-24 2001-11-20 Mitsui Chemicals, Inc. Method of producing benzamide derivatives
FR2783519B1 (fr) 1998-09-23 2003-01-24 Sod Conseils Rech Applic Nouveaux derives d'amidines, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant
DE19851184A1 (de) 1998-11-06 2000-05-11 Aventis Pharma Gmbh N-Arylsulfonyl-aminosäure-omega-amide
EE200100317A (et) 1998-12-16 2002-08-15 Bayer Aktiengesellschaft Uued bifenüül- ja bifenüülanaloogsed ühendid kui integriini antagonistid
CA2382751A1 (en) 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibitors of factor xa
SE9901875D0 (sv) 1999-05-25 1999-05-25 Astra Pharma Prod Novel compounds
EP1088821A1 (en) 1999-09-28 2001-04-04 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives
MXPA02005102A (es) 1999-10-18 2003-09-25 Alexipharma Inc Retro-anandamidas, ligandos de receptor de canabinoide de alta afinidad y estabilidad.
SE9904505D0 (sv) 1999-12-09 1999-12-09 Astra Pharma Prod Novel compounds
TWI258462B (en) 1999-12-17 2006-07-21 Astrazeneca Ab Adamantane derivative compounds, process for preparing the same and pharmaceutical composition comprising the same
SE9904738D0 (sv) 1999-12-22 1999-12-22 Astra Pharma Prod Novel compounds
DE10005284A1 (de) 2000-02-07 2001-08-09 Bayer Ag Verfahren zur Herstellung von 1-Amino-3-aryl-uracilen

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3789072A (en) * 1970-04-22 1974-01-29 Squibb & Sons Inc Carboxamides
WO1999029660A1 (en) * 1997-12-05 1999-06-17 Astrazeneca Uk Limited Adamantane derivatives
WO2000061569A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2001044213A1 (en) * 1999-12-17 2001-06-21 Astrazeneca Ab New p2x7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases
WO2001094338A1 (en) * 2000-06-07 2001-12-13 Astrazeneca Ab Admantane derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NARAYANAN V L: "ADAMANTYL ANALOGS OF 2'-(DIMETHYLAMINOPROPYLTHIO)CINNAMANILIDE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 15, no. 11, 1972, pages 1180 - 1182, XP002938144, ISSN: 0022-2623 *

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7176202B2 (en) 2002-12-31 2007-02-13 Pfizer Inc. Benzamide inhibitors of the P2X7 receptor
WO2004058270A1 (en) * 2002-12-31 2004-07-15 Pfizer Products Inc. 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases
US7407956B2 (en) 2002-12-31 2008-08-05 Pfizer, Inc. Benzamide inhibitors of the P2X7 receptor
US6974812B2 (en) 2002-12-31 2005-12-13 Pfizer Inc. Benzamide inhibitors of the P2X7 Ereceptor
NL1025148C2 (nl) * 2002-12-31 2007-09-28 Pfizer Prod Inc Benzamideremmers van de P2X7-receptor.
EA008591B1 (ru) * 2002-12-31 2007-06-29 Пфайзер Продактс Инк. Производные 3-(3,5-диоксо-4,5-дигидро-3h-(1,2,4)триазин-2-ил)бензамида в качестве ингибиторов p2xдля лечения воспалительных заболеваний
US7767398B2 (en) 2003-04-17 2010-08-03 Affectis Pharmaceuticals Ag Means and methods for diagnosing and treating affective disorders
WO2004092384A3 (en) * 2003-04-17 2005-06-02 Affectis Pharmaceuticals Ag Means and methods for diagnosing and treating affective disorders
JP2010011855A (ja) * 2003-04-17 2010-01-21 Affectis Pharmaceuticals Ag 情動障害の診断および治療のための手段および方法
WO2004092384A2 (en) * 2003-04-17 2004-10-28 Affectis Pharmaceuticals Ag Means and methods for diagnosing and treating affective disorders
US7408065B2 (en) 2003-06-02 2008-08-05 Astrazeneca Ab P2X7 receptor antagonists and their use
WO2006003500A1 (en) * 2004-06-29 2006-01-12 Pfizer Products Inc. Method for preparing 5-`4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h`1,2,4!triazin-2-yl!-benzamide derivatives by deprotecting the hydroxyl-protected precursers
WO2006003517A1 (en) * 2004-06-29 2006-01-12 Warner-Lambert Company Llc Combination therapies utilizing benzamide inhibitors of the p2x7 receptor
WO2006025783A1 (en) * 2004-08-30 2006-03-09 Astrazeneca Ab Adamantyl derivates as p2x7 receptor antagonists
WO2006059945A1 (en) * 2004-11-30 2006-06-08 Astrazeneca Ab Novel compounds
US7964616B2 (en) 2007-03-22 2011-06-21 Astrazeneca Ab Compounds 679
US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057
EP2105164A1 (en) 2008-03-25 2009-09-30 Affectis Pharmaceuticals AG Novel P2X7R antagonists and their use
WO2010118921A1 (en) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
EP2386541A1 (en) 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Novel methods for the preparation of P2X7R antagonists
WO2011141194A1 (en) 2010-05-14 2011-11-17 Affectis Pharmaceuticals Ag Novel methods for the preparation of p2x7r antagonists
WO2012110190A1 (en) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163792A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163456A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
US9221832B2 (en) 2011-07-22 2015-12-29 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9409917B2 (en) 2012-01-20 2016-08-09 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9718774B2 (en) 2012-12-12 2017-08-01 Idorsia Pharmaceuticals Ltd Indole carboxamide derivatives as P2X7 receptor antagonist
US9556117B2 (en) 2012-12-18 2017-01-31 Actelion Pharmaceuticals Ltd. Indole carboxamide derivatives as P2X7 receptor antagonists
US9388198B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9388197B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same
CN104496968A (zh) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 卤代金刚烷四氮唑结构的化合物、其制备方法和用途
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11124486B2 (en) 2015-04-24 2021-09-21 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
US11685740B2 (en) 2016-10-17 2023-06-27 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase

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