EP1581507A1 - Inhibiteurs benzamidiques du recepteur p2x7 - Google Patents

Inhibiteurs benzamidiques du recepteur p2x7

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Publication number
EP1581507A1
EP1581507A1 EP03780483A EP03780483A EP1581507A1 EP 1581507 A1 EP1581507 A1 EP 1581507A1 EP 03780483 A EP03780483 A EP 03780483A EP 03780483 A EP03780483 A EP 03780483A EP 1581507 A1 EP1581507 A1 EP 1581507A1
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EP
European Patent Office
Prior art keywords
alkyl
hydroxy
methyl
cycloalkyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03780483A
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German (de)
English (en)
Inventor
Allen J. c/o Pfizer Global R & D DUPLANTIER
Chakrapani c/o Pfizer Global R & D SUBRAMANYAM
Mark A. c/o Pfizer Global R & D DOMBROSKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
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Pfizer Products Inc
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Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1581507A1 publication Critical patent/EP1581507A1/fr
Withdrawn legal-status Critical Current

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    • C07D233/70—One oxygen atom

Definitions

  • the present invention relates to novel benzamide inhibitors of the P2X 7 receptor, 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 receptor.
  • the P2X 7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in 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.
  • P2X 7 antagonists are known in the art, such as those described in International
  • Benzamides, heteroarylamides and reverse amides for uses other than inhibition of the P2X 7 receptor are described in various publications, such as International Patent Publications WO 97/22600, EP 138,527, WO 00/71509, WO 98/28269, WO 99/17777 and WO 01/58883.
  • R 1 is (C ⁇ -C 6 )alkyl, optionally substituted by (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, (C C 10 )heterocyclyI, or (C C 10 )heteroaryl, wherein each of said (C C 6 )alkyl, (C 3 -
  • R 3 is a suitably substituted nitrogen linked (C C 10 )heterocyclyI of the formula:
  • the present invention relates to a compound of the formula
  • R 1 is (CrCeJalkyl, optionally substituted by (C 3 -C ⁇ 0 )cycloalkyl, (C 6 -C 10 )aryl, (C ⁇ -C 10 )heterocyclyl, or (CrC 10 )heteroaryl, wherein each of said (C 1 -C 6 )alkyl, (C 3 - C ⁇ o)cycloalkyl, (C 6 -C ⁇ 0 )aryl, (C.
  • R 3 is a nitrogen linked (C ⁇ -C ⁇ 0 )heterocyclyl of the formula:
  • suitable substituents such as hydrogen, halo, hydroxy, -CN, HO
  • R 6 and R 8 are each independently selected from the group consisting of hydrogen, (C C 6 )alkyl, HO-(C 2 -C 6 )alkyl and (C 3 -C 8 )cycloalkyl, or R 6 and R 8 may optionally be taken together with the nitrogen atom to which they are attached to form a 3 to 8 membered heterocycle; n is an integer from zero to two; and m is an integer from one to two; 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'-methyIene-bis-(2-hydroxy-3- naphthoate)]salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such
  • 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", 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1999).
  • 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 3 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 biological 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
  • spiro refers to a connection between two groups, substituents etc., wherein the connection can be depicted according to the following formula
  • 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, n-propyl, /sopropyl, n-butyl, /so-butyl, seconda/y-butyl, terf/a-y-butyl); 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 C 6 )alkyl.
  • suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C ⁇ -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C C 6 )alkyl.
  • each of said alkyl refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkylamino.
  • Preferred alkyls include (CrCeJalkyl, more preferred are (C C )alkyl, and most preferred are 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, (C C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C Ce)alkyl.
  • halogen includes fluoro, chloro, brom
  • alkenyl means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyI, 2-propenyl (ailyl), /so-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 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 ⁇ 0 )aryloxy, trifluoromethoxy, difluoromethoxy or (C C 6 )alkyI.
  • 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, (C 1 -C 6 )alkoxy, (C 6 -C ⁇ 0 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -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 (CrC 6 )alkyl.
  • 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-oxazoIyl), 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-thiadiazoIyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted by 1
  • heterocyclic refers to a cyclic group containing 1-9 carbon atoms and 1 to 4 hetero atoms selected from N, O, S(0) ⁇ or NR.
  • examples of such rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro- thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindoiinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like.
  • Examples of said monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrroIidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine, 1 ,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,
  • Embodiment 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 3 group. Other subgenera are cognizable according to combinations of various substituents, such as all compounds wherein R 2 is chloro and R is (CrC 4 )alkyl, optionally substituted by (C 3 -C 10 )cycloalkyl.
  • the phrase "in combination with each of the aforementioned embodiments” refers to combinations of the identified embodiment with each embodiment previously identified in the specification.
  • the invention contemplates compounds in which R 2 is halogen and (C C 6 )alkyl, and preferably compounds in which R 2 is chloro, methyl or ethyl.
  • R 3 is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV), wherein R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl, and R 7 is hydrogen.
  • a further embodiment of the invention are compounds in which R 3 is a nitrogen linked (C ⁇ -C 10 )heterocyclyl of formula (IV), wherein R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl, and R 7 is (C r C )alkyl optionally substituted with one to three substituents independently selected from halogens, hydroxy, -CN, (C C 4 )alkoxy-, (C 2 -C 4 )alkenoxy, and (C C 4 )alkyl-S0 2 -.
  • R 7 is (CrC )alkyl optionally substituted with one to three substituents independently selected from halogens, hydroxy, -CN, or (C C 4 )alkoxy-.
  • the invention also provides compounds in which R 3 is a nitrogen linked (C
  • R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl
  • R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl
  • R 7 is (C C 4 )alkyl optionally substituted with one to
  • R 3 is a nitrogen linked (C C ⁇ o)heterocyclyl of formula (IV), wherein R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl, and R 7 is (C C )alkyl optionally substituted with one to three substituents independently selected from (C 3 -C 10 )cycloalkyl-, (C 6 -C 10 )aryl-, (C ⁇ -C 10 )heterocyclyl-, and (C C 10 )heteroaryl-.
  • R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl
  • R 7 is (C C )alkyl optionally substituted with one to three substituents independently selected from (C 3 -C 10 )cycloalkyl-, (C 6 -C 10 )aryl-, (C ⁇ -C 10 )heterocyclyl-, and (C C 10 )heteroaryl-.
  • R 3 is a nitrogen linked (C ⁇ -C,o)heterocyclyl 0 f formula (V), wherein R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl, and R 7 is hydrogen.
  • a further embodiment of the invention are compounds in which R 3 is a nitrogen linked (C CioJheterocyclyl of formula (V), wherein R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl, and R 7 is (C 1 -C )alkyl optionally substituted with one to three substituents independently selected from halogens, hydroxy, -CN, (C C 4 )aIkoxy-, (C 2 -C 4 )alkenoxy, and (C C 4 )alkyl-S0 2 -.
  • R 7 is (C C )alkyl optionally substituted with one to three substituents independently selected from halogens, hydroxy, -CN, or (C C 4 )alkoxy-.
  • the invention also provides compounds in which R 3 is a nitrogen linked (C
  • R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl
  • R 4 and R 5 are independently hydrogen or (C C 4 )alkyl, preferably hydrogen or methyl
  • R 7 is (C C )alkyl optionally substituted with one to three
  • R 3 is a nitrogen linked (C C ⁇ o)heterocyclyl of formula (V), wherein R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl, and R 7 is (C C 4 )alkyl optionally substituted with one to three substituents independently selected from (C 3 -C 10 )cycloalkyl-, (C 6 -C 10 )aryl-, (CrC 10 )heterocyclyl-, and (C C 10 )heteroaryl-.
  • R 4 and R 5 are independently hydrogen or (C C )alkyl, preferably hydrogen or methyl
  • R 7 is (C C 4 )alkyl optionally substituted with one to three substituents independently selected from (C 3 -C 10 )cycloalkyl-, (C 6 -C 10 )aryl-, (CrC 10 )heterocyclyl-, and (C C 10 )heteroaryl-.
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C C ⁇ 0 )heterocyclyl of formula (IV):
  • R is hydrogen or methyl, and R 7 is selected from the group consisting of:
  • R 3 is a nitrogen linked (C r C 10 )heterocyclyl of formula (IV), R 4 is hydrogen or methyl, and R 7 is
  • R 3 is a nitrogen linked (C C ⁇ o)heterocyclyl of formula (IV), R 4 is hydrogen or methyl, and R 7 is selected from the group consisting of:
  • R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (IV), R 4 is hydrogen or methyl, and R 7 is
  • R 3 is a nitrogen linked (C-i C 10 )heterocyclyl of formula (IV), R 4 is hydrogen or methyl, and R 7 is selected from:
  • R is a nitrogen linked (C t -C ⁇ heterocyclyl of formula (IV), R 4 is hydrogen or methyl, and R 7 is selected from:
  • the present invention also provides compounds of formula (I) nitrogen linked (CrC ⁇ heterocyclyl of formula (IV), R 4 is hydrogen or methyl, R 7 is selected from the group consisting of:
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C r C ⁇ 0 )heterocyclyl of formula (IV), R 4 is hydrogen or methyl,
  • R 4 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • the present invention also contemplates compounds of formula (I) wherein R 3 is a nitrogen linked (CrC 10 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • the present invention also contemplates compounds of formula (I) wherein R 3 is a nitrogen linked (C ⁇ -C, 0 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 7 is selected from:
  • R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (IV), R is hydrogen or methyl,
  • R 7 is selected from:
  • R 1 is (C C )alkyl, optionally substituted by (C 6 -C 10 )aryl, wherein said (C C 4 )alkyl or (C 6 -C 10 )aryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, (C ⁇ -C 6 )alkyl, HO(C 1 -C 6 )alkyl,
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from:
  • R 3 is a nitrogen linked (C ⁇ -C ⁇ o)heterocyclyl of formula (IV), R 4 is hydrogen or methyl, R 7 is selected from:
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R is chloro, methyl or ethyl; and R 1 is (C ⁇ -C 4 )alkyl, optionally substituted by (C 3 -C 10 )cycloalkyl, wherein said (C r
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (CrC 10 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 4 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • the present invention also contemplates compounds of formula (I) wherein R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • the present invention also contemplates compounds of formula (I) wherein
  • R 2 is chloro, methyl or ethyl; and R 1 is (C- ⁇ -C 4 )alkyl, optionally substituted by (C 6 -C 10 )aryl, wherein said (CrC )alkyl or (C 6 -C 10 )aryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, (C 1 -C 6 )alkyl, HO(C C 6 )aIkyl, (CrC 6 )alkyl-NI-
  • R 4 is hydrogen or methyl
  • R 3 is a nitrogen linked (C r C 0 )heterocyclyl of formula (IV), R 4 is hydrogen or methyl, R 7 is
  • R 4 is hydrogen or methyl
  • R 7 is selected from:
  • R 4 is hydrogen or methyl
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked (C ⁇ -C ⁇ o)heterocyclyl of formula (IV),
  • R 4 is hydrogen or methyl
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C r C ⁇ o)heterocyclyl of formula (V):
  • R 4 and R s are independently hydrogen or methyl, and R 7 is selected from the group consisting of:
  • R is a nitrogen linked ⁇ C ⁇ C 10 )heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is
  • R is a nitrogen linked (C C-ioJheterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 3 is a nitrogen linked (C r C 10 )heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is
  • R 3 is a nitrogen linked (C C ⁇ o)heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • R 3 is a nitrogen linked (C C-ioJheterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • the present invention also provides compoun s o ormu a w ere n s a nitrogen linked (C C ⁇ 0 )heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl, R 7 is selected from the group consisting of:
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C C ⁇ 0 )heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 4 and R 5 are independently hydrogen or methyl
  • R 4 and R 5 are independently hydrogen or methyl
  • the present invention also contemplates compounds of formula (I) wherein R 3 is a nitrogen linked (C ⁇ -C ⁇ o)heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 4 and R 5 are independently hydrogen or methyl
  • R 4 and R 5 are independently hydrogen or methyl
  • R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked (C ⁇ -C 10 )heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked (CrC ⁇ o)heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (CrC ⁇ Jheterocyclyl of formula (V),
  • R 4 and R are independently hydrogen or methyl, R 7 is selected from the group consisting of:
  • the present invention also provides compounds of formula (I) wherein R 3 is a nitrogen linked (C C 10 )heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • R 4 and R 5 are independently hydrogen or methyl
  • R 4 and R 5 are independently hydrogen or methyl
  • the present invention also contemplates compounds of formula (I) wherein R 3 is a nitrogen linked (Ci-Cio)heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from the group consisting of:
  • the present invention also contemplates compounds of formula
  • R 4 and R 5 are independently hydrogen or methyl, R 7 is selected from the group consisting of:
  • R 4 and R 5 are independently hydrogen or methyl
  • R 3 is a nitrogen linked (C C ⁇ o)heterocyclyl of formula (V)
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) wherein R 3 is a nitrogen linked (CrC,o)heterocyclyl of formula (V),
  • R 4 and R 5 are independently hydrogen or methyl
  • R 7 is selected from:
  • the invention further provides compounds of formula (I) where
  • R 4 and R 5 are independently hydrogen or methyl, R 7 is selected from:
  • Certain specific compounds of the invention are those compounds identified in Examples 1-14, which are incorporated herein by reference.
  • the present invention also includes isotopically-labeled 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.
  • Certain 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.
  • 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 an IL-1 mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I.
  • an "IL-1 mediated condition” includes but is not limited to a disease or disorder 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
  • the present invention relates to a pharmaceutical composition for the treatment of an IL-1 mediated disease in a mammal which comprises an effective amount of a compound according of formula I and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition for the treatment of an IL-1 mediated condition in a mammal, including a human, comprising an amount of a compound of formula I, effective in treating such a condition and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • One embodiment of the processes of the invention relates to the preparation of compounds of formula I, which may be carried out by one or more of the synthetic methods outlined in Schemes l-VIII, detailed below.
  • the present invention also provides methods and intermediates useful in the synthesis of compounds of formula (I), and identified in Schemes I-
  • 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, paracoxib, 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, paracoxib, and e
  • 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-ferf-butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline 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 , LTC , LTD , and LTE 4 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 (CGP 45715A), and BAY x 7195.
  • a receptor antagonists for leukotrienes LTB , LTC , LTD , and LTE 4 selected from the group consisting of the phenothiazin-3-ones such as L-651,39
  • 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 H-i receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
  • a antihistaminic H-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 c ⁇ - and ⁇ 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agent, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.
  • 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.
  • the present invention still further relates to the combination of a compound of the invention together with a ⁇ i- to ⁇ -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.
  • 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-i and NK 3 receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and
  • 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), stromeIysin-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, flubipro
  • 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 the formula VI.
  • Compounds of the formula VI can be prepared from compounds of formula I by reaction with a compound of the formula VII: L-R 7 , in the presence of base, wherein L is a suitable leaving group, such as chloro, bromo, iodo tosylate or mesylate.
  • Suitable bases include, but are not limited to, triethylamine, polymer supported BEMP, cesium carbonate, potassium carbonate, and sodium hydride, where cesium carbonate is preferred.
  • the aforesaid reaction can be performed at temperatures ranging from 0 °C to 100 °C in the presence of a polar solvent including but not limited to dimethylsulfoxide, dimethylformamide, equal amounts of dimethylsulfoxide and acetone, or equal amounts of dimethylformamide and acetone, generally for a period of 2 hours to 72 hours, where the preferred conditions are dimethylsulfoxide at ambient temperature for 18 hours.
  • a polar solvent including but not limited to dimethylsulfoxide, dimethylformamide, equal amounts of dimethylsulfoxide and acetone, or equal amounts of dimethylformamide and acetone
  • Compounds of the formula VI may also be prepared from compounds of the formula I by reaction of an appropriately substituted epoxide of the formula VIII either neat or in the presence of a polar solvent including but not limited to dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
  • a polar solvent including but not limited to dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
  • the aforesaid reaction can be performed at temperatures ranging from 0 °C to 100 °C for a period of 2 to 72 hours, where the preferred conditions are dimethylforamide at 60 °C for 24 hours.
  • Scheme 2 refers to the preparation of compounds of the formula I.
  • Compounds of the formula I can be prepared from compounds of formula IX by reacting with a compound of formula XI, H 2 N-R 1 , in the presence of a coupling reagent such as 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 1,1'- carbonyldiimidazole (CDI) and a base such as dimethylaminopyridine (DMAP) or triethylamine in an aprotic solvent, such as methylene chloride, dimethylformamide, or dimethylsulfoxide, preferably 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and dimethylaminopyridine in dimethyl formamide.
  • a coupling reagent such as 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), dicycl
  • the aforesaid reaction may be run at a temperature from 22 °C to 60 °C, for a period of 1 hour to 20 hours, preferably 22 °C for 18 hours.
  • Compounds of the formula I may also be prepared from compounds of the formula X by reaction with a compound of formula XI in the presence of a base including but not limited to dimethylaminopyridine (DMAP), triethylamine, aqueous sodium hydroxide or aqueous potassium hydroxide in an aprotic solvent, such as methylene chloride, ethyl acetate, dichloroethane, dimethylformamide, or dimethylsulfoxide, preferably aqueous sodium hydroxide and dichloroethane.
  • a base including but not limited to dimethylaminopyridine (DMAP), triethylamine, aqueous sodium hydroxide or aqueous potassium hydroxide in an aprotic solvent, such as methylene chloride, ethyl
  • the aforesaid reaction may be run at a temperature from 22 °C to 60 °C, for a period of 1 hour to 24 hours, preferably at ambient temperature for 3 hours.
  • Compound X can be prepared from compound IX by reaction with a reagent capable of generating an acid chloride such as thionyl chloride or oxalyl chloride in the presence of a polar aprotic solvent such as ethyl acetate, methylene chloride, or dichloroethane at a temperature of 22 °C to 60 °C, for a period of 1 hour to 24 hours, preferably oxalyl chloride in methylene chloride at ambient temperature for 16 hours.
  • a reagent capable of generating an acid chloride such as thionyl chloride or oxalyl chloride in the presence of a polar aprotic solvent such as ethyl acetate, methylene chloride, or dichloroethane at a temperature of
  • Scheme 3 refers to the preparation of compounds of the formula XIV and IX.
  • Compounds of the formula IX can be converted into compounds of the formula I by the methods described in Scheme 2.
  • a compound of the formula IX can be prepared from a compound of the formula XIV by reaction with diphenylphosphoryl azide and a base such as triethylamine, pyridine, or diisopropyl ethylamine, preferably triethylamine, at a temperature between 80 and 120 °C for a period of 2 to 16 hours, preferably 120 °C for 2 hours.
  • Compounds of the formula XIV can be prepared from compounds of the formula XII by reaction with a compound of the formula XIII, H0 2 C(CO)R 4 , in the presence of 10% hydrochloric acid at a temperature between 20 and 80 °C for a period of 1 to 24 hours, preferably 1.5 hours at ambient temperature.
  • Scheme 4 refers to the preparation of compounds of the formula XVI and XII.
  • Compounds of the formula XII can be converted into compounds of the formula XIV by the methods described in Scheme 3.
  • a compound of the formula XII can be prepared from a compound of the formula XVI by reaction with an acid such as hydrochloric acid and/or glacial acetic acid, followed by treatment with sodium nitrite in a solvent such as water at a temperature from 0 °C to 25 °C, and the reaction is generally run from a period of 30 minutes to about 2 hours, preferably 0 °C for 30 minutes.
  • a compound of the formula XVI can be prepared from a compound of the formula XV by reaction with methanol in the presence of an acid such as sulfuric acid at a temperature between ambient temperature and reflux for a period of 4 to 24 hours, preferably at reflux for 4 hours.
  • Scheme 5 refers to the preparation of compounds of the formula XVII.
  • Compounds of the formula XVII can be prepared from compounds of formula I by reaction with a compound of the formula VII, in the presence of base, wherein L is a suitable leaving group, such as chloro, bromo, iodo tosylate or mesylate.
  • Suitable bases include, but are not limited to, triethylamine, polymer supported BEMP, cesium carbonate, potassium carbonate, and sodium hydride, where cesium carbonate is preferred.
  • the aforesaid reaction can be performed at temperatures ranging from 0 °C to 100 °C in the presence of a polar solvent including but not limited to dimethylsulfoxide, dimethylformamide, equal amounts of dimethylsulfoxide and acetone, or equal amounts of dimethylformamide and acetone, generally for a period of 2 hours to 72 hours, where the preferred conditions are dimethylsulfoxide at ambient temperature for 18 hours.
  • a polar solvent including but not limited to dimethylsulfoxide, dimethylformamide, equal amounts of dimethylsulfoxide and acetone, or equal amounts of dimethylformamide and acetone
  • Compounds of the formula XVII may also be prepared from compounds of the formula I by reaction of an appropriately substituted epoxide of the formula VIII either neat or in the presence of a polar solvent including but not limited to dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
  • a polar solvent including but not limited to dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
  • the aforesaid reaction can be performed at temperatures ranging from 0 °C to 100 °C for a period of 2 to 72 hours, where the preferred conditions are dimethylforamide at 60 °C for 24 hours.
  • Scheme 6 refers to the preparation of compounds of the formula XIX.
  • Compounds of the formula XIX can be prepared from compounds of formula XVIII by reacting with a base such as NaOH, followed by reaction with a compound of formula XI, in the presence of a coupling reagent such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (GDI) and a base such as dimethylaminopyridine (DMAP) or triethylamine in an aprotic solvent, such as methylene chloride, dimethylformamide, or dimethylsulfoxide, preferably 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide and dimethylaminopyridine in dimethyl formamide.
  • the aforesaid reaction may be run at
  • Scheme 7 refers to the preparation of compounds of the formula XXII and XVIII.
  • a compound of the formula XIX can be prepared from a compound of the formula XXII by reaction with an acid such as dilute sulfuric acid or concentrated hydrochloric acid at a temperature from ambient to reflux for 2 to 16 hours.
  • Compounds of the formula XXII can be prepared from compounds of the formula XX by reaction with a compound of the formula XXI, H 2 NCH(R 4 )CR 5 (OCH 3 ) 2 , in the presence of an organic base such as triethylamine, diisopropylethylamine, or pyridine in a solvent such a dimethyl sulfoxide at a temperature from ambient temperature to 60 °C for 2 to 24 hours.
  • an organic base such as triethylamine, diisopropylethylamine, or pyridine
  • a solvent such a dimethyl sulfoxide
  • Scheme 8 refers to the preparation of compounds of the formula XX.
  • Compounds of the formula XX can be converted into compounds of the formula XXII and XVIII by the methods described in Scheme 7.
  • a compound of the formula XX can be prepared from a compound of the formula XVI by reaction with phenyl chloroformate with an organic base such as pyridine in a solvent such as tetrahydrofuran at a temperature from 0 °C to ambient temperature for 2 to 24 hours, preferably ambient for 12 hours.
  • 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 10 ⁇ M in the in vitro assay described below.
  • the compounds of the invention have an IC 50 in the in vitro assays described below of less than 100 nM, more preferably less than 50 nM, and most preferably less than 10 nM. Still further, the compounds of the invention preferably have an IC 50 in the range of 0.01 nM -100 nM, more preferably between 0.05 nM - 50 nM, and most preferably between 0.10 nM -10 nM.
  • bbATP benzoylbenzoyl adenosine triphosphate
  • bbATP benzoylbenzoyl adenosine triphosphate
  • ethidium bromide a fluorescent DNA probe
  • the propidium dye YOPRO-1 can be substituted for ethidium bromide so as to detect uptake of the dye.
  • 96-Well flat bottomed microtitre plates are filled with 250 ⁇ l of 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 KCl, 5 mM D-glucose and 1.0% FBS at pH 7.5) containing 10 "5 M bbATP, and 25 ⁇ l of the high potassium buffer solution containing 3 x 10 " °M test compound (more preferably 5 x lO ⁇ M, more preferably 1 x
  • 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
  • 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); fillers (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
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • 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 (percent 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.
  • 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.
  • 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 formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff of aerosol contains from about 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 of the P2X 7 receptor 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 l through the carbonyl carbon prodrug sidechain. The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected.
  • NMR data are reported in parts per million (d) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified).
  • Mass Spectral data were obtained using a Micromass ZMD APCI Mass Spectrometer equipped with a Gilson gradient high performance liquid chromatograph. The following solvents and gradients were used for the analysis. Solvent A; 98% water/2% acetonirile/0.01% formic acid and solvent B; acetonitrile containing 0.005% formic acid. Typically, a gradient was run over a period of about 4 minutes starting at 95% solvent A and ending with 100% solvent B.
  • 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” (3rd Ed, John Wiley & Sons 1999).

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Abstract

La présente invention concerne des inhibiteurs benzamidiques du récepteur P2X7 de formule (I), dans laquelle R1 à R3 sont tels que définis dans la description. Les composés de l'invention sont utiles dans le traitement de troubles médiés par l'IL-1, y compris, entre autres, les maladies inflammatoires telles que l'ostéoarthrite et l'arthrite rhumatoïde, les allergies, l'asthme, la BPCO, le cancer, la reperfusion ou l'ischémie lors d'un AVC ou d'une crise cardiaque, les maladies auto-immunes et d'autres pathologies.
EP03780483A 2002-12-31 2003-12-30 Inhibiteurs benzamidiques du recepteur p2x7 Withdrawn EP1581507A1 (fr)

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WO2004058731A1 (fr) 2004-07-15
MXPA05007130A (es) 2005-08-26
BR0317844A (pt) 2005-12-06
CA2511189A1 (fr) 2004-07-15
JP2006513205A (ja) 2006-04-20
AU2003288640A1 (en) 2004-07-22

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