WO1995004046A1 - Composes utilises comme inhibiteurs de pde iv et du facteur de necrose tumorale (tnf) - Google Patents

Composes utilises comme inhibiteurs de pde iv et du facteur de necrose tumorale (tnf) Download PDF

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Publication number
WO1995004046A1
WO1995004046A1 PCT/GB1994/001631 GB9401631W WO9504046A1 WO 1995004046 A1 WO1995004046 A1 WO 1995004046A1 GB 9401631 W GB9401631 W GB 9401631W WO 9504046 A1 WO9504046 A1 WO 9504046A1
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compound according
compounds
dichloropyrid
oxido
dichloro
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PCT/GB1994/001631
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English (en)
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Andrew David Morley
Malcolm Norman Palfreyman
Andrew James Ratcliffe
Brian William Sharp
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Rhone-Poulenc Rorer Limited
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Publication of WO1995004046A1 publication Critical patent/WO1995004046A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • This invention is directed to [(ether or thioether)heteroaryl or aryl] compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
  • TNF is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
  • TNF The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and acute respiratory distress syndrome, and its role in many other immunological processes, this factor is regarded as an important mediator of general inflammation.
  • TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such ll_ ⁇ , ll_6, ll_8 and GM-CSF, which in some case mediate the end effects of TNF.
  • the ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state.
  • HIV Human Immunodeficiency Virus
  • Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages.
  • Endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells.
  • the cachexia associated with certain disease states is mediated through indirect effects on protein catabolism.
  • TNF also promotes bone resorption and acute phase protein synthesis.
  • disease states associated with TNF include those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL-1 , or IL-6, that are modulated by association with TNF.
  • disease states associated with other cytokines such as but not limited to IL-1 , or IL-6, that are modulated by association with TNF.
  • IL-1 IL-1 associated disease state
  • IL-6 IL-6
  • TNF-alpha and TNF-beta are also herein referred to collectively as "TNF” unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biologic responses and bind to the same cellular receptor.
  • Cyclic AMP phosphodiesterase is an important enzyme which regulates cyclic AMP levels and in turn thereby regulates other important biological reactions.
  • inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
  • Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
  • JP-A-62 158,253 also does not disclose or suggest that the moiety that is ortho to R " ! may be anything other than benzyloxy.
  • JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
  • Grammaticakis examines the ultraviolet and visible absorbances of compounds bearing different substituents. Grammaticakis does not disclose or suggest that the compound exhibits any pharmacological activity. JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
  • EP 232199 B1 discloses that phenyl compounds of formula
  • R2 is alpha.alpha'-disubstituted alkyl or mono- or poiycyclic cycloalkyl bonded to the phenyl moiety via a quaternary carbon, exhibit anti-inflammatory and/or anti-allergic activity.
  • EP 232199 B1 does not disclose or suggest compounds wherein R ⁇ is alkyl bonded to the phenyl moiety via a nonquaternary carbon, alkenyl, alkynyl, cyclothioalkyi or cyclothioalkenyl, or R 3 is azaheteroaryl having a nitrogen atom thereof oxidised to the corresponding N-oxide moiety.
  • EP 470,805 A1 discloses phenyl compounds of the formula
  • R may be C3-7 alkyl, C3-7 cycloalkyl or
  • EP 470,805 A1 discloses that these compounds are useful intermediates for preparing PDE IV inhibitors, but does not disclose or suggest that the compounds have any pharmacological activity.
  • EP 470,805 A1 furthermore does not disclose or suggest compounds wherein R or the methyl moiety is directly bonded to the phenyl moiety.
  • Japanese Patent Application Publication No. JP-A-0 4360847 discloses compounds of the formula
  • R " ! , R 2 and R3 may be the same or different and may be halo or lower alkoxy or lower alkyl both optionally substituted by halo; and A may be optionally substituted aryl or 5-6 membered heterocyclyl group.
  • JP-A-0 4360847 discloses that the compounds are useful intermediates for preparing antimicrobial agents, but does not disclose or suggest that the compounds have any pharmacological activity. JP-A-0 4360847 also does not disclose or suggest that the compounds wherein the phenylacyl moiety is substituted in the 3,4-positions relative to the acyl moiety by lower alkoxy groups.
  • JP-A-0 4360847 does not disclose or suggest compounds wherein R 2 is alkenyl, alkynyl, cyclothioalkyi or cyclothioalkenyl or R 3 is azaheteroaryl having a nitrogen atom thereof oxidised to the corresponding N- oxide moiety.
  • WO Patent Application No. 92/12961 does not disclose or suggest that these compound inhibit TNF.
  • WO Patent Application No. 92/12961 does not disclose or suggest compounds wherein R 1 or R 2 is directly bonded to the phenyl moiety.
  • WO Patent Application No. 93/25517 discloses that compounds of the following formula inhibit PDE IV. WO Patent Application No. 93/25517 does
  • WO Patent Application No. 93/25517 does not disclose or suggest compounds wherein X is a direct bond and R 2 is alkyl, alkenyl, alkynyl, cyclothioalkyi or cyclothioalkenyl, or R 3 is azaheteroaryl having a nitrogen atom thereof oxidised to the corresponding N-oxide moiety.
  • WO Patent Application No. 93/10228 does not disclose or suggest that these compounds inhibit TNF.
  • WO Patent Application No. 93/10228 does not disclose or suggest compounds wherein R 1 or R 2 is directly bonded to the phenyl moiety.
  • WO Patent Application No. 93/071 11 discloses that compounds of the following formula wherein X may be YR2; Y is O or S(0) m ; X 3 is halogen or
  • WO Patent Application No. 93/07111 does not disclose or suggest compounds wherein the A substituent is a [(-CXNH- or -CXCH2-)aryl or heteroaryl] moiety wherein X is O or S.
  • WO Patent Application No. 91/16303 discloses that compounds of the following formula wherein Ri, R and R3 may be hydrogen, halogen, lower alkyl,
  • WO Patent Application No. 92/19594 discloses that compounds of the following formula wherein X may be YR 2 ; Y is O or S(0) m ; and X3 may be
  • WO Patent Application No. 92/19594 does not disclose or suggest compounds wherein the lactam moiety is substituted by a [(-CXNH- or -CXCH2-)aryl or heteroaryl] moiety wherein X is 0 or S.
  • This invention is directed to a compound of formula I, which is useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF), where formula I is as follows:
  • R 1 is lower alkyl
  • R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclothioalkyi or cyclothioalkenyl;
  • R3 is aryl or heteroaryl
  • Z1 and Z 2 are independently oxygen, sulfur or direct bond, and only one of Z 1 and Z 2 is a direct bond;
  • Z3 is -CZCH2- or -CZNH-;
  • Z is oxygen or sulfur
  • R 2 when Z 2 is a direct bond, R 2 is alkyl bonded to the phenyl moiety via a nonquaternary carbon, alkenyl, alkynyl, cyclothioalkyi or cyclothioalkenyl, or R 3 is azaheteroaryl having a nitrogen atom thereof oxidised to the corresponding N-oxide moiety.
  • AMP phosphodiesterase and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase.
  • the present invention is therefore directed to their pharmacological use, pharmacological compositions comprising the compounds and methods for their preparation.
  • Patient includes both human and other mammals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl” means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl group is optionally substituted by one or more of halo, cycloalkyl, cycloalkenyl or cycloalkylidene groups.
  • Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentylfluoromethyl, cyclopentylidenemethyl, ethyl, fluoroethyl. ⁇ -propyl, /- propyl, n-butyl, f-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl; preferred are methyl, ethyl, difluoromethyl, fluoroethyl, cyclopentylmethyl and cyclopentylfluoromethyl.
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group is optionally substituted by one or more halo, cycloalkyl or cycloalkenyl.
  • alkenyl groups include ethenyl, propenyl, ⁇ -butenyl, /-butenyl, 3-methylpropenyl, n-pentenyl, heptenyl, octenyl and decenyl.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon- carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. "Lower alkynyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
  • alkynyl group is optionally substituted by one or more halo, cycloalkyl or cycloalkenyl.
  • exemplary alkynyl groups include ethynyl, propynyl, ⁇ -butynyl, 2-butynyI, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl; more preferred is cyclopentyl.
  • Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(1 - or 2-)yl, trinorbornyl and tricyclo[2.2.1.0 2 - 6 -]heptyl.
  • Cycloalkylidene means a non-aromatic monocyclic ring system of about 5 to about 7 carbon atoms of formula
  • n 1 to 3.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Preferred monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl; more preferred is cyclopentenyl.
  • a preferred multicyclic cycloalkenyl ring is a norbornylenyl.
  • Cyclothioalkyi means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon. Preferred rings include about 5 to about 6 ring atoms. Also preferred are rings in which one or two of the ring atoms is/are sulfur.
  • the cyclothioalkyi is optionally substituted by one or more halo.
  • the thio moiety of the cyclothioalkyi ring may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide.
  • Preferred monocyclic cyclothioalkyi rings include tetrahydrothiophenyl and tetrahydrothiopyranyl; more preferred is tetrahydrothiophenyl.
  • Cyclothioalkenyl means a non-aromatic monocyclic or multicyclic ring system having about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon and the ring system contains a carbon-carbon double bond.
  • Preferred rings include about 5 to about 6 ring atoms. Also preferred are rings in which one or two of the ring atoms is/are sulfur.
  • the cyclothioalkenyl is optionally substituted by one or more halo.
  • the thio moiety of the cyclothioalkenyl may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide.
  • Preferred monocyclic cyclothioalkyi rings include dihydrothiophenyl and dihydrothiopyranyl; more preferred is dihydrothiophenyl.
  • Aromatic means aryl or heteroaryl as defined below. Preferred aromatic groups include phenyl, halo substituted phenyl and azaheteroaryl.
  • Aryl means aromatic carbocyciic radical containing about 6 to about 10 carbon atoms.
  • exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, aralkylthio, Y Y 2 N
  • Preferred aryl group substituents include hydrogen, alkyl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, Y 3 Y 4 N-, Y3Y NCO- and Y 3 Y NS02-, where Y 3 and Y 4 are independently hydrogen and alkyl.
  • Heteroaryl means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • the heteroaryl may also be substituted by one or more aryl group substituents.
  • heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, pyridazinyl, 1 ,2,4-triazinyl, quinolinyl, and isoquinolinyl.
  • Preferred heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl and isothiazolyl.
  • Preferred azaheteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1 ,2,4-triazinyl.
  • Aralkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Hydroalkyi means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyi groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
  • Aroyl means an aryl-CO- group in which the aryl group is as previously described.
  • exemplary groups include benzoyl and 1- and 2-naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, Apropoxy, n-butoxy and heptoxy.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • exemplary aryloxy groups include phenoxy and naphthoxy.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl groups is as previously described.
  • exemplary aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, /-propylthio and heptylthio.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • Exemplary arylthio groups include phenylthio and naphthylthio.
  • Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • An exemplary aralkylthio group is benzylthio.
  • Y 3 Y 4 N- means a substituted or unsubstituted amino group, wherein Y 3 and Y 4 are as previously described.
  • exemplary groups include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Aryloxycarbonyl means an aryl-O-CO- group.
  • exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
  • Alkyloxycarbonyl means an aralkyl-O-CO- group.
  • An exemplary aralkyloxycarbonyl group is benzyloxycarbonyl.
  • Y 1 Y NCO- means a substituted or unsubstituted carbamoyl group, wherein Y " ! and Y 2 are as previously described.
  • exemplary groups are carbamoyl (H2NCO-) and dimethylcarbamoyl (Me2NCO-).
  • Y " ⁇ 2 NS ⁇ 2-” means a substituted or unsubstituted sulfamoyl group, wherein Y 1 and Y 2 are as previously described.
  • exemplary groups are sulfamoyl (H2NSO2-) and dimethylsulfamoyl (Me2NS02-).
  • acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as defined herein.
  • Alkylsulfonyl means an alkyI-S02- group. Preferred groups are those in which the alkyl group is lower alkyl.
  • Alkylsulfinyl means an alkyl-SO- group. Preferred groups are those in which the alkyl group is lower alkyl.
  • Arylsulfonyl means an aryl-S02- group.
  • Arylsulfinyl means an aryl-SO- group.
  • Halo means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo; more preferred are fluoro or chloro, and further preferred is fluoro.
  • N-oxide means a moiety of the following structure N + — .
  • a compound of formula I is preferred for use in treating a disease state associated with a physiologically detrimental excess of tumor necrosis factor.
  • Disease states associated with pathological conditions that are modulated by inhibiting tumor necrosis factor are treatable with a compound of formula I.
  • a compound of formula I is also preferred for use in treating a disease state associated with a physiologically detrimental excess of cyclic AMP phosphodiesterase.
  • Disease states associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase are treatable with a compound of formula I.
  • R 2 is alkyl, alkenyl or cycloalkyl
  • R 3 is phenyl, substituted phenyl or azaheteroaryl
  • Z 1 and Z 2 are independently oxygen or direct bond, and only one of Z " ! and Z 2 is a direct bond;
  • Z 3 is -COCH2- or -CONH-.
  • R 1 is methyl, ethyl, fluoroethyi or difluoromethyl
  • R 2 is 2-methylpropenyl, cyclopentylfluoromethyl, cyclopentylmethyl, cyclopentyl or trinorbornyl;
  • R 3 is azaheteroaryl.
  • N-oxide compounds of formula I that is compounds of formula I wherein R 3 is azaheterocyclyl having an imine moiety thereof as an N-oxide. Also futher preferred are compounds of formula I wherein R 3 is 3,5-dihalo-1-oxido-4- pyridinium.
  • R1 is lower alkyl optionally substituted by one or more halo, preferably fluoro
  • R 2 is substituted by one or more halo, preferably fluoro
  • the halo substitution is on a position of R 1 or R 2 that is attached respectively to Z " 1 and Z 2 .
  • R 2 is cyclothioalkyi or cyclothioalkenyl substituted by halo
  • the halo substitution is on a position adjacent to the thio moiety of the cyclothioalkyi or cyclothioalkenyl.
  • the phenyl group is preferably substituted on the 2-position or on both the 2- and 6-positions; more preferably on both the 2- and 6-positions. It is also preferred that the phenyl substituent is halo; preferably chloro or fluoro.
  • the heteroaryl group is preferably substituted on one or both, more preferably on both, of the positions adjacent to a position of R 3 that is attached to Z 3 .
  • Special embodiments of the compounds of the invention include those of formula I wherein R 3 is azaheteroaryl substituted on one or both, more preferably on both, of the positions adjacent to a position of R 3 that is attached to Z 3 , or an N-oxide thereof. Further preferred are compounds wherein R 3 is a 3,5-dihalopyrid-4-yl moiety, preferably wherein halo is chloro or fluoro, or an N- oxide thereof.
  • Special embodiments of the compounds of the invention also include those of formula I wherein Z 3 is -CZNH-, more preferably wherein Z is oxygen.
  • Special embodiments of the compounds of the present invention include those wherein R 2 is 2-methylpropenyl, cyclopentylfluoromethyl, cyclopentylmethyl, cyclopentyl, cyclopentylidenemethyl, trinorbornyl, trinorbornenyl, tricyclo[2.2.1.0 2 - 6 ]heptanyl or tetrahydrothiophenyl; more preferred 2-methylpropenyl, cyclopentylfluoromethyl, cyclopentylmethyl, cyclopentyl, cyclopentylidenemethyl and trinorbornyl.
  • R 1 is lower alkyl optionally substituted by halo, preferably fluoro; and R 2 is 2-methylpropenyl, cyclopentylfluoromethyl, cyclopentylmethyl, cyclopentyl and trinorbornyl.
  • preferred compounds of formula I wherein Z 1 is oxygen and Z 2 is a direct bond; Z 1 is sulfur and Z 2 is a direct bond; and Z 1 is a direct bond and Z 2 is oxygen are preferred; and more preferred are Z 1 is oxygen and Z 2 is a direct bond.
  • Preferred compounds for use according to the invention are selected from the following:
  • Preferred compounds include A-R; more preferred are ?.
  • A-R are allocated to compounds for easy reference in this specification.
  • Z 2 are as hereinbefore defined, Z 3 represents a -CZNH- linkage, and Z is oxygen, may be prepared by the reaction of compounds of formula II
  • R1 , R 2 , Z 1 and Z 2 are as hereinbefore defined, and X represents halo, such as bromo or, preferably, chloro, with a compound of the formula III
  • R 3 is as hereinbefore defined, preferably in the presence of a base such as an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0°C to the reflux temperature or at the melting point of the reaction mixture.
  • a base such as an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0°C to the reflux temperature or at the
  • compounds of formula I wherein R 1 , R 2 , R 3 , Z 1 and Z 2 are as hereinbefore defined, Z 3 represents a -CZNH- linkage, and Z represents oxygen may be prepared by the reaction of compounds of formula II as hereinbefore described, with a compound of the formula IV wherein R 3 is as
  • R 4 represents an alkyl or cycloalkyl group containing up to 5 carbon atoms, preferably a methyl group, preferably in the presence of a base, for example an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine, in an inert solvent, for example toluene, dimethylformamide, or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about 0°C to reflux, then a second base, for example an amine, such as piperidine.
  • a base for example an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine, in an inert solvent, for example toluene, dimethylformamide, or an ether, such as tetrahydrofuran or diethyl ether, at
  • compounds of formula I wherein R 1 , R 2 , R 3 , Z 1 and Z 2 are as hereinbefore defined, Z is oxygen, and Z 3 represents a -CZNH- linkage, may be prepared by the reaction of compounds of formula V wherein R 1 , R 2 ,
  • R 3 and X are as hereinbefore defined, preferably X is chloro, and preferably the preparation takes place in the presence of a base, for example an alkali metal hydride, such as sodium hydride, an alkali metal alkoxide, such as potassium t-butoxide, an alkali metal hydroxide, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0°C to reflux.
  • a base for example an alkali metal hydride, such as sodium hydride, an alkali metal alkoxide, such as potassium t-butoxide, an alkali metal hydroxide, such as sodium hydroxide or carbonate, or an amine, preferably a
  • compounds of formula I wherein R “ l , R 2 and R 3 are as hereinbefore defined, Z 1 is a direct bond, Z 3 represents a -CZNH- linkage, and Z and Z 2 are oxygen, may be prepared by the reaction of compounds of formula VII wherein R ⁇ I , R 3 , Z and Z " * are as hereinbefore defined and Z 3
  • X is bromo
  • a base for example an alkali metal hydride, such as sodium hydride, an alkali metal hydroxide or carbonate, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as.
  • oxidation by the application or adaptation of known methods.
  • the oxidation is carried out, for example, by reaction with oxalyl chloride and dimethyl sulfoxide, in the presence of a base, preferably a tertiary amine, preferably triethylamine, in an inert solvent such as dichloromethane, at temperatures from about -60°C to about room temperature, preferably at a reduced temperature, or by adaptation of known methods for the preparation of ketone from a secondary alcohol, for example the application of pyridinium dichromate.
  • the oxidation is carried out by reaction with chromium trioxide in the presence of 3,5-dimethylpyrazole.
  • compounds of formula I wherein R 1 , R 2 , R 3 , Z, Z 1 and Z 2 are as hereinbefore defined, Z 3 represents a -CZCH2- linkage, and preferably those wherein Z represents oxygen, are prepared from compounds of formula XI wherein R 1 , R 2 , Z,
  • Z "1 and Z 2 are as hereinbefore defined and R 5 and R 6 represent lower alkyl, such as methyl, groups, by coupling with compounds of the formula XII wherein
  • R 3 is as hereinbefore defined, in the presence of a strong base such as lithium diisopropyiamide (usually prepared in situ from ⁇ -butyl lithium and diisopropylamine), preferably at a low temperature.
  • a strong base such as lithium diisopropyiamide (usually prepared in situ from ⁇ -butyl lithium and diisopropylamine), preferably at a low temperature.
  • R 7 is alkyl, cycloalkyl or aralkyl containing up to 8 carbon atoms, by coupling with compounds of the formula XII above, wherein R 3 is as hereinbefore defined, in the presence of a strong base, such as an alkali metal amide or alkyl, for example n-butyl lithium or lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine), in an inert solvent, for example cyclohexane or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about -78°C to about room temperature.
  • a strong base such as an alkali metal amide or alkyl, for example n-butyl lithium or lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine)
  • an inert solvent for example cyclohexane or an ether, such as tetrahydr
  • compounds of formula wherein R 1 , R 2 , R 3 , Z 1 and Z 2 are as hereinbefore defined, Z 3 represents a -CZCH2- linkage, and Z represents oxygen are prepared by the reaction of compounds of formula XIV, wherein R 1 , R 2 , Z 1 and Z 2 are as hereinbefore
  • compounds of formula I wherein R " ! , R 2 , R 3 , Z ⁇ and Z 2 , are as hereinbefore defined, and Z 3 contains a -CS- moiety are prepared from compounds of formula I wherein R 1 , R 2 , R 3 , Z 1 and Z 2 are as hereinbefore defined, and Z 3 contains a -CO- moiety, by reaction with phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from about 0°C to reflux.
  • a solvent such as pyridine or toluene
  • compounds of formula I wherein R 3 is as hereinbefore defined and contains an alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl group, R " ! , R 2 , Z, Z " ! , Z 2 and Z 3 are as hereinbefore defined, are prepared by oxidising the corresponding compounds of formula I wherein R 3 is as hereinbefore defined and contains an alkylthio or arylthio group, R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, preferably wherein Z, Z " !
  • R 2 is alkyl or cycloalkyl, preferably with a peroxyacid, such as 3-chloroperbenzoic acid, preferably in an inert solvent, such as dichloromethane, preferably at about room temperature.
  • a peroxyacid such as 3-chloroperbenzoic acid
  • an inert solvent such as dichloromethane
  • the oxidation is carried out by reaction with a peroxomonosulfate, such as potassium peroxomonosulfate, conveniently in a solvent such as methanol, buffered to about pH 5, at temperatures from about 0°C to about room temperature.
  • a peroxomonosulfate such as potassium peroxomonosulfate
  • This latter method is preferred for compounds containing an acid-labile group, such as those wherein the moiety R 2 is unsaturated, such as a cyclopent-2-enyloxy group.
  • compounds of formula I wherein R 3 is as hereinbefore defined and contains a hydroxymethyl group, and R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined are prepared by the reduction of the corresponding compounds of formula I wherein R 3 is as hereinbefore defined and contains an aryloxycarbonyl or, preferably, alkoxycarbonyl group, R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, and Z is preferably oxygen, preferably by means of reacting an alkali metal borohydride, preferably in an inert solvent, such as tetrahydrofuran, preferably at about room temperature.
  • compounds of formula I wherein R 3 is as hereinbefore defined and contains a formyl group, and R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined are prepared by the oxidising the corresponding compounds of formula I wherein R 3 is as hereinbefore defined and contains a hydroxymethyl group, R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, and Z preferably being an oxygen atom, for example with oxalyl chloride and dimethyl sulfoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than about -65°C, or, preferably, by reaction with a complex of sulfur trioxide with an amine such as pyridine, preferably in the presence of an amine such as triethylamine, preferably at about room temperature.
  • compounds of formula I wherein R 3 is as hereinbefore defined and contains an amino group, and R " ! , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, are prepared by the reducing the corresponding compounds of formula I wherein R 3 is as hereinbefore defined and contains a nitro group, R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, and Z is preferably oxygen, preferably with iron in acidic conditions, such as in acetic acid, preferably at or above room temperature, more especially at the reflux temperature.
  • the reduction are carried out by reaction with hydrazine hydrate in the presence of ferric chloride and activated carbon, conveniently in a solvent such as methanol, at temperatures from about 25°C to about 80°C.
  • a solvent such as methanol
  • compounds of formula I wherein R 3 is as hereinbefore defined and contains an alkanoylamino or aroylamino group, and R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined, are prepared from compounds of formula I wherein R 3 is as hereinbefore defined and contains an amino group, R 1 , R 2 , Z, Z ⁇ , Z 2 and Z 3 are as hereinbefore defined, and Z is preferably oxygen, preferably by means of reaction with the appropriate acid halide or acid anhydride in the presence of a tertiary base, such as triethylamine, optionally in an inert solvent, and preferably at a temperature from about 0°C to reflux.
  • a tertiary base such as triethylamine
  • reaction for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
  • Z, Z ⁇ and Z 2 each represent oxygen
  • R 2 is an oxidised cyclothioalkyi, such as cyclosulphinyl or sulphonyl
  • the reaction is carried out at a temperature from about room temperature to reflux, preferably at a reduced temperature.
  • the oxidation is carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures from about room temperature to about 60°C.
  • R 3 represents an azaheteroaryl group containing a nitrogen ring atom as an N-oxide
  • R1 , R 2 , Z, Z 1 , Z 2 and Z 3 are as hereinbefore defined
  • R 1 , R 2 , Z, Z 1 , Z 2 and Z 3 are hereinbefore defined, preferably by reacting in a deoxygenating system, for example diphosphorus tetraiodide in an inert solvent, such as dichloromethane, preferably at room temperature, or with a chlorotrialkylsilane, preferably chlorotrimethylsilane, in the presence of an alkali metal iodide, such as potassium iodide, and zinc, in an inert solvent, for example acetonitrile, at temperatures from about 0°
  • compounds of formula I wherein R1 is as hereinbefore defined and is substituted by fluorine on a carbon atom thereof alpha to the attachment of R 1 to Z 1 as sulfur, or wherein R 2 is as hereinbefore defined and is substituted by fluorine on a carbon atom thereof alpha to the attachment of R 2 to Z 2 as sulfur, and R 3 and Z 3 as hereinbefore defined are prepared by reacting xenon difluoride with corresponding compounds of formula I wherein said alpha-carbon atoms carry hydrogen atoms instead of said fluorine atoms.
  • reaction is conveniently carried out in a solvent, such as dichloromethane, in the presence of a molecular sieve, and in an inert atmosphere, at a low temperature, such as at about 0°C.
  • a solvent such as dichloromethane
  • compounds of formula I wherein R 1 is a difluoromethyl group may be prepared by reacting a compound of formula I or precursor wherein Z 1 is hydroxy or thio! with HCBrF2 in the presence of a strong base in an inert solvent.
  • compounds of formula I wherein R 1 or R 2 is halo substituted may be prepared by reacting the corresponding compound of formula I wherein R 1 or R 2 is hydroxy substituted with diethylaminosulphur trifluoride (DAST) in an inert solvent such as methylene chloride.
  • DAST diethylaminosulphur trifluoride
  • the compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
  • acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
  • organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic
  • the corresponding acid addition salts comprise the following: hydrohalides, such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-beta-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • hydrohalides such as hydrochloride and hydrobromide
  • sulfate, phosphate, nitrate, sulfamate acetate, citrate, lactate, tarta
  • acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the acid addition salts of the compounds of this invention can be regenerated from the salts by . the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, such as aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non- toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free acid are not vitiated by side effects ascribable to the cations.
  • salts including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-giucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
  • Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound.
  • the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
  • Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound.
  • Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone.
  • Amino acid salts may be similarly prepared.
  • the base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, such as hydrochloric acid.
  • acid addition salts are most likely to be formed by compounds of this invention wherein R 3 represents a nitrogen-containing heteroaryl group and/or wherein R 3 contains an amino group as a substituent.
  • Preferable acid addition salts of the compounds of the invention are those wherein R 2 is other than an acid labile group.
  • salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • geometrical isomerism for example geometrical isomerism and optical isomerism.
  • Optical isomers include compounds of the invention having asymmetric centers that may independently be in either the R or S configuration.
  • Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. Individual geometrical isomers, stereoisomers and mixtures thereof are within the scope of the present invention.
  • Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
  • R 1 , R 2 , Z 1 and Z 2 are as hereinbefore defined, by the application or adaptation of known methods for the preparation of acid halides from carboxylic acids.
  • the reaction may be carried out by means of thionyl chloride or, preferably, oxalyl chloride in the presence of triethylamine, or as prepared by adaptation of the procedures described by K.R.Reistad et al., Acta. Chemica. Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.
  • R 2 , Z 1 and Z 2 are as hereinbefore defined, and R 7 is alkyl, cycloalkyl or aralkyl containing up to 8 carbon atoms, by using potassium carbonate in water and an alcohol, such as methanol or ethanol, at a temperature between 50°C and 10Q O C.
  • R 8 is alkyl containing up to about 3 carbon atoms
  • R 9 is alkyl, alkynyl or alkenyl containing up to about 14, preferably up to 11 , carbon atoms, are prepared by reducting of compounds of formulae XX,
  • R 1 , R 2 , R 3 , R 8 , R 9 , Z and Z 2 are as hereinbefore defined, using sodium borohydride in a solvent, such as ethanol, at between 0°C and room temperature.
  • DAST diethylaminosulphur trifluoride
  • a base such as an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0°C to the reflux temperature or at the melting point of the reaction mixture-
  • a base such as an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine or pyridine
  • an inert solvent for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0°C to the reflux temperature or at the melting point of the reaction mixture-
  • a base such as potassium hydroxide
  • a solvent such as ethylene glycol
  • R 8 and R 9 are as defined hereinbefore, in the presence of a Lewis acid catalyst, such as aluminium chloride, preferably in a solvent such as nitrobenzene, at temperatures between room temperature and 200°C.
  • a Lewis acid catalyst such as aluminium chloride
  • reaction is carried out by reacting compounds of formulae XVII above, wherein R 1 and R 2 are as hereinbefore defined, and , Z 1 and Z 2 are oxygen, with compounds of formulae IX and XXIX respectively in the presence of triphenylphosphine and
  • diisopropylazodicarboxylate optionally in a solvent, such as toluene, at temperatures between 0°C and 80°C.
  • a trace of acid such as concentrated sulphuric acid
  • an inert solvent such as toluene
  • a base such as butyllithium
  • a solvent such as tetrahydrofuran
  • R 7 and Z " * are as hereinbefore defined, by reaction with compoundsof formula XXVllI, wherein R 1 and X are as hereinbefore defined, with the aid of a metal hydride, such as sodium hydride, or base, such as potassium carbonate, preferably in a solvent, such as dimethylformamide, between room temperature and 100°C.
  • a metal hydride such as sodium hydride
  • base such as potassium carbonate
  • a solvent such as dimethylformamide
  • a base such as potassium hydroxide
  • a solvent such as ethylene glycol
  • a metal hydride such as sodium hydride, or base, such as potassium carbonate
  • a solvent such as dimethylformamide
  • compounds of formulae XXII wherein R 1 , R 2 , R 8 and R 9 are as hereinbefore defined, are prepared by reacting compounds of formulae XXXXX, wherein R 1 and R 2 are as hereinbefore defined, with compounds
  • R 8 and R 9 are as defined hereinbefore, in the presence of cuprous bromide in an inert solvent, such as tetrahydrofuran, at temperatures from room temperature to 80°C.
  • an inert solvent such as tetrahydrofuran
  • Z 1 is a direct bond, with corresponding compounds of formula VIII, wherein R 2 and X are as hereinbefore defined, using a metal hydride, such as sodium hydride, or base, such as potassium carbonate, preferably in a solvent, such as dimethylformamide, between room temperature and 100°C.
  • a metal hydride such as sodium hydride
  • base such as potassium carbonate
  • solvent such as dimethylformamide
  • R 7 are as hereinbefore defined, and Z is a direct bond, with corresponding compounds of formula VIII above, wherein R 2 and X are as hereinbefore defined, using a metal hydride, such as sodium hydride, preferably in a solvent, such as dimethylformamide, between room temperature and 100°C.
  • a metal hydride such as sodium hydride
  • a solvent such as dimethylformamide
  • the reaction is carried out using compounds of formula IX above, wherein R 2 is as hereinbefore defined, in the presence of triphenylphosphine and diisopropyl azodicarboxylate, optionally in a solvent, such as toluene, at temperatures between 0°C and 80°C.
  • R 7 are as hereinbefore defined, and Z 2 is a direct bond, by reaction with corresponding compounds of formula XXVllI, wherein R 1 and X are as hereinbefore defined, with a metal hydride, such as sodium hydride, or base, such as potassium carbonate, preferably in a solvent, such as dimethylformamide, between room temperature and 100°C.
  • a metal hydride such as sodium hydride
  • base such as potassium carbonate
  • Z 2 is a direct bond, and R 2 contains an unsaturated moiety, by using hydrogen in the presence of a catalyst, such as palladium on carbon, preferably in a solvent, such as ethanol.
  • a catalyst such as palladium on carbon
  • a base such as butyliithium
  • a solvent such as tetrahydrofuran
  • compounds of formula XXIVa wherein R 2 and R 8 are as hereinbefore defined, and Z 2 is oxygen, are prepared from alkylation of compounds of formula XXXXXVII, wherein R 8 is as
  • the solution is diluted with dichloromethane (50 mL), washed successively with water (2 x 10 mL), saturated aqueous sodium hydrogen carbonate solution (2 x 10 mL) and water (2 x 10 mL), dried over anhydrous magnesium sulphate and the solvent removed in vacuo.
  • Hydrogen peroxide (3.5 mL) is added to a stirred suspension of N-(3,5- dichloropyrid-4-yl) 3-cyclopentylmethyl-4-methoxybenzamide (0.47 g, prepared as described in Example 1 ) in glacial acetic acid (10 mL). The mixture is stirred at 70-80 °C for 4 hours. After cooling, the mixture is basified by treatment with aqueous sodium hydroxide (2 M), and extracted with ethyl acetate (100 mL). The extracts are washed with brine, dried over sodium sulphate and evaporated.
  • N-(3,5-dichloropyrid-4-yI)-3-cyclopentylhydroxymethyl-4- methoxybenzamide (0.3 g, prepared as described in Reference Example 23) in dry dichloromethane (5 mL) is added dropwise to a solution of diethylaminosulphur trifluoride (0.12 g) in dry dichloromethane (5 mL) at -78°C. Stirring at this temperature is continued for a further 25 minutes before the reaction is quenched with water (15 mL).
  • solution A containing 3-cyclopentane-carbonyl-4-methoxybenzoic formic anhydride.
  • aqueous potassium carbonate solution (690 mL; 5%w/v) with cooling and stirring.
  • the mixture is then stirred below -60°C for 10 minutes, before allowing to warm to room temperature and stirring for a further 30 minutes.
  • the mixture is then quenched with water (50 mL), the layers separated and the aqueous layer further extracted with ethyl acetate (3 x 20 mL).
  • the combined organic extracts are dried over magnesium sulphate and evaporated.
  • the resulting residue is purified by flash chromatography on silica gel, using a mixture of ethyl acetate and pentane (2:3 v/v) to give methyl 3-cyclopentylidenemethyl-4- methoxybenzoate (1.23 g) in the form of an off white solid, m.p. 55-57°C.
  • the compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors.
  • the present invention provides compounds of formula I, and compositions containing compounds of formula I, which are of use in a method for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase.
  • compounds within the present invention are useful as bronchodilators and asthma-prophylactic agents and agents for the inhibition of eosinophil accumulation and of the function of eosinophils, such as for the treatment of inflammatory airways disease, especially reversible airway obstruction or asthma, and for the treatment of other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
  • inflammatory diseases such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatic arthritis, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome and diabetes insipidus
  • other proliferative skin diseases such as keratosis and various types of dermatitis
  • conditions associated with cerebral metabolic inhibition such as cerebral senility, multi- infarct dementia, senile dementia (Alzheimer's disease), and memory impairment associated with Parkinson's disease
  • neuroprotectant activity such as cardiac arrest, stroke, and intermittent claudication.
  • a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
  • the compounds are also inhibitors of tumor necrosis factor, especially a-TNF.
  • the present invention provides compounds of formula I, and compositions containing compounds of formula I, which are of use in a method for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF-alpha.
  • compounds of the present invention are useful in joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis.
  • the compounds are useful in treatment of sepsis, septic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, asthma and other chronic pulmonary diseases, bone resorption diseases, reperfusion injury, graft vs. host reaction and allograft rejection.
  • infections such as viral infections and parasitic infections, for example malaria such as cerebral malaria, fever and myalgias due to infection, HIV, AIDS, cachexia such as cachexia secondary to AIDS or to cancer.
  • Other disease states that may be treated with the compounds of the present invention include Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, type I diabetes mellitus, psoriasis, Be ⁇ het's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease and leukemia.
  • a special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase or of TNF, especially TNF-alpha, for example conditions as hereinbefore described which comprises the administration to the patient of an effective amount of compound of formula I or a composition containing a compound of formula I.
  • Effective amount is meant to describe an amount of compound of the present invention effective in inhibiting cyclic AMP phosphodiesterase and/or TNF and thus producing the desired therapeutic effect.
  • the present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
  • compounds of the present invention may generally be administered parenterally, rectally or orally, but they are preferably administered by inhalation
  • compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine.
  • compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • the choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • emulsions, suspensions or solutions of the products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • aqueous-organic solutions such as water and propylene glycol
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.
  • compositions containing the compounds of the invention may be prepared by conventional means.
  • compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
  • the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
  • several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient.
  • the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about C.001 to about 10, preferably 0.01 to 1 , mg/kg body weight per day by intravenous administration.
  • the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • the products according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • aortas of freshly slaughtered pigs are placed in Hepes buffered krebs solution, extraneous tissue on the outside of the aorta is trimmed off and the endothelial layer on the intimal surface is removed by rubbing with a cotton swab. Smooth muscle strips are plucked from the aorta and 25 g are homogenized using a Waring Blender in homogenization buffer (20 mM Tris/HCI, pH 7.5, 2 mM MgCl2, 1 mM dithiothreitol, 5 mM EDTA and 1 mg/ml aprotinin).
  • the homogenate is further homogenized with an Ultra- Turrax and then centrifuged (3000 g, 5 minutes). The supernatant is removed, and the pellet is sonicated in a small volume (25-50 mL) of homogenization buffer. The sonicate is centrifuged (3000 g, 5 minutes), the pellet discarded and the supernatant is pooled with that from the first centrifugation step.
  • the pooled supernatants are centrifuged (100,000 g, 1 hour), the resulting high ⁇ speed supernatant is filtered (0.45 microm) and then applied to a DEAE- trisacryl (IBF) column (50 x 2.44 cm) preequilibrated in column buffer (20 mM Tris/HCI, pH 7.5, 2 mM MgCl2, 1 mM dithiothreitol, 20 microM TLCK).
  • the column is washed with 500-700 mL of column buffer and PDE activities are eluted with 2 successive linear gradients of NaCI (0-200 mM, 400 mL and 200-300 mM, 200 mL) in column buffer.
  • the fractions in the separated peaks of activity corresponding to the different PDE isozymes are pooled and stored at -20°C in 30% (v/v) ethylene glycol.
  • PDE activity is determined by the two-step radioisotopic method of Thompson et al., Adv. Cyclic Nucl. Res.. 10, 69-92 (1979).
  • the reaction mixture contains 20 mM Tris/HCI (pH 8.0), 10 mM MgCl2, 4 mM 2-mercaptoethanol, 0.2 mM EGTA and 0.05 mg of BSA7 mL.
  • the concentration of substrate is 1 microM.
  • the IC50 values for the compounds examined are determined from concentration-response curves in which concentrations range from 0.1 nM to 40 microM. 1.3 Results.
  • PDE IV porcine aortic cyclic AMP-specific phosphodiesterase
  • concentrations from about 10 -9 M up to about 10 -5 M, preferably from about 10" 9 up to about 10" 8 M.
  • the compounds of the invention are from about 10, 000-fold to about 50-fold more selective for cyclic AMP phosphodiesterase IV than cyclic nucleotide phosphodiesterase types I, III or V.
  • Superoxide anion generation is determined as the superoxide dismutase inhibitable reduction of p-iodonitrotetrazolium violet (INTV) (Souness et al, Biochem. Pharmacol.. 42. 937-945, 1991). Briefly, cells are incubated in 96 well microtitre plates in 0.25 mL of Hanks buffered salt solution (HBSS) containing INTV (0.5mg/mL) plus other additions for 45 minutes at 37°C. The cells are then centrifuged at 500 g for 5 minutes and the supernatant is aspirated. The pellet is solubilized by incubation overnight at room temperature in DMSO containing 0.6 M HCI and the absorbance of the reduced dye is measured at 492 nm. The results are expressed in absorbance units.
  • HBSS Hanks buffered salt solution
  • INTV 0.5mg/mL
  • Compounds within the scope of the invention produce up to about 50% inhibition of superoxide generation from eosinophiis harvested from the peritoneal cavities of guinea-pigs at concentrations from about 10 "8 M to about 10 "5 M, preferably from about 10 ⁇ 8 M up to about 10 "7 M. 3. Effects of compounds on tracheal smooth muscle contractility.
  • tracheas are removed from male, Dunkin-Hartley guinea-pigs (400-500 g) are placed in Krebs Ringer Bicarbonate (KRB) solution and fat and connective tissue are dissected away. Epithelium is removed by mechanical abrasion and the tracheal strips are suspended under an applied load, such that they are at their optimal length, derived from preliminary experiments, and equilibrated for 90 minutes, washing at 15 minute intervals.
  • KRB Krebs Ringer Bicarbonate
  • Cumulative concentration-response curves to spasmogens are constructed and the concentration producing 30% of maximum contraction (EC30) is determined by computerized linear regression analysis.
  • tissue are contracted with spasmogens (such as methacholine, histamine, leukotriene D4) (EC30) and when the response plateaus, PDE inhibitors (10 nM-100 microM) or vehicle control (DMSO) are added cumulatively.
  • the concentration of relaxant producing 50% inhibition (IC50) of the agonist response is calculated by linear regression.
  • PDE inhibitors, as above may be added to tissues under basal tone and the concentration producing 50% relaxation (EC50) calculated as above.
  • Compounds within the scope of the invention produce about 50% relaxation of guinea-pig tracheal strips (under basal tone or which had been contracted by treatment with spasmogens) at concentrations from about 5x10" 9 M to about 10 "5 M, preferably from about 5x10" 9 M to about 10 '7 M. 4. in vivo bronchodilator actions of compounds.
  • Bronchorelaxant activity is measured in in vivo tests in the anaesthetized guinea-pig or rat according to the method described in Underwood et al., Pulm. Pharmacol.. 5, 203-212, (1992) in which the effects on bronchospasm induced by histamine (or other spasmogens such as methacholine or leukotriene D4) is determined.
  • Nebulized aerosols generated from aqueous solutions of compounds of the invention are each administered for one minute to the anaesthetized animals.
  • dry powder formulations made up from compounds of the invention and lactose are blown into the airways of the anaesthetized guinea-pigs or rats by the method described in Underwood et al., J. Pharm. Methods. 26, 203-210, 1991.
  • Compounds within the scope of the invention produce from about 30% up to about 90% decrease in bronchospasm when administered at effective doses of about 4 to about 1000 microg/kg, preferably about 4 to about 50 microg/kg, without any significant effect on blood pressure.
  • Sensitized guinea-pigs are anaesthetised and dry powder formulations of PDE inhibitors or lactose are administered (i.t.) into the airways. In some cases PDE inhibitors are administered orally. 23 hours later the procedure is repeated and 60 minutes later the guinea-pigs are challenged with nebulised saline or ovalbumin (1 % in saline) for 15 seconds. 24 hours after challenge the guinea-pigs are killed and the lungs are lavaged with warm saline. Total and differential cell counts are made.
  • Compounds within the scope of the invention administered one hour before challenge, inhibit by at least 50% ovalbumin-induced eosinophilia in guinea-pigs which is measured 24 hours after challenge, at oral doses of about 1 to about 50 mg/kg, preferably about 1 to 10 mg/kg and inhaled doses of about 4 to 1000 microg/kg, preferably.4 to 50 microg/kg.
  • PBMs peripheral blood monocytes
  • Blood is drawn from normal donors, mixed with dextran, and the erythrocytes allowed to sediment for 35 minutes at 37°C.
  • Leukocytes are fractionated by centrifugation through a discontinuous (18, 20 and 22%) metrizamide gradient.
  • the mononuclear cell fraction comprising 30-40% PBMs is suspended in HBSS and stored at 4°C until use.
  • Cells from the PBM-rich metrizamide fraction are spun down (200 g for 10 minutes at 20°C), resuspended at 10 6 PBMs/ mL of medium; RPMI 1640 containing 1%v/v FCS, 50 U/ mL penicillin and 50 mg/ mL streptomycin (Gibco, U.K.), then plated out in 96 well plates at 2 x1 ⁇ 5 cells/ well.
  • TNF-alpha levels in cell supematants are quantified using a standard sandwich ELISA technique.
  • ELISA plates (Costar, U.K.) are coated ovemight at 4°C with 3 mg/ mL polyclonal goat anti-human TNF-alpha antibody (British Biotechnology, U.K.) in pH 9.9 bicarbonate buffer.
  • Rabbit polyclonal anti- human TNF-alpha antiserum (Janssen Biochimicha, Belgium) at 1/500 dilution is used as the second antibody and polyclonal goat anti-rabbit IgG horseradish peroxidase (Calbiochem, U.S.A.) at 1/8000 dilution is used as the detection antibody.
  • Color development is measured by absorbance at 450 nm using a Titertek plate reader.
  • TNF-alpha levels are calculated by interpolation from a standard curve using recombinant human TNF-alpha (British Biotechnology U.K.)(0.125-8 ng/ mL). Data (log-cone. vs. log-resp) are fitted by linear regression (p > 0.99) using a Multicalc (Wallac Pharmacia, U.K.) software program. Basal TNF-alpha levels are less than 100 pg/ mL whilst LPS stimulation of the PBMs increases TNF-alpha levels to 3-10 ng/ mL.
  • Compounds within the scope of the invention produce 50% inhibition of LPS-induced TNF-alpha release from human PBMs at concentrations within the range of about 10 -9 M to about 10 -6 M., preferably about 10 -9 M to about 10 "8 M.
  • SRaw Specific airways resistance
  • Test compounds or vehicle (lactose carrier) are instilled into the airways as dry powders through a metal gavage needle. 30 minutes later, the animals are injected with mepyramine (30 mg/kg i.p.) to prevent anaphylactic collapse and placed into the plethysmography chambers where SRaw is determined at 1 minute intervals. Resting SRaw is then determined. Animals are challenged with an aerosol of ovalbumin and SRaw is determined every 5 minutes for 15 minutes.
  • Compounds within the scope of the invention inhibit antigen-induced bronchoconstriction by up to 80% at doses of between about 1 to about 1000 ⁇ g/kg (i.t.), preferably about 1 to about 20 ⁇ g/kg (i.t.).
  • mice Female Balb/c mice (age 6-8 weeks, weight 20-22 g from Charles River, U.K.) in groups of five or more animals are dosed p.o. with compounds suspended in 1.5% (w/v) carboxymethyl cellulose then challenged after a minimum period of 30 min with 30 mg of LPS i.p. After 90 min the animals are killed by CO2 asphyxiation and bled by cardiac puncture. Blood is allowed to clot at 4°C, centrifuged (12,000 g for 5 minutes) and serum taken for TNF-alpha analysis.
  • TNF-alpha levels are measured using a commercially available murine TNF-alpha ELISA kit, purchased from Genzyme (Cat. no. 1509.00 ), as recommended by the manufacturer. Values for TNF-alpha are calculated from a recombinant murine TNF-alpha standard curve.
  • Compounds within the scope of the invention inhibit LPS-induced serum TNF-alpha at doses between about 10 and about 10,000 mg/kg, preferably about 10 to about 250 ⁇ g/kg.
  • the value of the compounds of the invention is enhanced by their very low mammalian toxicity levels.
  • compositions according to the present invention illustrate pharmaceutical compositions according to the present invention.
  • compositions similar to those above are prepared from other compounds of formula I.

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Abstract

Cette invention concerne un composé [(éther ou thioéther)hétéroaryle ou aryle] ou un N-oxyde de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, qui est utilisé dans l'inhibition de la production ou des effets physiologiques du facteur de nécrose tumorale (TNF) dans le traitement d'un patient souffrant d'un état pathologique associé à un excès physiologiquement nocif du facteur de nécrose tumorale (TNF). Les composés de la présente invention inhibent également l'AMP-cyclique phosphodiestérase et sont utiles dans le traitement d'un état pathologique associé à des états pathologiques qui sont modulés par l'inhibition de l'AMP-cyclique phosphodiestérase, ces états pathologiques comprenant les maladies inflammatoires et auto-immunes, notamment l'AMP-cyclique phosphodiestérase du type IV. La présente invention concerne par conséquent l'utilisation pharmacologique de ces composés dans l'inhibition du TNF et/ou de l'AMP-cyclique phosphodiestérase, les compositions pharmacologiques comprenant les composés et leurs procédés de préparation.
PCT/GB1994/001631 1993-07-28 1994-07-28 Composes utilises comme inhibiteurs de pde iv et du facteur de necrose tumorale (tnf) WO1995004046A1 (fr)

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US5962492A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics Limited 2 cyclo(alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same
US5962483A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
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US6197792B1 (en) 1994-06-22 2001-03-06 Celltech Therapeutics Limited Tetra-substituted phenyl derivatives and processes for their preparation
EP0796093A1 (fr) * 1995-01-10 1997-09-24 Euroceltique S.A. Composes et procede pour inhiber la phosphodiesterase iv
EP0796093A4 (fr) * 1995-01-10 1998-05-13 Euro Celtique Sa Composes et procede pour inhiber la phosphodiesterase iv
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WO1996040636A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. Derives de diethers de catechol utilises comme agents pharmaceutiques
US6028086A (en) * 1995-06-07 2000-02-22 P Pfizer Inc Catechol diethers derivatives useful as pharmaceutical agents
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US6133257A (en) * 1997-06-20 2000-10-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US7205320B2 (en) 2001-01-22 2007-04-17 Memory Pharmaceuticals Corp. Phosphodiesterase 4 inhibitors
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US7291624B2 (en) 2001-05-29 2007-11-06 Bayer Schering Pharma Ag CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents
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