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WO1997003967A1 - Composes aromatiques substitues et leur utilisation pharmaceutique - Google Patents

Composes aromatiques substitues et leur utilisation pharmaceutique Download PDF

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Publication number
WO1997003967A1
WO1997003967A1 PCT/GB1996/001746 GB9601746W WO9703967A1 WO 1997003967 A1 WO1997003967 A1 WO 1997003967A1 GB 9601746 W GB9601746 W GB 9601746W WO 9703967 A1 WO9703967 A1 WO 9703967A1
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WIPO (PCT)
Prior art keywords
methoxy
dichloropyridin
pyridin
benzamide
group
Prior art date
Application number
PCT/GB1996/001746
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English (en)
Inventor
David John Aldous
Graham Frank Smith
Peter Charles Astles
Stephen Dennis Pickett
Iain Mcfarlane Mclay
Keith Alfred James Stuttle
Andrew James Ratcliffe
Original Assignee
Rhone-Poulenc Rorer Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9515058.7A external-priority patent/GB9515058D0/en
Priority claimed from GBGB9515729.3A external-priority patent/GB9515729D0/en
Priority claimed from GBGB9604531.5A external-priority patent/GB9604531D0/en
Application filed by Rhone-Poulenc Rorer Limited filed Critical Rhone-Poulenc Rorer Limited
Priority to AU65268/96A priority Critical patent/AU6526896A/en
Publication of WO1997003967A1 publication Critical patent/WO1997003967A1/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
    • C07D213/04—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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to novel substituted aromatic 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-
  • Tumour necrosis factor is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of some 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 amongst 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 adult respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of 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 as I ⁇ , ILg, IL ⁇ and GM-CSF, which in some cases mediate the end effects of TNF.
  • pro-inflammatory cytokines such as I ⁇ , ILg, IL ⁇ and GM-CSF
  • TNF Cytokines
  • 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 including those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL ⁇ , or ILg, that are modulated by and/or associated with TNF.
  • IL ⁇ cytokines
  • ILg ILg
  • a L ⁇ associated disease state where IL ⁇ production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF.
  • 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 (lyxnphotoxin) and each of them has a capacity to induce similar biologic responses and bind to the same cellular receptor.
  • Cyclic AMP phosphodiesterases are important enzymes which regulate cyclic AMP levels and in turn thereby regulate other important biological responses.
  • inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators, prophylactic agents useful against asthma and as agents for inhibiting eosinophil accumulation and 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.
  • R! represents a straight- or branched-chain alkyl group of 1 to about 6 carbon atoms, optionally substituted by one or more halogen atoms, or when Z 1 is a direct bond
  • R* may also represent a hydrogen atom
  • R 2 represents an optionally substituted aryl, partially saturated bicycloaryl, heteroaryl or R a R ⁇ N- group
  • R 3 represents an optionally substituted aryl or heteroaryl group
  • A* represents a direct bond, a straight- or branched-chain alkyiene linkage containing from 1 to about 6 carbon atoms optionally substituted by halogen, hydroxyl, alkoxy or oxo, or
  • a 3 - represents a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond, or is interrupted by an oxygen or sulphur atom, a phenylene, imino (-NH-) or alkylimino linkage, or a sulphinyl or sulphonyl group;
  • Z 1 represents an oxygen or sulphur atom or a direct bond
  • Z 2 represents an oxygen or sulphur atom or a direct bond
  • Z represents an oxygen or sulphur atom
  • R a and R each independently represents an alkyl or arylalkyl group, or NR a R ⁇ forms a 4-6 membered cyclic amine which optionally contains an additional heteroatom selected from 0, S, NH or NR C , or is substituted with an oxo group;
  • R c represents an alkyl or arylalkyl group
  • ⁇ # Q 2 and Q 3 which may be the same or different, each represents a CH or CX 1 linkage or a nitrogen atom
  • X 1 represents a halogen atom; and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof; but excluding compounds of formula (I) where R 1 represents a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms substituted by one or more fluorine atoms, R 2 represents a phenyl group, R 3 represents an optionally substituted phenyl or pyridyl group, A ⁇ represents methylene group, Q 1 , Q 2 and Q 3 each represent a CH linkage, Z 1 and Z 2 each represent an oxygen atom, and Z 3 represents a -CO-NH- linkage, and compounds of formula (I) where R 1 represents methyl, ethyl, difluoromethyl or trifluoromethyl, R 2 represents a phenyl group optionally substituted with C _4alkyl,
  • R 3 represents an optionally substituted aryl or heteroaryl group.
  • a 1 represents a C ⁇ .galkylene (optionally substituted by halogen, hydroxy or alkoxy) , a -OC2_6alkylene, or a -NHC2_6alkylene linkage
  • Q 1 , Q 2 and Q 3 each represent a CH linkage
  • Z 1 and Z 2 each represent an oxygen atom
  • Z 3 represents a -CH2-0-, -CH2-NH-, -CH2-S-, -0-CH2-, -S-CH 2 -, -NH-CH 2 -, -CH 2 -CO-, -CO-CH 2 -, -CO-NH-, -O-CO- or -NH-CO- linkage.
  • Patient includes both human and other mammals.
  • Alkyl as a group or part of a group means straight- or branched-chain alkyl. Particular alkyl groups, unless otherwise specified, have 1 to about 12 carbon atoms in the chain, more particularly from 1 to about 6 carbon atoms and include, for example C ⁇ _ alkyl groups exemplified by methyl, ethyl, n-propyl, s-propyl, n-butyl, s-butyl and t-butyl.
  • Aryl as a group or part of a group denotes a monocyclic or ulticyclic aromatic carbocyclic moiety of about 6 to about 10 carbon atoms.
  • R 3 represents an optionally substituted aryl group this may particularly represent an aromatic carbocyclic moiety of about 6 to about 10 carbon atoms such as phenyl or naphthyl optionally substitutedwith one or more aryl group substituents which may be the same or different, where "aryl group substituent” includes, for example, hydrogen, alkyl, aryl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy arylalkoxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, acylamino aroylamino, alkylsulfonyl, arylsulfonyl, al
  • R 2 contains an optionally substituted aryl group this may particularly represent a phenyl group optionally substituted by one or more substituents selected from, for example, halogen atoms and alkyl, haloalkyl (for example trifluoromethyl), phenyl, phenylalkyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, phenylalkoxy, nitro arid cyano groups.
  • Partially saturated bicycloaryl means a group in which an aryl and a cycloalkyl group are fused together to form a bicyclic structure.
  • exemplary arylalkyl groups include indanyl and tetrahydronaphthyl, especially indanyl.
  • Arylalkyl means a group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C ⁇ _4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl as a group or part of a group means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyl groups contain C ⁇ _4alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
  • Aroyl as a group or part of a group means an aryl-CO- group in which the aryl group is as previously described.
  • exemplary groups include benzoyl and 1- and 2-naphthoyl.
  • Y 1 Y 2 N- means a substituted or unsubstituted amino group, wherein Y 1 and Y 2 are as previously described.
  • exemplary groups include amino (H2N-), methyl mino, 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.
  • Arylalkoxycarbonyl means an arylalkyl-O-CO- group.
  • An exemplary arylalkoxycarbonyl group is benzyloxycarbonyl.
  • ⁇ l ⁇ 2 N CO- » means a substituted or unsubstituted carbamoyl group, wherein Y 1 and Y 2 are as previously described.
  • exemplary groups are carbamoyl (H2NCO-) and dimethylcarbamoyl (Me2NC0-) .
  • Y 1 Y 2 NS ⁇ 2- means a substituted or unsubstituted sulfamoyl group, wherein Y and Y 2 are as previously described.
  • exemplary groups are sulfamoyl (H2NSO2-) and dimethylsulfamoyl (M ⁇ 2NS02-).
  • Alkylsulfonyl means an alkyl-S02- group. Preferred groups are those in which the alkyl group is C ⁇ _4alkyl.
  • Alkylsulfinyl means an alkyl-SO- group. Preferred groups are those in which the alkyl group is C ⁇ _4alkyl.
  • Halo or "halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo; more preferred are fluoro or chloro.
  • Heteroaryl denotes an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur.
  • suitable optionally substituted heteroaryl groups include pyrazinyl, furyl, benzofuranyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiazolyl,
  • R 3 contains an optionally substituted heteroaryl group this may particularly represent an optionally substituted "azaheteroaryl” group (where the term “azaheteroaryl” means a heteroaryl group of about 5 to about 10 ring members in which one or more of the ring members is/are nitrogen) .
  • Preferred heteroaryl groups within R 2 include thienyl, thiazolyl, pyridyl, 1,2,4-oxadiazole or 1,3,4-oxadiazole.
  • Optional substituents for the heteroaryl group within R 2 include, for example, halogen atoms and alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, oxo, hydroxyalkyl, haloalkyl (for example trifluoromethyl), alkoxy, haloalkoxy, aryloxy, heteroaryloxy, arylalkoxy and heteroarylalkoxy groups.
  • Preferred heteroaryl groups represented by R 3 are optionally substituted pyridyl groups, especially wherein the optional substituents are alkyl groups or, more particularly, halogen atoms.
  • Substituted oxadiazole denotes substituted by, for example, a halogen atom, or an alkyl, haloalkyl (for example trifluoromethyl), aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, heteroaryloxy, arylalkoxy, or heteroarylalkoxy group.
  • Prodrug means a compound which is convertible jja vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof, for example an ester of a compound of formula (I) containing a hydroxy group.
  • Suitable esters are of many different types, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -kydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • esters may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 22., (1989), 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino- methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4_(4-alkylpiperazin-1-yl)benzoates.
  • substituted (aminomethyl)-benzoates for example dialkylamino- methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen
  • Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are 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 inherent in the free base are not vitiated by side effects ascribable to the anions.
  • compositions of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalide ⁇ , e.g.
  • hydrochlorides and hydrobromides sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • 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.
  • R1 preferably represents a C ⁇ _4alkyl group optionally substituted by one or more halogen (e.g. fluorine) atoms.
  • halogen e.g. fluorine
  • R! more preferably represents methyl or difluoromethyl.
  • R 2 particularly represents an optionally substituted heteroaryl group, preferably optionally substituted thienyl, thiazolyl, pyridyl, oxidopyridinio, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl.
  • R 2 also particularly represents an optionally substituted aryl group, such as a phenyl or alkoxyphenyl, or preferably a 4-methoxyphenyl, group.
  • R 2 also particularly represents a partially saturated bicycloaryl group.
  • Preferred bicycloaryl groups contain a cyclopentyl moiety fused to an aryl ring, for example indanyl, especially a 2-indanyl group.
  • R 2 also particularly represents a R a R ⁇ N- group, such as a piperidinyl, morpholinyl or pyrrolidinyl, especially 2-oxo-pyrrolidinyl.
  • R 2 preferably represents substituted 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl particularly where the substituent is an optionally substituted phenyl group or a heteroaryl (e.g. pyridy1) group.
  • R 2 more preferably represents substituted l,2,4-oxadiazol-5-yl or l,3,4-oxadiazol-5-yl each substituted in the 3- and 2-positions respectively by an optionally substituted phenyl group (e.g. 4-halophenyl or 4-alkoxyphenyl) or more especially substituted in the 3- and 2-positions respectively by a heteroaryl (e.g. pyridyl such as 2-pyridyl) group.
  • R 3 preferably represents a heteroaryl group substituted on both the positions next to the position which is directly attached to Z 3 .
  • R 3 also preferably represents a heteroaryl group substituted by one or two halogen, e.g. chlorine, atoms.
  • R 3 more preferably represents an optionally substituted azaheteroaryl group, such as an optionally substituted pyridyl group, especially a pyridyl group substituted by one or two halogen, e.g. chlorine, atoms, particularly where the halogen atom(s) is/are positioned next to the position which is directly attached to the linkage Z 3 .
  • an optionally substituted azaheteroaryl group such as an optionally substituted pyridyl group, especially a pyridyl group substituted by one or two halogen, e.g. chlorine, atoms, particularly where the halogen atom(s) is/are positioned next to the position which is directly attached to the linkage Z 3 .
  • R 3 is especially a 3,5-dihalopyrid-4-yl moiety, more especially a 3,5-dichloropyrid-4-yl moiety.
  • R 3 when containing at least one nitrogen atom may be presented as the corresponding N-oxides, and such N-oxides are also preferred.
  • R 3 may preferably represent a 3,5-dihalo-l-oxido-4-pyridinio group, such as a 3,5-dichloro-l-oxido-4-pyridinio group.
  • Z preferably represents an oxygen atom.
  • Z 2 preferably represents an oxygen atom or a bond.
  • Q 1 , Q 2 and Q 3 may particularly each independently represent CH,
  • Q 1 and Q 3 are CH and Q 2 is CH, CF, N or N(O) .
  • Examples of the moiety A 1 include a direct bond, an unsubstituted straight chain alkyiene linkage containing from 1 to 6 carbon atoms, or a straight carbon chain comprising from 2 to 6 carbon atoms and contains a double or triple carbon-carbon bond, or is interrupted by an oxygen atom;
  • A* particularly represents a direct bond, a straight chain alkyiene linkage containing from 1 to 4 carbon atoms, i.e. a methylene, ethylene, propylene or butylene linkage, or a straight chain alkyiene linkage containing from 3 to 4 carbon atoms interrupted by an oxygen atom especially a -CH2OCH2CH2- or -OCH2CH2-linkage.
  • a further particular group of compounds of the present invention are compounds of formula (la)
  • R 1 , R 2 , A 1 , Q 2 and Z 2 are as defined previously, X 2 and X 3 each represent a halogen atom, and Z 4 is NH or CH2, and N-oxides thereof and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof.
  • R 2 represents an optionally substituted phenyl (particularly 4-methoxyphenyl) , indanyl (particularly 2-indanyl), optionally substituted pyrrolidinyl (particularly 2-oxo-pyrrolidinyl) , furyl, thienyl, thiazolyl, pyridyl or pyridazyl group, or a substituted oxadiazole (particularly a 1,2,4- or a 1,3, -oxadiazole) group are preferred.
  • R 2 represents an optionally substituted phenyl (particularly 4-methoxyphenyl) , indanyl (particularly 2-indanyl), optionally substituted pyrrolidinyl (particularly 2-oxo-pyrrolidinyl) , furyl, thienyl, thiazolyl, pyridyl or pyridazyl group, or a substituted oxadiazole (particularly a 1,2,4- or a 1,3, -ox
  • R 2 is particularly a 3-heteroaryl-l,2,4-oxadiazol- 5-yl group such as a 3-pyridyl-l,2,4-oxadiazol-5-yl group, especially 3-(2-pyridyl)-l,2,4-oxadiazol-5-yl.
  • a preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is an optionally substituted aryl group, especially phenyl or
  • 4-methoxyphenyl, X 2 and X 3 each represent a chlorine atom, and A*, Q 2 , z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is a 2-indanyl group, X 2 and X 3 each represent a chlorine atom, and A 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is a 2-oxo-pyrrolidinyl group, X 2 and X 3 each represent a chlorine atom, and A 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is an optionally substituted pyridyl group, especially a 2-pyridyl, 3-pyridyl or 4-pyridyl group or an N-oxide thereof, X 2 and X 3 each represent a chlorine atom, and
  • a 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is an optionally substituted thienyl group, especially a 2-thienyl group, X 2 and X 3 each represent a chlorine atom, and A 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is a l,2,4-oxadiazol-5-yl group substituted in the 3-position by an optionally substituted phenyl group (e.g. 4-halophenyl or 4-alkoxyphenyl) or substituted in the 3-position by a heteroaryl group (e.g. a pyridyl group such as 2-pyridyl), X 2 and X 3 each represent a chlorine atom, and A 1 ,
  • Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a further preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is a l,3,4-oxadiazol-5-yl group, substituted in the 2-position by an optionally substituted phenyl group
  • X 2 and X 3 each represent a chlorine atom, and A 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • a particularly preferred group of compounds of the invention are compounds of formula (la) in which R 1 is methyl or difluoromethyl, R 2 is a 3-pyridyl-l,2,4-oxadiazol-5-yl group, especially 3-(2-pyridyl)-l,2,4-oxadiazol-5-yl, X 2 and X 3 each represent a chlorine atom, and A 1 , Q 2 , Z 2 and Z 4 are as defined above, and N-oxides and solvates (e.g. hydrates) thereof.
  • Preferred compounds include:-
  • the compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.
  • the present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
  • Compounds of the invention are inhibitors of tumor necrosis factor, especially TNF- ⁇ .
  • the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially of TNF- ⁇ .
  • compounds of the present invention are useful in joint inflammation, including 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, adult respiratory distress syndrome, asthma and other chronic pulmonary diseases, bone resorption diseases, reperfusion injury, graft vs. host reaction and allograft rejection.
  • the compounds are useful in the treatment of 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.
  • 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.
  • Compounds of the invention are also cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors.
  • cyclic AMP phosphodiesterase inhibitors in particular type IV cyclic AMP phosphodiesterase inhibitors.
  • compounds within the present invention are useful as bronchodilators and prophylactic agents useful against asthma, and agents for the inhibition of eosinophil accumulation and of the function of eosinophils, e.g.
  • inflammatory airways disease especially reversible airway obstruction or asthma
  • other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
  • inflammatory diseases such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatoid arthritis
  • inflammatory bowel diseases e.g.
  • autoimmune diseases e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • type I diabetes mellitus e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • type I diabetes mellitus e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • type I diabetes mellitus e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • psoriasis e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • type I diabetes mellitus e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis
  • type I diabetes mellitus e.g.
  • a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • 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.
  • a compound of the invention in the manufacture of a medicament 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, especially type IV cyclic AMP phosphodiesterase.
  • a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially of TNF- ⁇ .
  • references herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
  • the present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
  • Compounds of the invention may be administered by any suitable means.
  • compounds of the present invention may generally be administered parenterally, rectally, by inhalation or, especially, by the oral route.
  • compositions according to the invention 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.
  • the compositions may be presented in the form of tablets, capsules, 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.
  • 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 sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions or solutions are used they can contain emulsifying agents or agents which facilitate suspension or solubilisation. 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.
  • inhalation 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 the invention.
  • 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. Obviously, 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. In the adult, 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 0.001 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 compounds 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 arid 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.
  • the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
  • the compounds of the present invention may also be formulated for use in conjunction with other therapeutic agents such as agents which increase cyclic AMP production including ⁇ -agonists and PGE2. It is to be understood that the present invention includes combinations of compounds of the present invention with one or more of the aforementioned therapeutic agents.
  • T 1 represents a group of the general formula:-
  • R 3 are as hereinbefore defined and T 2 represents a group of the general formula:-
  • R 2 and A are as hereinbefore defined and A 1 represents an alkyiene linkage, in the presence of a triarylphosphine, such as triphenylphosphine, and a dialkyl ester, such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, preferably at a temperature from about 0°C to about 60°C.
  • T 1 -COX 4 (IV) wherein T 1 is as hereinbefore defined and X 4 represents an azido group or a halogen, e.g. bromine or, preferably, chlorine atom, with compounds of the general formula (V) :-
  • R 3 is as hereinbefore described, including N-oxides of heteroaryl groups, and R 4 represents a hydrogen atom or an alkanoyl, e.g. acetyl group.
  • the reaction may be carried out in the presence of an amine, preferably a tertiary amine, e.g. triethylamine or pyridine, optionally in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, dimethylformamide, or an ether (e.g. diethyl ether or tetrahydrofuran) , preferably at a temperature from 0°C to the reflux temperature or at the melting point of the reaction mixture.
  • an amine preferably a tertiary amine, e.g. triethylamine or pyridine
  • an inert solvent for example a halogenated hydrocarbon such as dichloromethane, dimethylformamide, or an ether (e.g. diethyl
  • the reaction may be carried out in the presence of a base such as an alkali metal hydride, e.g. sodium hydride, optionally in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, dimethylformamide, or an ether (e.g. diethyl ether or tetrahydrofuran) , preferably at a temperature from 0°C to the reflux temperature or at the melting point of the reaction mixture, and this method is preferred when R 3 represents a heteroaryl group containing at least one nitrogen atom, preferably a substituted heteroaryl group containing at least one nitrogen atom wherein the substitution is such that the pKa of the said nitrogen atom is about 10 or less, e.g. a 3,5-dichloropyrid-4-yl group.
  • a base such as an alkali metal hydride, e.g. sodium hydride
  • an inert solvent for example a halogenated hydrocarbon such as dichloromethan
  • T 1 is as hereinbefore defined and R ⁇ represents an alkyl group with compounds of the general formula (VII):-
  • R 3 is as hereinbefore defined, in the presence of a strong base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine) , in an inert solvent, for example an ether, e.g. tetrahydrofuran, preferably at a temperature from -65°C to 0°C.
  • a strong base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine)
  • an inert solvent for example an ether, e.g. tetrahydrofuran, preferably at a temperature from -65°C to 0°C.
  • T 1 and R 3 are as hereinbefore defined, by the application or adaptation of known methods.
  • the oxidation can be carried out, for example, by reaction with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than -65°C. These conditions are especially convenient for the preparation of compounds wherein Z 1 and Z 2 each represents an oxygen atom.
  • compounds of formula (I), wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CZ-CH2- linkage, and preferably Z represents an oxygen atom may be prepared by the reaction of compounds of the general formula (IX):-
  • T 1 and Z are as hereinbefore defined and R ⁇ and R 7 represent C ⁇ _4alkyl, e.g. methyl, groups, with compounds of formula (VII) wherein R 3 is as hereinbefore defined, in the presence of a strong base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine) , preferably at a low temperature.
  • a strong base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine) , preferably at a low temperature.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CO-CH2- linkage may be prepared by the reaction of compounds of the general formula (X):-
  • R 3 is as hereinbefore defined and X 5 represents a halogen, preferably a bromine atom.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CZ-NH- linkage, more especially those wherein Z and Z 1 represent oxygen may be prepared by the reaction of compounds of the general formula (XII):-
  • T 1 and Z are as hereinbefore defined and Z preferably represents oxygen, with compounds of the general formula (XIII) :-
  • R 3 is as hereinbefore defined and X 6 represents a halogen, preferably a chlorine atom.
  • a base for example an alkali metal hydride, e.g. sodium hydride, an alkali metal alkoxide, e.g. potassium t-butoxide, an alkali metal hydroxide, e.g. sodium hydroxide or an alkali metal carbonate, e.g. sodium carbonate, or an amine, preferably a tertiary amine, e.g. triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • a base for example an alkali metal hydride, e.g. sodium hydride, an alkali metal alkoxide, e.g. potassium t-
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents an -0-CH2- linkage may be prepared by the reaction of compounds of the general formula (XIV):-
  • T 1 is as hereinbefore defined, with compounds of the general formula (XV):- R 3 CH2X 7 (XV)
  • R 3 is as hereinbefore defined and X 7 represents a halogen atom, especially a chlorine atom, preferably in the presence of a base such as an alkali metal carbonate, e.g. potassium carbonate, preferably in a solvent such as dimethylformamide.
  • a base such as an alkali metal carbonate, e.g. potassium carbonate, preferably in a solvent such as dimethylformamide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -O-CO- linkage may be prepared by the reaction of compounds of formula (XIV) wherein T 1 is as hereinbefore defined, with compounds of the general formula (XVI) :-
  • R 3 is as hereinbefore defined, and X 8 represents a halogen, preferably a chlorine atom, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -NH-CO- linkage may be prepared by the reaction of the general formula (XVII):-
  • T 1 is are as hereinbefore defined, with compounds of formula (XVI) wherein R 3 and X 8 are as hereinbefore defined, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -NH-CO-NH- linkage may be prepared by the reaction of compounds of formula (XVII) wherein T 1 is as hereinbefore defined with compounds of the general formula (XVIII) :-
  • R 3 is as hereinbefore defined, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -NH-CO-NH- linkage may be prepared by the reaction of compounds of formula (XVII) wherein T 1 is as hereinbefore defined with compounds of formula (V) wherein R 3 is as hereinbefore defined and R 4 represents a hydrogen atom, together with phosgene or a source thereof.
  • the reaction is preferably carried out by reacting the compound of formula (XVII) with phosgene or, preferably, bis(trichloromethyl) carbonate, and by then reacting the product of that reaction with the cation derived from the compound of formula (V) , for example by reaction with a base such as sodium hydride.
  • phosgene or, preferably, bis(trichloromethyl) carbonate for example by reaction with a base such as sodium hydride.
  • the reactions are preferably carried out in suitable solvents such as dichloromethane and tetrahydrofuran.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH2-NH- linkage may be prepared by the reaction of compounds of the general formula (XIX):-
  • T 1 is as hereinbefore defined, with compounds of formula (V) wherein R 3 is as hereinbefore defined and R 4 represents a hydrogen atom, followed by reduction with a compound such as sodium cyanoborohydride.
  • R 3 represents an optionally substituted phenyl or naphthyl group.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH2-NH- linkage may be prepared by the reaction of compounds of the general formula (XX):-
  • T 1 is as hereinbefore defined and X 9 represents a halogen, preferably bromine, atom with compounds of formula (V) wherein R 3 is as hereinbefore defined and R 4 represents a hydrogen atom.
  • the reaction preferably takes place in the presence of a base such as sodium hydride.
  • the reaction is especially suitable for the preparation of compounds wherein R 3 represents an optionally substituted heteroaryl group.
  • SO2-NH- linkage may be prepared by the reaction of compounds of the general formula (XXI):- T 2 -S02NHR 3 (XXI)
  • R 2 and A 1 are as hereinbefore defined and X 10 represents a halogen, preferably bromine, atom or an alkylsulphonyl or arylsulphonyl, e.g. p-toluene-sulphonyl, group, preferably after treatment with a base such as sodium hydride, preferably in a solvent such as dimethylformamide.
  • a base such as sodium hydride
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and z 3 represents a -S-CH2- linkage may be prepared by the reaction of compounds of the general formula (XXIII):-
  • T 1 is as hereinbefore defined, with compounds of formula (XV) wherein R 3 and X 7 are as hereinbefore defined, and preferably X 7 represents a bromine atom, preferably after reaction with a base such as an alkali metal alkoxide, e.g. sodium methoxide.
  • a base such as an alkali metal alkoxide, e.g. sodium methoxide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CF2-0- linkage may be prepared by the reaction of compounds of the general formula (XXIV):- T 1 -CF2Br (XXIV)
  • T 1 is as hereinbefore defined, with compounds of the general formula (XXV):-
  • R 3 is as hereinbefore defined, preferably with the aid of a base such as sodium hydride, preferably in a solvent such as dimethylformamide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -NH-CO-O- linkage may be prepared by the reaction of compounds of the general formula (XXVI):-
  • T 1 is as hereinbefore defined, with compounds of formula (XXV) wherein R 3 is as hereinbefore defined, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • compounds of formula (I) wherein T and R 3 are as hereinbefore defined and Z 3 represents a -NH-CH2- linkage may be prepared by the reaction of compounds of formula (XVII) wherein T 1 is as hereinbefore defined, with compounds of the general formula (XXVII) :-
  • R 3 CHO (XXVII) wherein R 3 is as hereinbefore defined, preferably with the aid of a reducing agent such as sodium cyanoborohydride.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -NH-SO2- linkage may be prepared by the reaction of compounds of formula (XVII, T 1 -NH2) wherein T 1 is as hereinbefore defined with compounds of the general formula (XXVIII):-
  • R 3 is as hereinbefore defined and X 11 represents a halogen, preferably chlorine, atom, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as tetrahydrofuran.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as tetrahydrofuran.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -O-CO-NH- linkage may be prepared by the reaction of compounds of formula (XIII, T 1 -OH) wherein
  • T 1 is as hereinbefore defined with compounds of formula (XVIII,
  • R 3 NC0 wherein R 3 is as hereinbefore defined, or with compounds of formula (V) wherein R 3 is as hereinbefore defined and R 4 represents a hydrogen atom, together with phosgene or a source thereof, preferably, bis(trichloromethyl)carbonate, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -0-CF2- linkage may be prepared by the reaction of compounds of formula (XIV, T 1 -OH) wherein T 1 is as hereinbefore defined with compounds of the general formula (XXIX) :-
  • R 3 is as hereinbefore defined, preferably with the aid of a base such as sodium hydride, preferably in a solvent such as dimethylformamide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents an ethynyl linkage may be prepared by the reaction of compounds of the general formula (XXX):-
  • reaction is carried out with the aid of a catalyst, e.g. palladium on carbon and cuprous iodide, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dimethylformamide.
  • a catalyst e.g. palladium on carbon and cuprous iodide
  • a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dimethylformamide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH2-0- linkage may be prepared by the reaction of compounds of the general formula (XXXII):- T 1 -CH20H (XXXII )
  • T 1 is as hereinbefore defined, with compounds of formula (XIII) wherein R 3 and X 6 are as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.
  • a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.
  • the reaction is preferably carried out in a solvent such as tetrahydrofuran.
  • compounds of formula (I) wherein T 3 - and R 3 are as hereinbefore defined and Z 3 represents a -CH2-0- linkage may be prepared by the reaction of compounds of formula (XX) wherein T 1 and X 9 are as hereinbefore defined with compounds of formula (XXV) wherein
  • R 3 is as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.
  • a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CO-CO-NH- linkage may be prepared by the reaction of compounds of the general formula (XXXIII):-
  • T 1 is as hereinbefore defined, with dichloromethyl methyl ether in dichloromethane, followed by reaction with compounds of formula (V) wherein R 3 is as hereinbefore defined and R 4 represents a hydrogen atom, preferably with the aid of a base such as sodium hydride, preferably in a solvent such as tetrahydrofuran.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and z 3 represents a -CO-CO- linkage may be prepared by the oxidation of compounds of formula (VIII) wherein T 1 and R 3 are as hereinbefore defined, for example by reaction with pyridinium dichromate, preferably in a solvent such as dichloromethane. This reaction is particularly suitable for the preparation of compounds wherein R 3 represents a heteroaryl, for example an optionally substituted pyridyl, group.
  • T 1 is as hereinbefore defined, with compounds of the general formula (XXXV) :-
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH2-S- linkage may be prepared by the reaction of compounds of formula (XX) wherein T 1 and X 9 are as hereinbefore defined with compounds of the general formula (XXXVI) :-
  • a base such as an alkali metal carbonate, e.g. potassium carbonate.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH2-CO- linkage may be prepared by the oxidation of compounds of the general formula (XXXVII):-
  • T 1 and R 3 are as hereinbefore defined.
  • the oxidation may conveniently be carried out, for example, by reaction with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than -65°C.
  • the oxidation may be carried out by reaction with chromium trioxide in the presence of 3,5-dimethylpyrazole.
  • compounds of formula (I) wherein T 1 and R 3 are as hereinbefore defined and Z 3 represents a -CH(F)-CH2- linkage may be prepared by reaction of compounds of the general formula (VIII), wherein T 1 and R 3 are as hereinbefore defined, with diethylaminosulphur trifluoride in an inert solvent, such as dichloromethane, and at a temperature at about room temperature.
  • compounds of the invention may be prepared by interconversion of other compounds of the invention.
  • compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to the corresponding N-oxides.
  • This interconversion is especially convenient for the preparation of compounds of the invention wherein Z 1 and Z 2 both represent oxygen atoms and wherein the linkage A 1 contains no oxidizable groups containing sulphur.
  • the oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90°C.
  • the oxidation may be carried out by reaction with a peracid, for example m-chloroperoxybenzoic acid, in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
  • a peracid for example m-chloroperoxybenzoic acid
  • an inert solvent such as dichloromethane
  • the oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60°C. This last method is preferred for compounds containing an acid-labile group.
  • an N-oxide group within a compound of formula (I) may be reduced to a nitrogen atom. More particularly, one of the N-oxide groups in a compound of formula (I) wherein Q , Q 2 or Q 3 represents a nitrogen atom in its oxidised form and R 2 and/or R 3 represents a heteroaryl group containing one or more nitrogen ring atoms in its oxidised form, may be reduced to a nitrogen atom.
  • the N-oxide group in the group R 2 and/or R 3 in such a compound can be reduced to a nitrogen leaving the other N-oxide group unchanged.
  • the reduction of an N-oxide group may be carried out by reaction with diphosphorus tetraiodide in an inert solvent, such as dichloromethane, preferably at or near room temperature, or by reaction with a chlorotrialkylsilane, preferably chlorotrimethylsilane, in the presence of zinc and an alkali metal iodide, e.g. potassium iodide, in an inert solvent, e.g. acetonitrile, at a temperature between about 0°C and about room temperature, preferably below room temperature.
  • an inert solvent such as dichloromethane
  • a chlorotrialkylsilane preferably chlorotrimethylsilane
  • an alkali metal iodide e.g. potassium iodide
  • an inert solvent e.g. acetonitrile
  • compounds of the invention containing hydroxy moieties may be converted to their esters by the application or adaptation of known methods of esterification.
  • the appropriate acid may be converted to an acid halide, e.g. by reaction with thionyl chloride or oxalyl chloride, and then the acid halide may be reacted with the appropriate alcohol of formula (I), preferably in the presence of a base, for example a tertiary amine, e.g. triethylamine.
  • the appropriate alcohol of formula (I) may be reacted with the appropriate acid in the presence of compounds such as diisopropyl azodicarboxylate and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
  • a dry ethereal solvent e.g. diethyl ether or tetrahydrofuran
  • compounds of the invention containing hydroxy moieties may be prepared by hydrolysis of corresponding esters of the invention.
  • the hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide or carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux.
  • a base such as an alkali metal hydroxide or carbonate
  • organic solvents such as dioxan, tetrahydrofuran or methanol
  • the hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • an inorganic acid such as hydrochloric acid
  • organic solvents such as dioxan or tetrahydrofuran
  • compounds of formula (I) wherein R 2 and/or R 3 represents or contain an aryl group which is substituted by a formyl group may be prepared by oxidising the corresponding compounds of formula
  • R 2 and/or R 3 represents or contain an aryl group which is substituted by a hydroxymethyl group for example with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than about -65°C, or, preferably, by reaction with a complex of sulphur 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 2 and/or R 3 represents or contain an aryl group which is substituted by an amino group may be prepared by reducing the corresponding compounds of formula
  • R 2 and/or R 3 represents or contains an aryl group which is substituted by a nitro group, preferably with iron in acidic conditions, such as in acetic acid, preferably at or above room temperature, more especially at the reflux temperature.
  • acidic conditions such as in acetic acid
  • the reduction may be 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.
  • compounds of formula (I) wherein R 2 and/or R 3 represents or contains an aryl group which is substituted by an acylamino or aroylamino group may be prepared from compounds of formula (I) wherein R 2 and/or R 3 represents or contains an aryl group which is substituted by an amino group, 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
  • compounds of formula (I) wherein R 2 and/or R 3 represents or contains an aryl group which is substituted by a carboxamido group may be prepared from compounds of formula (I) wherein R 2 and/or R 3 represents or contains an aryl group, which is substituted by a cyano group, by means of reaction with hydrogen peroxide and potassium carbonate in dimethyl sulphoxide.
  • compounds of formula (I) wherein R 2 and/or R 3 represents or contains an aryl group which is substituted by a cyano group may be prepared from compounds of formula (I) wherein R 2 and/or R 3 represents or contains .an aryl group which is substituted by a bromine atom, by means of reaction with zinc cyanide in the presence of tetrakis(triphenylphosphine) palladium(O) in an inert solvent, such as dimethylformamide, at a temperature at about 100°C.
  • compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing -S- linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g.
  • 3-chloroperbenzoic acid preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • an inert solvent e.g. dichloromethane
  • potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing -S- or sulphoxide linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively the oxidation can be carried out by means of sodium metaperiodate in a medium such as aqueous methanol.
  • compounds of formula (I) wherein Z 3 represents a -CS-CH2- linkage may be prepared from compounds of formula (I) wherein Z 3 represents a -CO-CH2- linkage by reaction with phosphorus pentasulphide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2, -diphosphetane-2, - disulphide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from 0°C to the reflux temperature.
  • compounds of formula (I) containing a hydroxymethyl group may be prepared by the reduction of the corresponding compounds of formula (I) containing an aryloxycarbonyl or, particularly, alkoxycarbonyl group, preferably by means of reaction with an alkali metal borohydride, preferably in an inert solvent, e.g. tetrahydrofuran, and preferably at or near room temperature.
  • an alkali metal borohydride preferably in an inert solvent, e.g. tetrahydrofuran, and preferably at or near room temperature.
  • compounds of formula (I) wherein R 1 is as hereinbefore defined and is substituted on its ⁇ -carbon atom by fluorine and Z 1 is sulphur may be prepared by the reaction of xenon difluoride with corresponding compounds of formula (I) wherein said ⁇ -carbon atoms carry hydrogen atoms instead of said fluorine atoms.
  • the reaction may be 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, e.g. at or near 0°C.
  • This method is especially convenient for the conversion of compounds wherein R represents a methyl group to compounds wherein R 1 represents a difluoromethyl group.
  • acid addition salts of the compounds of this invention may be 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 may be prepared either by dissolving the free base in water 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, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. 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.
  • the starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
  • R 3 preferably represents a heteroaryl group containing at least one nitrogen atom, preferably a substituted heteroaryl group containing at least one nitrogen atom wherein the substitution is such that the pKa of the said nitrogen atom is about 10 or less, e.g. a 3,5-dichloropyrid-4-yl group, may conveniently be prepared by reaction of compounds of the general formula (1):-
  • T 2 and R 3 are as immediately hereinbefore defined with diethylaminosulphur trifluoride.
  • the reaction preferably takes place in an inert solvent, such as dichloromethane, preferably at a temperature from about 0°C to about room temperature.
  • R 1 , R 3 , Q 1 , Q 2 , Q 3 , and Z 1 are as hereinbefore defined, by treatment with aluminium chloride.
  • the reaction preferably takes place in an inert solvent, such as dichloromethane, preferably at a temperature from about 0°C to about room temperature.
  • R 2 is aryl or heteroaryl and A 1 is an alkyiene linkage.
  • the hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide or carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as acetonitrile, dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux.
  • Compounds of formula (3) wherein R 2 is an alkyl-, aryl-, or heteroaryl-1,2,4-oxadiazole and A 1 is an alkyiene linkage may be prepared by reaction of an alkyl-, aryl- or heteroarylamidoxi e (which may be prepared by reaction of the corresponding alkyl-, aryl- or heteroarylnitrile with hydroxylamine hydrochloride in the presence of an alkali metal hydroxide, such as sodium hydroxide, in aqueous ethanol at a temperature at about reflux) with an acetoxyalkanoyl chloride according to the procedure of G.D.Diana et al J.Med.Chem., 1994, 21. 2421-2436.
  • R 8 CONHNHCOA 1 OCOCH 3 ( ) wherein R 8 represents aryl or heteroaryl and A 1 is an alkyiene linkage.
  • the reaction is carried in the presence of 4-toluene sulphonic acid in an inert solvent, such as toluene, at a temperature at about 125°C.
  • Compounds of formula (4) wherein R 8 represents aryl or heteroaryl and A is an alkyiene linkage may be prepared by reaction of aryl- or heteroaryl-acid hydrazides with an acetoxyalkanoyl chloride in the presence of an organic base, such as pyridine, in an inert solvent, such as dichloromethane, at a temperature at about 0°C to about room temperature.
  • an organic base such as pyridine
  • an inert solvent such as dichloromethane
  • T 1 is as hereinbefore defined, by the application or adaptation of known methods for the preparation of acid halides from carboxylic acids.
  • X 4 represents a chlorine atom
  • the reaction may be carried out by means of thionyl chloride or, preferably, oxalyl chloride, optionally in the presence of a small amount of dimethylformamide.
  • Z 1 and Z 2 represent oxygen atoms, e.g. by reaction with potassium permanganate, or with a mixture of sulphamic acid and sodium chlorite in acetic acid, or with sodium chlorite in the presence of sodium dihydrogen phosphate, preferably in the presence of an alkene, e.g. 2-methylbut-2-ene, conveniently in t-butanol.
  • compounds of formula (5) wherein T 1 is as hereinbefore defined may be prepared by the hydrolysis of intermediates of formula (VI, ⁇ 1 -COOR 5 ) wherein T and R 5 are as hereinbefore defined, for example by reaction with a base, such as an alkali metal hydroxide, carbonate or bicarbonate in the presence of water, in an alcohol such as methanol and at a temperature from about ambient to about reflux, followed by reaction with an aqueous acid such as dilute hydrochloric acid.
  • a base such as an alkali metal hydroxide, carbonate or bicarbonate
  • an alcohol such as methanol
  • an aqueous acid such as dilute hydrochloric acid
  • a 1 represents a straight- or branched- carbon chain comprising from 2 to about 6 carbon atoms, may be prepared by hydrogenation of compounds of formula (5), wherein T 1 is as hereinbefore defined, but where Z 2 represents a direct bond and
  • a 1 represents a straight- or branched- carbon chain comprising from 2 to about 6 carbon atoms which contains a double or triple carbon-carbon bond.
  • the hydrogenation may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • compounds of formula (5) wherein T 1 is as hereinbefore defined, but where Z 2 and A 1 each represent a direct bond and Q 1 , Q 2 and Q 3 each represent CH, may be prepared from compounds of formula (6):-
  • R 2 is as hereinbefore defined, in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(O) .
  • R 4 represents a lower alkanoyl, preferably acetyl, group
  • R 4 represents a lower alkanoyl, preferably acetyl, group
  • R 3 is as hereinbefore defined and R 4 is hydrogen with an alkanoyl halide, for example acetyl chloride when R 4 represents an acetyl group.
  • the reaction may be preferably carried out in the presence of a base such as an alkali metal hydride, e.g. sodium hydride optionally in an inert solvent, for example dimethylformamide, or an ether, for example tetrahydrofuran, preferably at a temperature from 0°C to about 50°C.
  • a base such as an alkali metal hydride, e.g. sodium hydride optionally in an inert solvent, for example dimethylformamide, or an ether, for example tetrahydrofuran, preferably at a temperature from 0°C to about 50°C.
  • intermediates of formula (V, R NHR 4 ) wherein R 3 represents a 3,5-dichloro-l- oxido-4-pyridinio group and R 4 represents a lower alkanoyl group, preferably acetyl, may be prepared by oxidation of the corresponding compounds of formula (V) wherein R 3 represents a
  • the oxidation may be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature at 60-90°C.
  • the oxidation may be carried out by reacting a peracid, for example m-chloroperoxybenzoic acid, in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
  • the oxidation may also be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60°C.
  • T 2 is as hereinbefore defined, by reaction with a compound of formula (XXII, R ⁇ -X 10 ) wherein R 2 and X 10 are as hereinbefore defined, X*0 preferably representing a bromine atom, and A 1 represents a straight- or branched-chain alkyiene linkage.
  • the alkylation may be carried out preferably in the presence of a base, for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, e.g.
  • triethylamine or pyridine optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • an inert solvent for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • intermediates of formula (XIX, T 1 -CHO) wherein T 1 is as hereinbefore defined, but where Z 2 represents an oxygen atom and A ⁇ represents a straight- or branched-chain alkyiene linkage may be prepared from compounds of formula (8,
  • T 2 -CHO wherein T 2 is as hereinbefore defined by reaction with compounds of formula (III, R A 1 OH) wherein R 2 is as hereinbefore defined and A 1 represents a straight- or branched- chain alkyiene linkage.
  • the reaction may be carried out in the presence of a triarylphosphine, such as triphenylphosphine, and a dialkyl ester, such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, preferably at a temperature from about 0°C to about 60°C.
  • reaction is carried out in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine.
  • the reaction preferably takes place in an inert solvent, such as dimethylformamide, preferably at a temperature at about 90°C.
  • R 1 and Z 1 are as hereinbefore defined, with trifluoromethanesulphonic anhydride in the presence of an organic base, such as pyridine, at a temperature from about -10°C to about room temperature.
  • organic base such as pyridine
  • T 2 and R 5 are as hereinbefore defined, by reaction with compounds of formula (III) wherein R 2 and A 1 are as hereinbefore defined, in the presence of a triarylphosphine, such as triphenylphosphine, and a dialkyl ester, such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • a triarylphosphine such as triphenylphosphine
  • a dialkyl ester such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, preferably at a temperature from about 0°C to about 60°C.
  • CH and Z 2 represents a direct bond, may be prepared from compounds of formula (13):-
  • R 1 , R 5 , A 1 and Z 1 are as hereinbefore defined, by reaction with an alkyl-, aryl- or heteroarylamidoxi e (which may be prepared by reaction of the corresponding alkyl-, aryl- or heteroarylnitrile with hydroxylamine hydrochloride in the presence of an alkali metal hydroxide such as sodium hydroxide, in aqueous ethanol at a temperature at about reflux) .
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, in the presence of pyridine, at a temperature from about ambient to about reflux.
  • Z 2 represents a direct bond
  • a 1 represents a
  • R 2 , R 9 and n are as hereinbefore defined, R* 1 represents an aryl, such as phenyl group, and X 11 represents halo, preferably bromo, with a base such as an alkali metal alkoxide (for example potassium t-butoxide), or an alkali metal hydride (for example sodium hydride), or butyl lithium.
  • a base such as an alkali metal alkoxide (for example potassium t-butoxide), or an alkali metal hydride (for example sodium hydride), or butyl lithium.
  • the reaction is preferably carried out in a solvent such as dimethylformamide or tetrahydrofuran.
  • CH, Z 2 represents a direct bond
  • a 1 represents a
  • R 2 is as hereinbefore defined, in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction takes place in an inert solvent, such as an ether, for example tetrahydrofuran, at a temperature from about 0°C to about reflux.
  • R 1 and Z 1 are as hereinbefore defined, with N-bromosuccinimide in the presence of benzoyl peroxide.
  • the reaction takes in a chlorinated hydrocarbon solvent, for example chloroform, at a temperature at about reflux.
  • R 2 is as hereinbefore defined, in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction takes place in an inert solvent, such as an ether, for example tetrahydrofuran, at a temperature from about 0°C to about reflux.
  • T 1 is as hereinbefore defined but where Q 1 , Q 2 and Q 3 each represent CH, Z 2 represents a direct bond, and A 1 represents a
  • R 2 is as hereinbefore defined and X* 2 represents a halogen atom, preferably a bromine atom, in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction takes place in an inert solvent, such as an ether, for example tetrahydrofuran, at a temperature from about 0°C to about reflux.
  • R 1 and Z 1 are as hereinbefore defined, with sodium borohydride in methanol.
  • T 1 is as hereinbefore defined and X 13 represents halo, e.g. bromine, with compounds of the general formula (24):-
  • R 3 is as hereinbefore defined, in the presence of a base such as butyl lithium.
  • a base such as butyl lithium.
  • the reaction takes place in an inert solvent, such as an ether, for example tetrahydrofuran, preferably at a temperature lower than -65°C.
  • intermediates of formula (VIII, T 1 -CH(OH)CH 2 R 3 ) wherein T 1 and R 3 are as hereinbefore defined may be prepared by the reaction of compounds of formula (XIX, T ⁇ —CHO) wherein T 1 is as hereinbefore defined, with compounds of formula (VII, R 3 -CH 3 ) wherein R 3 is as hereinbefore defined, in the presence of a base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine) .
  • a base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine) .
  • the reaction takes place in an inert solvent, such as an ether, for example tetrahydrofuran, preferably at a temperature lower than -65°C.
  • T 1 is as hereinbefore defined.
  • the hydrogenation may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • a suitable metal catalyst e.g. palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • T 1 is as hereinbefore defined, but where R 1 is methyl, Z 1 and Z 2 represents an oxyge atom, Q 1 , Q 2 and Q 3 each represent a CH linkage and A 1 represents a straight- or branched-chain alkyiene linkage
  • R 1 is methyl
  • Z 1 and Z 2 represents an oxyge atom
  • Q 1 , Q 2 and Q 3 each represent a CH linkage and A 1 represents a straight- or branched-chain alkyiene linkage
  • a 1 represents a straight- or branched-chain alkyiene linkage.
  • the alkylation may be carrie out preferably in the presence of a base, for example an alkal metal hydride, e.g.
  • sodium hydride an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, e.g. triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • an inert solvent for example dichloromethane, dimethylformamide
  • an ether e.g. diethyl ether or tetrahydrofuran
  • compounds of formula (25) wherein T 1 is as hereinbefore defined, but where R 1 is methyl, Z 1 and Z 2 represents an oxygen atom, Q 1 , Q 2 and Q 3 each represent a CH linkage and A* represents a straight- or branched-chain alkyiene linkage, may be prepared from 3-hydroxy-4- methoxynitrobenzene by reaction with compounds of formula (III,
  • R 2 A 1 OH wherein R 2 is as hereinbefore defined and A 1 represent a straight- or branched-chain alkyiene linkage.
  • the reaction may be carried out in the presence of a triarylphosphine, such as triphenylphosphine, and a dialkyl ester, such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, preferably at a temperature from about 0°C to about 60°C.
  • Intermediates of formula (XX, T 1 -CH2X 9 ), wherein T 1 is as hereinbefore described and X 9 is a bromine atom may be prepared by bromination of compounds of formula (26):-
  • T 1 is as hereinbefore described, with N-bromosuccinimide, optionally in the presence of a catalyst, such as benz ⁇ yl peroxide, in an inert solvent such as dichloromethane and at a temperature at about room temperature to about reflux temperature.
  • a catalyst such as benz ⁇ yl peroxide
  • T 1 is as hereinbefore defined, but where R 1 is methyl, Z 1 and Z 2 represents an oxygen atom, Q 1 , Q 2 and Q 3 each represent a CH linkage and A 1 represents a straight- or branched-chain alkyiene linkage, may be prepared by reaction of 2-methoxy-5- methylphenol with compounds of formula (III, R 2 A 1 OH) wherein
  • R 2 is as hereinbefore defined
  • a 1 represents a straight- or branched-chain alkyiene linkage.
  • the reaction may be carried out in the presence of a triarylphosphine, such as triphenylphosphine, and a dialkyl ester, such as the diisopropyl or diethyl ester of azodicarboxylic acid.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, preferably at a temperature from about 0°C to about 60°C.
  • compounds of formula (26, T 1 -CH 3 ), wherein T 1 is as hereinbefore defined, but where R 1 is methyl, Z 1 and Z 2 represents an oxygen atom, Q 1 , Q 2 and Q 3 each represent a CH linkage and A 1 represents a straight- or branched-chain alkyiene linkage, may be prepared by reaction of 2-methoxy-5- methylphenol with compounds of formula (XXII, R 2 A 1 X 10 ) wherein
  • R 2 , X 10 are as hereinbefore defined and A 1 represents a straight- or branched-chain alkyiene linkage.
  • the alkylation may be carried out preferably in the presence of a base, for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, optionally in an inert solvent, for example dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • a base for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, optionally in an inert solvent, for example dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably
  • T 1 is as hereinbefore defined, by reaction with bromine in carbon tetrachloride and ultraviolet radiation, at a temperature from about ambient to about reflux.
  • T 1 is as hereinbefore defined, in the presence of pyridine, at or below room temperature, or alternatively by the action of diethylaminosulphur trifluoride, preferably in an inert solvent, such as dichloromethane, preferably at a temperature from about 0°C to about room temperature.
  • sodium hydroxide or carbonate optionally in an inert solvent, for example dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • an inert solvent for example dimethylformamide
  • an ether e.g. diethyl ether or tetrahydrofuran
  • compounds of formula (XXXII, T 1 -CH2 ⁇ H) wherein T is as hereinbefore described, may be prepared by the reduction of compounds of formula (XIX, T 1 -CHO), preferably by means of reaction with an alkali metal borohydride, preferably in an inert solvent, e.g. tetrahydrofuran, and preferably at or near room temperature.
  • an alkali metal borohydride preferably in an inert solvent, e.g. tetrahydrofuran, and preferably at or near room temperature.
  • T 1 is as hereinbefore defined, but where R 1 is a methyl group, Z 1 and Z 2 represent oxygen atoms, and A 1 represents a straight- or branched-chain alkyiene linkage,, by reaction with selenium dioxide in the presence of pyridine, in mild conditions, e.g. in a solvent such as ethanol, at or below room temperature.
  • T 1 is as hereinbefore defined, but where R 1 is a methyl group, Z 1 and Z 2 represent oxygen atoms, and A 1 represents a straight- or branched-chain alkyiene linkage, may be prepared by alkylation of 3-hydroxy-4-methoxyacetophenone with compounds of formula
  • a 1 represents a straight- or branched-chain alkyiene linkage.
  • the alkylation may be carried out preferably in the presence of a base, for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, optionally in an inert solvent, for example dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • a base for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or sodium carbonate, e.g. sodium hydroxide or carbonate, optionally in an inert solvent, for example dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • T 1 is as hereinbefore defined, with compounds of formula (XXV, R 3 OH) wherein R 3 is as hereinbefore defined in the presence of a base such as lithium diisopropylamide.
  • R 4 represents a lower alkanoyl group, more especially an acetyl group are key intermediates and, as such, they and their preparation as described herein constitute further features of the present invention.
  • the present invention is further illustrated but not limited b the following Examples and Reference Examples.
  • Example 7(i) By proceeding in a similar manner to Example 1(a) but using N-(3,5-dichloropyridin-4-yl)-4-methoxy-3- (phenoxymethyl)benzamide [Example 7(i)] there was prepared N-(3.5-dichloro-l-oxido-4-pvridinio)-4-methoxv-3- ( henoxvmethvl)benzamide. which was recrystallised from acetonitrile as colourless crystals, m.p. 160-161°C. [Elemental analysis:-. C57.40; H,3.82; N,6.68%. Calculated for C20H16CI2N2O4:- C57.30; H,3.85; N,6.68%];
  • Example 7(k) N-(3.5-dichloro-l-oxido-4-pvridinio)-4-methoxv-3-(4- methoxyphenyl)benzamide, which was recrystallised from acetonitrile as a pale cream solid, m.p. 206-208°C. [Elemental analysis:- C57.36; H,3.91; N,7.02%.
  • N-(3,5-Dichloropyridin-4-yl)-4-methoxy-3-(3-methyl-l,2,4- oxadiazol-5-ylmethoxy)benzamide [0.34g, Example 6(b)] was treated with peracetic acid (2.5ml, 32% in dilute acetic acid). The mixture was stirred at ambient temperature for 2.25 hours and then at 60°C for 45 minutes. The reaction mixture was cooled to ambient temperature, then diluted with water (20ml). The pH of the mixture was adjusted to 7 by addition of concentrated aqueous sodium hydroxide solution then solid sodium sulphite was added until the solution was negative to starch iodide paper. This mixture was extracted twice with ethyl acetate (20ml) .
  • Example 7(b) By proceeding in a similar manner to Example 2(a) but using Nr(3,5-dichloropyridin-4-yl)-4-methoxy-3-(2- phenylethoxy)benzamide [Example 7(b)] there was prepared N-(3.5-dichloro-l-oxido-4-pvridinio)-4-methoxv-3-(2- phenylethoxy)benzamide. which was recrystallised from a mixture of acetone and petroleum ether (b.p. 40-60°C) as a cream coloured solid, m.p. 188-194°C. [Elemental analysis:- C58.3; H,4.3; N,6.4%. Calculated:- C58.2; H,4.2; N,6.5%].
  • Example 6(f) there was prepared 3-benzyloxv-N- (3.5-dichloro- l-oxido-4-pyridinio)-4-methoxybenzamide which was recrystallised from acetonitrile as a white solid, m.p. 163- 166°C. [Elemental analysis:- C,55.39; H,3.88; N,6.36%. Calculated for C 2 ⁇ Hi6Cl2 2 ⁇ 3 »H 2 0:- C54.92; H,4.29; N,6.40%].
  • Example 1(d)] there was prepared N-( .5-dichloropvridin-4-vl)- 4-methoxv-3-(2-f4-methvlthiazol-5-vllethoxv)benzamide as a colourless solid, m.p. 188-189°C. [Elemental analysis:- C52.6; H,4.0; N,9.7; S,7.3%. Calculated:- C52.1; H,3.9; N,9.6; S,7.3%].
  • Example 7(1) there was prepared N-(3.5-dichloropy ⁇ idin-4-yl)- 4-methoxy-3-(2-phenylethvnyl)benzamide. which was recrystallised from acetonitrile as a white crystalline solid, m.p. 244-246°C. [Elemental analysis:- C,63.42; H,3.51; N,6.96%. Calculated for C21H- J L4C12N2C-2:- C,63.49; H,3.55; N,7.05%].
  • Example 7(p)] there was prepared N-(3,5-dichloropvridin-4-vl)- 4-methoxv-3-(benzvloxvmethvl)benzamide which was recrystallised from ethyl acetate as colourless crystals, m.p. 142-143°C. [Elemental analysis:- C,60.45; H,4.35; N,6.71%. Calculated for C2iH 18 Cl2N 2 0 3 :- C,60.49; H,4.44; N,6.79%].
  • N-(3.5-dichloropvridin-4-vl)-4-methoxv-3-(3-phenvl-1.2.4- oxadiazol-5-vl)benzamide recrystallised from a mixture of tetrahydrofuran and methanol as a white solid, m.p. 249-251°C.
  • reaction mixture was partially evaporated to remove about 50ml of methanol then the thick suspension was treated with hydrochloric acid to adjust the pH of the mixture to between 1 and 2.
  • the mixture was allowed to stand at ambient temperature for 18 hours, then cooled, then filtered.
  • the solid was dried at 80°C under vacuum affording the title compound (2.19g) as colourless crystals.
  • N-(3.5-pjch ⁇ ?rp- ⁇ - ⁇ >xidp-4-pvridinip)acetamide A stirred mixture of peracetic acid (50ml) and hydrogen peroxide (5ml, 30% w/w solution in water), at 55-60°C, was treated portion-wise with N-(3,5-dichloropyridin-4-yl)acetamide (20.88g, Reference Example 15). The resulting solution was stirred at 55-60°C for a further 2 hours then allowed to cool to room temperature. The reaction mixture was added to ice
  • reaction mixture was stood at room temperature for 3 days then treated with sodium hydride (0.22g), then stirred for 8 hours, then treated with 4-methoxybenzyl triphenyl phosphonium chloride (0.65g) and then stirred for 18 hours.
  • the mixture was evaporated and the residual brown oil was washed with diethyl ether to give the title compound as a rust coloured solid which was used without further purification.
  • the pellet was homogenised in 20mM tris(hydroxymethyl)aminomethane HCl, pH 7.5, 2mM magnesium chloride, l M dithiothreitol, 5mM ethylenediaminetetraacetic acid, 0.25mM sucrose, 20 ⁇ M p-tosyl- 1-lycine-chloromethyl-ketone, lO ⁇ g/ml leupeptin and 2000U/ml aprotinin.
  • PDE activity was determined in macrophage homogenates by the two-step radioisotopic method of Thompson et. al., (Adv. Cyclic Nucl. Res., 10., 69-92, 1979).
  • the reaction mixture contained 20mM tris(hydroxymethyl)aminomethane HCl (pH 8.0), lOmM magnesium chloride, 4mM 2-mercaptoethanol, 0.2mM ethylenebis(oxyethylenenitrilo) etraacetic acid and 0.05mg of bovine serum albumin/ml.
  • the concentration of substrate was l ⁇ M.
  • the IC 5 0 values i.e. concentrations which produced 50% inhibition of substrate hydrolysis) for the compounds examined were determined from concentration-response curves in which concentrations ranged from O.lnM to 0 ⁇ M.
  • Bronchorelaxant activity are measured in in vivo tests in the anaesthetized guinea-pig or rat according to the method described in Underwood et al. (Pul . Pharmacol. 5., 203-212, 1992) in which the effects on bronchospasm induced by histamine (or other spasmogens such as methacholine or leukotriene D4) was determined. Compounds are administered orally 1 hour prior to administration of spasmogen.
  • Rats Male Brown Norway rats weighing 150-250g are sensitized on days 0, 12 and 21 with ovalbumin (lOO ⁇ g, i.p.). Rats are challenged on any one day between days 27-32.
  • Rats 24 hours and 1 hour before antigen challenge rats are dosed orally. Rats are challenged by exposure for 30 minutes to nebulized saline or ovalbumin (1 % in saline). 24 hours after challenge, rats are killed and the airways are lavaged with physiological salt solution. Total and differential cell counts are made.
  • PBMs peripheral blood monocytes
  • Mononuclear cells (monocytes and lymphocytes) were obtained by centrifugation of heparinised whole blood on Histopaque-1077, and resuspending the mononuclear cell fraction in modified Hank's balanced salt solution. Mononuclear cells comprised 70-80% monocytes complemented by lymphocytes.
  • Purified mononuclear cells were spun down (200 g for 10 minutes at 20°C), resuspended at 10 6 PBMs/ml of medium; RPMI 1640 containing l%v/v PCS, 50U/ml penicillin and 50 ⁇ g/ml streptomycin, and plated out in 96 well plates at 2 xlO 5 cells/well. After incubating for 1.5 hours at 37°C in a 5% CO2 incubator the medium (200 ⁇ l) was changed to remove any non-adherent cells. One hour prior to challenge, the medium was changed to that containing compound for test or drug vehicle. Control treatments and compounds for test were assayed in quadruplicate wells.
  • TNF-alpha levels in cell supernatants were quantified using a standard sandwich ELISA technique.
  • ELISA plates (Costar, U.K.) were coated overnight 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 was used as the second antibody and polyclonal goat anti-rabbit IgG horseradish peroxidase (Calbiochem, U.S.A.) at 1/8000 dilution was used as the detection antibody.
  • Color development was measured by absorbance at 450nm using a Titek plate reader.
  • TNF-alpha levels were calculated by interpolation from a standard curve using recombinant human TNF-alpha (British Biotechnology U.K.) (0.125-8ng/ml) . Basal TNF-alpha levels were less than lOOpg/ml whilst LPS stimulation of the PBMs increased TNF-alpha levels to 3-10ng/ml.
  • Rats Male Brown Norway rats weighing 150-250g are sensitized on days 0, 12 and 21 with ovalbumin (lOO ⁇ g, i.p.). Rats are challenged on any one day between days 27-32.
  • Rats 24 hours and 1 hour before antigen challenge rats are dosed orally. Rats are anaesthetized to allow recording of lung function (airway resistance and lung compliance) using respiratory mechanics software. Rats are challenged with ovalbumin i.v. and the peak changes in airway resistance and lung compliance are determined.
  • mice Female Balb/c mice (age 6-8 weeks, weight 20-22g from Charles River, U.K.) in groups of five or more animals were dosed p.o. with compounds suspended in 1% (w/v) carboxymethyl cellulose : 0.2% Tween 80 in PBS then challenged after a minimum period of 30 min with 30 ⁇ g of LPS i.p. After 90 minutes the animals were killed by carbon dioxide asphyxiation and bled by cardiac puncture. Blood was allowed to clot at 4°C, centrifuged (12,000 g for 5 minutes) and serum taken for TNF-alpha analysis.
  • TNF-alpha levels were 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 were calculated from a recombinant murine TNF-alpha standard curve.
  • Purified S. pyo ⁇ enes cell wall is prepared from the cell pellet of a log-phase culture of S. pyo ⁇ enes. group A, strain D-58. The whole bacteria are homogenized by grinding with glass beads and the crude cell wall collected by centrifugation and subsequently washed with 2% SDS in PBS followed by PBS to remove contaminating proteins and nucleic acids. The cell wall is further purified by sonication and differential centrifugation to obtain a purified preparation which pelleted at 100,000 x g. This material is suspended in sterile PBS and the quantity of cell wall determined by measuring the rhamnose content of the preparation (purified cell wall contains 28% rhamnose by weight). The material is filtered through a 0.22 ⁇ m filter and stored at 4°C until used for arthritis induction
  • mice Female Lewis rats weighing 140-160 g are injected intra-articularly into the left or right tibio-tarsal joint on day 0 with purified S. pyo ⁇ enes cell wall (lO ⁇ g in lO ⁇ l sterile saline) .
  • rats receive an intravenous injection of purified cell wall (lOO ⁇ g in 100 ⁇ l sterile saline) via the lateral vein of the tail.
  • Joint diameters are measured with calipers across the lateral and medial malleoli of the previously intra-articularly injected joint immediately prior to the i.v. injection and then daily through day 24. The net joint diameter is determined by subtracting the value for the contralateral joint.
  • Body weights are also measured daily.
  • Compounds or vehicle are administered by oral gavage on days 20-23. Typically, 8-10 animals are used per group. For each dose, the total daily dose is divided into two equal aliquots which are given at approximately 9 a.m. and 3 p.m
  • the value of the compounds of the invention is enhanced by their very low mammalian toxicity levels.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I). dans cette formule générale (I), R1 représente alkyle éventuellement substitué, ou lorsque Z1 représente une liaison directe, R1 peut également représenter hydrogène; R2 représenter un aryle éventuellement substitué, bicycloaryle partiellement saturé, hétéroaryle ou R?aRbN-; R3¿ représente aryle éventuellement substitué ou un groupe hétéroaryle; A1 représente une liaison, alkyléne C¿1-6? éventuellement substitué ou C2-6 alkylène contenant une liaison double, triple ou interrompue par un oxygène, soufre, phénylène, imino, alkylimino, sulfinyle ou sulfonyle; Z?1¿ représente oxygène, soufre ou une liaison; Z2 représente oxygène, soufre ou une liaison; Z3 représente -C C-, -CH¿2?-CZ-, -CZ-CH2-, -CZ-CZ-, CH2-NH-, -CH2-O-, -CH2-S-, CH2-SO-, -CH2-SO2-, -CF2-O-, -CZ-NH-, -NH-CH2-, -O-CH2-, -S-CH2-, -SO-CH2-, -SO2-CH2-, -O-CF2-, -O-CZ, -NH-CZ-, -N=N-, -NH-SO2-, -SO2-NH-, -CZ-CZ-NH-, -NH-CO-O-, -O-CO-NH-, -C(=NOR?c)CH¿2-, -C(F)=N-, -CH(F)-CH2- ou -NH-CO-NH-; Z représente oxygène ou soufre; Ra et Rb représentent indépendamment chacun alkyle ou arylalkyle, et NRaRb forme une amine cyclique à 4-6 membres contenant éventuellement un hétéroatome additionnel sélectionné parmi O, S, NH ou NRc, ou bien est substitué par un groupe oxo; Rc représente alkyle ou arylalkyle; Q?1, Q2 et Q3¿ représentent chacun CH, CX1 ou N, et X1 représente halogène. L'invention concerne également des N-oxydes ces composés, leurs promédicaments, leurs sels pharmaceutiquement admis, et leur solvates (hydrates par exemple). L'invention concerne enfin des procédés de préparation des composés représentés par la formule générale (I), des compositions pharmaceutiques comprenant de tels composés, et leur utilisation thérapeutique comme inhibiteurs du facteur de nécrose tumorale (TNF) et de la phosphodiestérase (PDE) de l'adénosine-monophosphate cyclique de type IV.
PCT/GB1996/001746 1995-07-22 1996-07-22 Composes aromatiques substitues et leur utilisation pharmaceutique WO1997003967A1 (fr)

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