NOVEL COMPOUNDS

Abstract: The invention provides novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.

Description: NOVEL COMPOUNDS The present invention relates to novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy. The P2Xγ receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflamjmatory/ixnmune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-lβ (IL-lβ) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2Xγ receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes. It would be desirable to make compounds effective as P2X receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2Xγ receptor may play a role. In accordance with the present invention, there is therefore provided a compound of general formula wherein X represents an oxygen or sulphur atom or a group NH, CH2, CH2CH2 or OCH2; Y represents a group CH2 or C=O; R represents a pyridyl (especially 3-pyridyl or 4-pyridyl) orpyrimidinyl group; 2 R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or more substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, Ci-C^-alkyl, halo-Cj-Cg-alkyl, Cj-Cg-alkoxy, Ci-Cg-alkylthio, (di)Cι-C6-alkylamino, Ci-Cό-alkylcarbonyl, -Cό-alkoxycarbonyl, Cι-C 6 -alkylsulphinyl, Cι-C 6 -alkylsulphonyl, -NR 3 SO 2 R 4 or -SO 2 NR 5 R 6 group, or a group -Z-(CH2)p-Z-(CH2)q-H wherein each Z independently represents a nitrogen or oxygen atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5; R 3 and R 4 each independently represent a hydrogen atom or a Q-Cg-alkyl group; and R and R each independently represent a hydrogen atom or a Q-Cg-alkyl group, or together with the nitrogen atom to which they are attached form apyrrolidinyl or piperidinyl group; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched and also the alkyl moieties in a dialkylamino substituent group may be the same or different. Furthermore, when X represents a group OCH 2 , the oxygen atom is positioned adjacent the carbonyl group in the ring. 2 The group R preferably represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one, two, three or four substituents independently selected from a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or an amino, cyano, hydroxyl, nitro, Ci-Cg-alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), halo-Ci-Cό-alkyl (e.g. trifluoromethyl), -Cg-alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), Ci-Cζ-alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio),, (di)Cι-C6-alkylamino (e.g. methylamino, dimethylamino, ethylamino or diethylamino), Ci-Cg-alkylcarbonyl (e.g. methyl-, ethyl-, propyl-, butyl-,pentyl- or hexylcarbonyl), -Cό-alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), Ci-Cg-alkylsulphinyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphinyl), Ci-Cg-alkylsulphonyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphonyl), -NR SO2R or -SO2NR R group, or a group -Z-(CH2)p-Z-(CH2)q-H wherein each Z independently represents a nitrogen or oxygen atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5. 2 More preferably R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one, two or three substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, Cι-C 4 -alkyl, halo-Cι-C 4 -alkyl, Cι-C 4 -alkoxy, Cι-C4-alkylthio, (di)C 1-C 4 -alkylam.no, Cι-C4-alkylcarbonyl, Cι-C4-alkoxycarbonyl, -C4-alkylsulphinyl, Cι-C4-alkylsulphonyl, -NR SO2R or -SO2NR 5 R 6 group. 2 Even more preferably, R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or two substituents independently selected from a halogen atom or an amino, cyano, nitro, Cι-C4-alkyl, halo-Cι-C4-alkyl, Cι-C 4 -alkoxy or -SO 2 NR 5 R 6 group. 2 Most preferably, R represents a phenyl or pyridyl group optionally substituted by one or two substituents independently selected from a fluorine or chlorine atom or an amino, cyano, nitro, trifluoromethyl, methoxy or -SO2NR R group. 3 4 Preferably, R and R each independently represent a hydrogen atom or a Cι-C4-alkyl group (e.g. methyl or ethyl group). Preferably, R and R each independently represent a hydrogen atom or a Cι-C4-alkyl group (e.g. methyl or ethyl group), or together with the nitrogen atom to which they are attached form apyrrolidinyl or piperidinyl group, especially apyrrolidinyl group. Preferred compounds of the invention include: (+/-)-(N- [ 1 -(Bipheny l-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N-[l-(3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (+/-)-N-[l-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N-[l-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- [ 1 -(3 ' -Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- [ 1 -(3 ' -Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N-[l-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N-[ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (2R)-N-[l-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[l-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[l-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one, (2R)-N-[l-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-ρyridyl)-2-butyl]-thiazolidin-2,4- dione, (2R)-N-[l-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5- dione, (2R)-N-[l-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (2R)-N- [ 1 -(3 ' -Fluorobiphenyl-4-yloxy)-4-(3-ρyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1 -(3 ' -(Trifluoromethyl)biphenyl-4-y loxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4- dione, (+/-)-N- [ 1 -(2' -Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-dione, (+/-)-N- [ 1 -(3 ' -Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[l,3]-oxazinan-2-one, (2S)-N- [ 1 -(3 ' -Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2S)-N- [ 1 -(3 ' - Aminobiphenyl-4-y loxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (25)-N-[l-(3 , -Melhanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine- 2,4-dione, (2S,3S)-N-[ 1 -(3'-(Pyrrolidine- 1 -sulfonyl)bipheny l-4-yloxy)-4-(3-pyridyl)-3-pentyl]- pyrrolidine-2,5-dione, (2S,3S)-N-[l-(3 , -Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]-pynOlidine-2,5- dione, (2S)-N- [ 1 -(3 ' -Cyano-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4- dione, (+/-)-N- [ 1 -(4' -Fluoro-3 ' -sulf onamidobipheny 1-4-y loxy )-4-(4-pyridy l)-2-butyl] -oxazolidin- 2-one, (+/-)-N- [ 1 -(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [ 1 -(3 ' ,4' -Dichlorobiphenyl-4-yloxy )-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [ 1 -(4-(6-Methoxypyridin-2-y l)-phenoxy )-4-(4-pyridyl)-2-butyl]-piperidin-2,6- dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione, (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one, and (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one. The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises: (a) reacting a compound of general formula wherein L represents a leaving group (e.g. a hydroxyl group) and R 1 and R 2 are as wherein X and Y are as hereinbefore defined except that when X is an oxygen atom or OCH 2 group, then Y is not a CH 2 group; or (b) when X is an oxygen atom and Y is a CH 2 group, reacting a compound of general formula 1 2 wherein R and R are as hereinbefore defined, with 2-chloroethyl chloroformate; or (c) when X is an OCH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, with 3-chloropropanol in the presence of phosgene; or (d) when X is a CH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, with 4-chlorobutyryl chloride; or (e) when X is a CH 2 CH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, with 5-valerylchloride; or (f) when X is an oxygen atom or OCH 2 group, reacting a compound of general formula wherein X represents an oxygen atom or OCH 2 group and Y and R 1 are as hereinbefore defined, with a compound of general formula (VI), R 2 -B(OH) 2 , wherein R 2 is as hereinbefore defined; or (g) when X is an oxygen atom or OCH 2 group, reacting a compound of general formula wherein X represents an oxygen atom or OCH 2 group and Y and R 1 are as hereinbefore defined, with a compound of general formula (VHI), R^-Br, wherein R 2 is as hereinbefore defined; and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I). The processes (a), (b), (c), (d), (e), (f) and (g) may conveniently be carried out in a solvent (e.g. dichloromethane, chloroform, acetonitrile, dioxan or tetrahydrofuran), at a temperature in the range from 0 to 100 °C, preferably in the range from 10 to 80 °C, and especially at ambient temperature (20 °C). The compounds of formula (II) are known from WO 97/20815 and WO 98/42670 or may be prepared by processes analogous to those described in WO 97/20815 and WO 98/42670. The compounds of formula (UI), (VI) and (VD3) are known or commercially available compounds, or may be prepared by processes known in the art. The compounds of formula (IV) may be prepared by methods known in the art starting from the compounds of formula (II). The compounds of formula (V) and (VII) may be prepared by processes analogous to (a), (b) or (c) above using the corresponding bromo- or boron-containing compound of formula (II) or (IN). It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the intermediate compounds may need to be protected by protecting groups. Thus, the final stage in the preparation of the compounds of formula (I) may involve the removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991). The compounds of formula (I) can be converted into further compounds of formula 2 (I) using standard procedures. For example, compounds of formula (I) where R is a 2 nitrophenyl group can be converted to compounds of formula (I) where R is an aminophenyl group by reduction using iron powder and ammonium chloride in ethanol or an ethanol water mixture under reflux conditions. The compounds of formula (I) above may be converted to a pharmaceutically- acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. The compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myocardial ischaemia, cardiac reperfusion damage, cerebral ischaemia, stroke, myoblastic leukaemia, diabetes, Alzheimer's disease, osteoporosis, burn injury, stroke, varicose veins and meningitis. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined to a patient. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The compounds of formula (I) and pharmaceutically-acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically-acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition. Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically-acceptable adjuvant, diluent or carrier. The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. The present invention will be further understood by reference to the following Illustrative examples in which the terms MS, NMR and DMSO denote respectively mass spectrometry, nuclear magnetic resonance and dimethylsulphoxide. Example 1 (+/-)-(N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrroIidine-2,5-dione To a solution of triphenylphosphine (0.16 g) in tetrahydrofuran (2 ml) was added diethyl azodicarboxylate (0.1 ml); a slight exotherm was noted. The resulting orange solution was stirred for 5 minutes before addition of succinimide (0.062 g) and stirring was continued for a further 5 minutes before addition of (±)-l-(biphenyl-4-yloxy)-4-(3-pyridyl)- 2-butanol (0.10 g) prepared as described in Example 25 of WO 97/20815. After stirring for 1.5 hours, the reaction mixture was concentrated under reduced pressure and the residue obtained purified by silica gel chromatography, eluting with ethyl acetate to deliver the title compound as a colourless solid (0.09 g). Melting point: 150-151 °C MS (APCI +ve) 401 (M+H) + *H NMR (DMSO-dό) δ 8.42-8.40 (2H, m), 7.64 -7.55 (5H, m), 7.43 (2H, t), 733-7.28 (2H, m), 6.97 (2H, d), 4.45-4.33 (2H, m), 4.27-4.23 (1H, m), 2.62-2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m) Example 2 (+/-)-N-[l-(3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione Prepared according to the method of Example 1 above with succinimide (0.30 g) and (±)-l-(3'-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.25g) prepared as described in Example 42 of WO 97/20815 to give the title compound as a white solid (0.17 g). Melting point: 92-94 °C MS (El) 430 (M+H) + l U NMR (DMSO-d6) δ 8.42-8.40 (2H, m), 7.61 (1H, m), 7.59 (2H, t), 7.33-7.28 (2H, m), 7.16 (1H, d), 7.12 (1H, t), 6.97 (2H, d), 6.88 (1H, dd), 4.44-4.33 (2H, m), 4.26-4.24 (1H, m), 3.81 (3H, s), 2.62-2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m) Example 3 (+/-)-N-[l-(Biphenyl-4-yIoxy)-4-(3-pyridyI)-2-butyl]-thiazolidine-2,4-dione Prepared according to the method of Example 1 above with (±)-l-(biphenyl-4-yloxy)- 4-(3-ρyridyl)-2-butanol (0.32 g) prepared as described in Example 25 of WO 97/20815 and 2,4-thiazolinedione (0.23 g) to give the title compound as a white solid (0.08 g). Melting point: 125-126 °C MS (FAB) 419 (M+H) + *H ΝMR (DMSO-dό) δ 8.42-8.40 (2H, m), 7.55 -7.49 (5H, m), 7.41 (2H, t), 7.33-7.28 (2H, m), 6.97 (2H, d), 4.76 (IH, m), 4.52 (IH, t), 4.16 (IH, dd), 3.83 (2H, s), 2.73-2.60 (2H, m), 2.55-2.49 (IH, m), 2.15-2.06 (IH, m) Example 4 (+/-)-N-[l-(3'-ChlorobiphenyI-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrroIidine-2,5-dione Prepared according to the method of Example 1 above with (±)-l-(3'-chlorobiphenyl- 4-yloxy)-4-(3-pyridyl)-2-butanol (0.42 g) prepared as described in Example 33 of WO 97/20815 and succinimide (0.24 g) to give the title compound as a white solid (0.21 g). Melting point: 154 °C MS (APCI +ve) 436/438 (M+H) + l H NMR (DMSO-dό) 5 8.47-8.45 (2H, m), 7.53 -7.23 (8H, m), 6.92 (2H, d), 4.63 (IH, m), 4.50 (IH, t), 4.16 (IH, dd), 2.73 (IH, m), 2.62-2.57 (6H, m), 2.11-2.02 (IH, m) Example 5 ( + /.).Λr.[l.(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione Prepared according to the method of Example 1 above with (±)-l-(3'-fluorobiphenyl- 4-yloxy)-4-(3-pyridyl)-2-butanol (0.05 g) prepared as described in Example 43 of WO 97/20815 and succinimide (0.03 g) to give the title compound as a white solid (0.06 g). Melting point: 148 °C MS (APCI +ve) 419 (M+H) + H NMR (DMSO-d6) δ 8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7.38-7.20 (4H, m), 7.01 (IH, m), 6.91 (2H, d), 4.62 (IH, m), 4.50 (IH, t), 4.16 (IH, dd), 2.75-2.47 (2H, m), 2.56 (4H, s), 2.53 (IH, m), 2.11-2.02 (IH, m) Example 6 (+/-)-N-[l-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyI)-2-butyl]-pyrrolidine-2,5-dione a) (+/-)-4-Bromophenyloxymethyloxirane To a solution of 4-bromophenol (17 g) and epichlorohydrin (25 ml) in acetonitrile (50 ml) was added caesium carbonate (24 g) and the resulting suspension was heated at reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue obtained was partitioned between ether and water. An organic phase was separated, washed with brine, dried over magnesium sulphate (MgSQψ) and concentrated under reduced pressure to yield another residue. Distillation of the residue under vacuum gave the sub-title compound as a colourless oil (13 g). Boiling point: 140 °C (oil pump) MS (gems) 228/230 M + b) (+/-)-l-(4-BromophenyIoxy)-4-(4-pyridyI)-2-butanol To a solution of 4-methylpyridine (1.2 g) in tetrahydrofuran (10 ml) cooled to -78 °C was added a hexanes solution of n-butyl lithium (5.8 ml of a 2.5M solution) and the reaction mixture was warmed to 0 °C, whereupon it was added slowly via a cannula to a solution of 4-bromophenyloxymethyloxirane (3.0 g) prepared as described in step a) above in tetrahydrofuran (5 ml) cooled to 0 °C. After stirring for 1.5 hours at ambient temperature, the reaction mixture was firstly quenched by addition of aqueous ammonium chloride solution and secondly extracted with ethyl acetate. An organic phase was then separated, washed with brine, dried over magnesium sulphate (MgSQ ) and concentrated under reduced pressure to yield a residue. Purification of the residue by silica gel chromatography (eluting with 5% methanol in dichloromethane) gave the sub-title compound as a yellow solid (1.8 g). MS (APCI +ve) 322/324 (M+H) + c) (+/-)-l-(3'-MethoxybiphenyI-4-yloxy)-4-(4-pyridyl)-2-butanol A mixture of l-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (1.8g) prepared as described in step b) above, 3-methoxyphenylboronic acid (0.90 g), tetrakis- (triphenylphosphine)palladium(O) (0.16 g), aqueous sodium carbonate (3.5 ml of a 2M solution), ethanol (2 ml) and toluene (7.5 ml) was heated to reflux temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water and an organic phase was separated, washed with brine, dried over magnesium sulphate (MgSO4) and then concentrated under reduced pressure to yield a residue. Purification of the residue by silica gel chromatography (eluting with 5% methanol in dichloromethane) gave the sub- title compound as a white solid ( 1.0 g). Melting point: 74-76 °C MS (APCI +ve) 350 (M+H) + d) (+/-)-N-[l-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- pyrrolidine-2,5-dione Prepared according to the method of Example 1 with (+/-)- 1 -(3 '-methoxybipheny 1-4- yloxy)-4-(4-pyridyl)-2-butanol (0.42 g) prepared as described in step c) above and succinimide (0.30 g) to give the title compound as a white solid (0.15 g). Melting point: 111-113 °C MS (EI) 431 (M+H) + l K NMR (DMSO-d6) δ 8.42 (2H, s), 7.48 (2H, d), 7.34 (IH, t), 7.15 (3H, m), 7.06 (IH, m), 6.88 (2H, d), 6.84 (IH, m), 4.61 (IH, m), 4.47 (IH, t), 4.16 (IH, dd), 3.83 (3H, s), 2.78 (IH, m), 2.61-2.50 (2H, m), 2.46 (4H, s), 2.11-2.02 (IH, m) Example 7 (+/-)-N-[l-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyI]-thiazoIidine-2,4-dione Prepared according to the method of Example 1 above with (+/-)- 1 -(3'- methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0. lOg) prepared as described in Example 6c) above and 2,4-thiazolinedione (0.067 g) to give the title compound as a colourless solid (0.07 g). Melting point: 111-112 °C MS (El) 449 (M+H) + l H NMR (DMSO-d6) δ 8.46 (2H, d), 7.58 (2H, d), 7.34 (IH, t), 7.23 (2H, d), 7.17 (2H, d), 7.12 (IH, d), 6.88 (2H, d), 4.53 (IH, m), 4.44 (IH, t), 4.28 (IH, dd), 4.18 (2H, s), 3.81 (3H, s), 2.62 (2H, t), 2.37-2.24 (IH, m), 2.16-2.06 (IH, m) Example 8 (2R)-N-[l-(3'-Cyanobiphenyl-4-yIoxy)-4-(3-pyridyl)-2-butyI]-thiazolidine-2,4-dione Prepared according to the method of Example 1 above with (2S)-l-(3'- cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.20g) prepared as described in Example 38 of WO 97/20815 and 2,4-thiazolinedione (0.13 g) to give the title compound as a white solid (0.14 g). Melting point: 110-112 °C MS (El) 444 (M+H) + H NMR (DMSO-d<5) δ 8.43 (2H, m), 8.10 (IH, s), 7.97 (IH, d), 7.76 (IH, d), 7.70-7.60 (4H, m), 7.32 (IH, dd), 7.01 (2H, d), 4.56 (IH, m), 4.46 (IH, t), 4.30 (IH, dd), 4.19 (2H, s), 2.65 (2H, t), 2.30 (IH, m), 2.09 (IH, m) Example 9 (2R)-N-[l-(3'-NitrobiphenyI-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione Prepared according to the method of Example 1 above with (2S)-l-(3'-nitrobiphenyl- 4-yloxy)-4-(3-pyridyl)-2-butanol (0.10g) prepared as described in Example 41 of WO 97/20815 and succinimide (0.054 g) to give the title compound as a white solid (0.03 g). Melting point: 115-117 °C MS (El) 446 (M+H) + H NMR (DMSO-d6) δ 8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7.63 (IH, d), 7.32 (IH, ddd), 7.03 (2H, d), 4.42 (2H, m), 4.28 (IH, dd), 2.61 (6H, m), 2.28 (IH, m), 2.07 (lH, m) Example 10 (2R)-N-[l-(3 , -Cyanobiphenyl-4-yIoxy)-4-(3-pyridyl)-2-butyl]-pyrroUdin-2,5-dione Prepared according to the method of Example 1 above with (2S)-l-(3'- cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.15g) prepared as described in Example 38 of WO 97/20815 and succinimide (0.09 g) to give the title compound as a white solid (0.09 g). Melting point: 136-137 °C MS (El) 426 (M+H) + *H NMR (DMSO-d 6 ) δ 8.41 (2H, m), 8.11 (IH, s), 7.97 (IH, d), 7.77 (IH, d), 7.69-7.60 (4H, m), 7.32 (IH, dd), 6.99 (2H, d), 4.39 (2H, m), 4.28 (IH, dd), 2.60 (6H, m), 2.27 (lH, m), 2.02 (lH, m) Example 11 (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4 yridyl)-2^utyl]-tWazoUdin-2,4-dione a) (+/-)-l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) above using l-(4- bromophenyloxy)-4-(4-pyridyl)-2-butanol (3.12 g) as prepared in Example 6b) and 3-nitrophenylboronic acid (2.59 g), to give the sub-title compound as an orange oil (2.20 g). MS (APCI +ve) 365 (M+H) + b) (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4- dione Prepared according to the method of Example 1 above with (+/-)- 1 -(3' -nitrobiphenyl- 4-yloxy)-4-(4-pyridyl)-2-butanol (0.14g) prepared as described in step a) above and 2,4-thiazolinedione (0.09 g) to give the title compound as a pale yellow solid (0.11 g). Melting point: 145-150 °C MS (El) 446 (M+H) + H NMR (DMSO-dό) δ 8.47 (2H, d), 8.38 (IH, s), 8.17 (IH, d), 8.11 (IH, d), 7.75 -7.70 (3H, m), 7.23 (2H, dd), 7.04 (2H, d), 4.60-4.44 (2H, m), 4.31 (IH, dd), 4.19 (2H, s), 2.65 (2H, t), 2.32 (IH, m), 2.09 (IH, m) Example 12 (+/-)-N-tl-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione Prepared according to the method of Example 1 above with (+/-)- 1 -(3' -nitrobiphenyl- 4-yloxy)-4-(4-pyridyl)-2-butanol (0.09 g) prepared as described in Example 11a) and succinimide (0.05 g) to give the title compound as a yellow solid (0.03 g). Melting point: 116-118 °C MS (El) 426 (M+H) + H NMR (DMSO-c ) δ 8.46 (2H, m), 8.38 (IH, s), 8.16 (IH, d), 8.11 (IH, d), 7.75-7.70 (3H, m), 7.22 (2H, d), 7.03 (2H, d), 4.76-4.34 (2H, m), 4.28 (IH, dd), 2.65-2.60 (6H, m), 2.29 (IH, m), 2.08 (IH, m) Example 13 (+/-)-N-[l-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dioιιe a) (+/-)-l-(4'Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) using l-(4-bromophenyloxy)-4- (4-pyridyl)-2-butanol (0.40 g) prepared as described in Example 6b) and 4-fluorophenylboronic acid (0.28 g), to deliver the sub-title compound as a colourless solid (0.23 g). MS (APCI +ve) 338 (M+H) + b) (+/-)-N-[l-(4'Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5- dione Prepared according to the method of Example 1 above with (+/-)- 1 -(4' -fluorobiphenyl-4-yloxy 4-(4-pyridyl)-2-butanol (0.10g) prepared in step a) and succinimide (0.06 g) to give the title compound as a pale yellow solid (0.06 g). Melting point: 113-114 °C MS (El) 419 (M+H) + H NMR (DMSO-d6) δ 8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d), 7.28-7.21 (4H, m), 6.87 (2H, d), 4.45-4.33 (2H, m), 4.26 (IH, m), 2.59 (6H, m), 2.28 (IH, m), 2.08 (IH, m) Example 14 ( + /.).Λr.[l.(4 , .Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyI]-thiazoIidin-2,4-dione Prepared according to the method of Example 1 above with (+/-)- 1 -(4' -fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.12g) prepared as described in Example 13a) and 2,4-thiazolinedione (0.08 g) to give the title compound as a pale grey solid (0.06 g). Melting point: 88-90 °C MS (El) 437 (M+H) + H NMR (DMSO-dό) δ 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7.23 (4H, m), 6.97 (2H, d), 4.50 (IH, m), 4.44 (IH, t), 4.28 (IH, dd), 4.18 (2H, s), 2.65 (2H, t), 2.30 (lH, m), 2.12 (lH, m) Example 15 (+/-)-N-[l-(Biphenyl-4-yIoxy)-4-(3-pyridyI)-2-butyI]-oxazolidine-2-one a) (+/-)-N-[l-(BiphenyI-4-yloxy)-4-(3-pyridyl)-2-butyI]-isoindole-l,3-dione Prepared according to the method described in Example 1 from (±)-l-(biphenyl-4- yloxy)-4-(3-pyridyl)-2-butanol (2.55g) (prepared as described in Example 25 of WO97/20815), triphenylphosphine (3.62g), diethyl azodicarboxylate (2.52ml) and phthalimide (2.36g) in tetrahydrofuran. The residue obtained purified by flash column chromatography, eluting with hexane:ethyl acetate (3:2) gave the sub-title compound as a colourless solid (3.9g). Melting point: 132-133 °C MS (El) 448 (M+H) + H NMR (DMSO-d 6 ) δ 8.40 (IH, d), 8.25 (IH, d), 7.85 (4H, m), 7.62-7.51 (5H, m), 7.41(2H, t), 7.29 (IH, t), 7.23(1H, dd); 6.93 (2H, d), 4.52 (2H, m), 4.38 (IH, dd), 2.70 (2H, t), 2.40 (IH, m), 2.20 (IH, m). b) (±)-l-(Biphenyl-4-yloxy)-4-(3 yridyl)-2-butyIamine (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-l ,3-dione (3.41 g) was dissolved in a solution of 30 % methylamine in methanol (100 ml). The solution was heated to reflux temperature for 3 hours. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate, washed with water, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography over neutral alumina, eluting with 10% methanol in dichloromethane gave the sub-title compound as a cream solid (1.08g). Melting point: 52-53 °C MS (EI) 318 (M+H) + H ΝMR (CDC1 3 ) δ 8.51(1H, d); 8.45(1H, d); 7.56-7.51(5H, m); 7.42(2H, t); 7.32-7.31(lH, m); 7.24-7.22(lH, m); 6.96(2H, d); 4.00-3.96(lH, m); 3.82(1H, t); 3.25-3.15(lH, m); 2.89-2.82(lH, m); 2.78-2.72(lH, m); 1.92-1.88(1H, m); 1.80-1.72(3H, m). c) (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one 2-Chloroethyl chloroformate (0.516ml) was added, drop-wise, to a solution of (±)-l- (biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylamine (0.318g) in acetonitrile (30ml). The solution was stirred for 3 hours at ambient temperature. The solvent was removed under reduced pressure, the residue dissolved in tetrahydrofuran (5ml) and dimethylformamide (lml). Sodium hydride (60% dispersion in mineral oil) (0.12g) was added to the solution. Stirring continued for 1 hour at ambient temperature, water (20ml) was added to the reaction mixture, the product was extracted into ethyl acetate and organic extract dried over magnesium sulphate and concentrated under reduced pressure. Purification by silica gel chromatography eluting with 3% methanol in dichloromethane, then recrystallisation from diethylether gave the title compound as a white solid (0.093g). Melting point: 5S-59 °C MS (FAB) 389 (M+H) + H NMR (CDC1 3 ) δ 8.50-8.49(2H, m); 7.58-7.52(5H, m); 7.42(2H, t); 7.31(1H, t); 7.29-7.23(lH, m); 6.95(2H, d); 4.43-4.26(3H, m); 4.15(2H, d); 3.73-3.60(2H, m); 2.74(2H, t); 2.16-2.03(2H, m). Example 16 (2R)-N-[l-(3'-Cωoro-4^fluorobiphenyl-4-yloxy)^-(3 yridyl)-2-butyl]-thiazolidin- 2,4-dione a) (25)-l-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol Prepared according to the method of Example 1 with (2R)-l-(4-bromophenoxy)-4-(3- pyridyl)-2-butanol (0.214 g) as prepared in Example 40a) of WO 97/20815 and 3-chloro- 4-fluorophenylboronic acid (0.18 g), yielding the sub-title compound as a yellow gum (0.24 g). MS (APCI +ve) 372/374 (M+H) + b) (2R)-N-[l-(3'-Chloro-4'.fluorobiphenyI.4-yIoxy)-4-(3-pyridyl)-2-butyl]- thiazolidin-2,4-dione Prepared according to the method of Example 1 with (2S)-l-(3'-Chloro-4'- fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.14g), prepared from step a) and 2,4-thiazolinedione (0.088 g) to give, after purification by silica gel chromatography (eluting with 80% ethyl acetate in iso-hexane), the title compound as a colourless gum (0.077 g). MS (APCI +ve) 471/473 (M+H) + H NMR (DMSO-dό) δ 8.43-8.40 (2H, m), 7.81 (IH, dd), 7.65 -7.60 (4H, m), 7.46 (IH, t), 7.32 (IH, dd), 6.97 (2H, d), 4.50 (IH, m), 4.45 (IH, t), 4.28 (IH, dd), 4.19 (2H, d), 2.64 (2H, t), 2.39-2.26 (IH, m), 2.18-2.03 (IH, m) Example 17 (2R)-N-[l-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5- dione Prepared according to the method of Example 7 above with (2S)-l-(3'-chloro-4'-fluorobiphenyi-4-yloxy)-4-(4-pyridyl)-2-butanol (0.10g), from Example 16a) and succinimide (0.053 g) to give, after purification by silica gel chromatography (eluting with 50% acetone in iso-hexane), the title compound as a pale brown foam (0.05 g). MS (APCI +ve) 453/455 (M+H) + H NMR (DMSO-d 6 ) δ 8.41 (IH, s), 8.39 (IH, m), 7.81 (IH, dd), 7.65 -7.59 (4H, m), 7.56 (IH, t), 7.32 (IH, dd), 6.97 (2H, d), 4.45-4.32 (2H, m), 4.26 (IH, m), 2.51 (6H, m), 2.25 (lH, m), 2.07 (lH, m) Example 18 (2R)-N-[l-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazoIidin-2,4-dione a) (25)-l-(4-Bromophenoxy)-4-(3-pyridyI)-2-(tert-butyldimethyIsilyloxy)butane A solution of (2S)-4-(3-pyridyl)- 1 ,2-butanediol ( 10 g), prepared according to the method described in Example 26c) of WO 97/20815, and 1,1-carbonyldiimidazole (12 g) in chloroform (250 ml) was stirred at room temperature overnight. The mixture was partly concentrated under reduced pressure then filtered through a pad of silica. Evaporation of the filtrate gave a residue which was dissolved in dimethylformamide (100 ml). 4- Bromophenol (11.6 g) and caesium carbonate (16.6 g) were then added and the mixture heated at reflux temperature for 18 hours. The cooled reaction mixture was acidified with 2M hydrochloric acid and extracted with diethyl ether (x3). The aqueous phase was separated and 2M sodium hydroxide added, until the mixture achieved pH9, and extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a residue. Dimethylformamide (10 ml) was added to the residue followed by imidazole (6 g) andtert- butyldimethylsilyl chloride (8.4 g) and the resulting mixture stirred at room temperature overnight. The reaction mixture was then added to water and extracted twice with 1 : 1 diethyl ether/hexane. The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography eluting with 1 : 1 diethyl ether/hexane delivered the sub-title compound as an oil (13.27 g). MS (APCI +ve) 436/438 (M+H) b) (25)-4-[4-(3-pyridyl)-2-(fert-butyldimethyIsiIyloxy)butoxy]benzeneboronic acid A solution of t-butyllithium (1.7 M in hexanes, 15.0 ml, CAUTION— PYROPHORIC) was added drop-wise to a stirred solution of (2S)-l-(4-bromophenoxy)- -4-(3-pyridyl 2-(tert-butyldimethylsilyloxy)butane (5.0 g) prepared as described in step a) above, and triwopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at -78°C. After the addition was complete the reaction mixture was stirred at -70°C for 1 hour. Water (200 ml) and ethyl acetate (200 ml) were then added. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give an oil. This was purified by silica gel chromatography, eluting with 5:1 ethyl acetate/methanol to yield the sub-title compound as a foam (4.06 g). MS (APCI +ve) 402 (M + H) + c) (25)-l-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol A mixture of (2S)-4-[4-(3-pyridyl 2-(tert-butyldimethylsilyloxy)butoxy]- benzeneboronic acid (0.479 g), prepared as described in step b), 5-bromo-l,3- benzenedicarbonitrile (0.371 g, see Ref. J. Het. Chem. (1994), 31(6), pl417-1420, Registry No. 160892-07-9), tetrakis-(triphenylphosphine)palladium(0) (0.035 g), aqueous sodium carbonate (0.9 ml of a 2M solution), toluene (10 ml), and ethanol (4ml) were heated at 100°C for 2 hours. The reaction mixture was partitioned between diethyl ether and 2N hydrochloric acid and the layers separated. The aqueous phase was neutralised with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in tetrahydrofuran (25ml) and tetrabutylammonium fluoride (0.163 g) was added. After stirring at room temperature overnight the mixture was concentrated under reduced pressure and partitioned between diethyl ether and 2N hydrochloric acid. The layers were separated. The aqueous phase was neutralised with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a residue. Purification by chromatography on silica gel, eluting with 2: 1 dichloromethane/acetone followed by re-crystallisation from ethyl acetateiso- hexane gave the sub-title compound as a white solid. MS (APCI +ve) 370 (M+H) + d) (2R)-N-[l-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazoKdin-2,4- dione Prepared according to the method of Example 1 with (2S)-l-(3',5'-dicyanobiphenyl- 4-yloxy)-4-(3-pyridyl)-2-butanol (0.05 g), prepared in step c) and 2,4-thiazolinedione (0.032 g) to give, after purification by super critical fluid chromatography (eluting with 0% - 45% methanol/liquid carbon dioxide), the title compound as a glass (0.015 g). MS (APCI +ve) 469 (M+H) + H ΝMR (DMSO-dό) δ 8.49 (2H, m), 8.41 (2H, m), 8.36 (IH, s), 7.80 (2H, d), 7.63 (IH, d), 7.32 (IH, dd), 7.03 (2H, m), 4.47 (2H, m), 4.31 (IH, dd), 4.19 (2H, s), 2.65 (2H, t), 2.30 (IH, m), 2.20 (IH, m) Example 19 (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one a) (+/-)-N-2-[l-(4-Bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-l,3-dione Prepared according to the method of Example 15 a) with l-(4-bromophenyloxy)-4-(4- pyridyl)-2-butanol (6.02 g) prepared as described in Example 6b) and phthalimide (5.49 g) to give the sub-title compound as a golden oil (10.13 g). MS (APCI) 451/453 (M+H) + b) (+/-)-N-2-(4-Bromophenoxy)-4-(4 yridyl)-bu ylamine Prepared according to the method of Example 15b) with (+/-)-N-2-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-l,3-dione (9.78 g) to give the sub-title compound as a yellow solid (3.04 g). Melting point 168-169°C MS (APCI) 321/323 (M+H)- c) (+/-)-N-2-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine A mixture of (+/-)-N-2-(4-bromophenoxy)-4-(4-pyridyl)-butylamine (0.5 g) prepared as described in step b) above, 3-nitrophenylboronic acid (0.31 g), tetrakis- (triphenylphosphine)palladium(O) (0.03 g), aqueous sodium carbonate (2M solution, 0.93 ml) and ethanol (2 ml) was heated at reflux for 4 hours. After cooling at room temperature, solvents were removed in vacuo. Dilute hydrochloric acid was then added and the mixture extracted with diethyl ether. The aqueous mixture was made alkaline with some solid sodium bicarbonate, and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over neutral alumina gel eluting with dichloromethane : ethanol (98:2) then ethanol to give the sub-title compound as a yellow oil (0.28 g). MS (APCI) 364 (M+H) + d) (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazoIidin-2-one Prepared according to the method of Example 15c) with 2-chloroethyl chloroformate (0.030 ml). Final product was purified by NPHPLC eluting a gradient of 0-10% of ethanol in dichloromethane to give the title compound as a yellow foam (0.025 g). Melting point: 67-69°C MS (APCI) 434 (M+H) + l H NMR (DMSO-d 6 ) δ 8.46 (2H, dd), 8.39 (IH, t), 8.18-8.09 (2H,m), 7.76-7.70 (3H, m), 7.30 (2H, d), 7.09 (2H, d), 4.32-4.20(2H, m), 4.16 (2H, d), 4.14 (IH, m), 3.63-3.47 (2H, m), 2.72-2.58 (2H, m), 1.95 (2H, q) Example 20 <2«)-NH;i-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione a) (25)-l-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol Prepared according to the method of Example 18c) above using (2S)- 4-[4-(3-pyridyl 2-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic acid (0.30 g), prepared as described in Example 18b) above, and l-bromo-3-fluorobenzene (0.15 ml), to yield the subtitled compound as a colourless oil (0.21 g). MS (APCI +ve) 338 (M+H) + b) (2R)-N-[l-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4- dione Prepared according to the method of Example 1 with (2S)-l-(3'Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.205 g), from step a) and 2,4-thiazolinedione (0.14 g) to give, after purification by normal phase HPLC (eluting with 0% - 10% ethanol in dichloromethane) and re-crystallisation from ethanol, the title compound as a colourless solid (0.032 g). Melting point: 117-118 °C MS (APCI +ve) 437 (M+H) + H NMR (DMSO-d 6 ) δ 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m), 7.33 (IH, dd), 7.13 (IH, m), 6.98 (2H, d), 4.54 (IH, m), 4.45 (IH, t), 4.27 (IH, dd), 4.19 (2H, s), 2.62 (2H, t), 2.30 (lH, m), 2.10 (lH, m) Example 21 ( + /.)-Λr-[l-(3MTrifluoromethyI)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin- 2,4-dione a) (+/-)-l-(3 , -(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) using l-(4-bromophenoxy)-4-(4- pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 3-trifluoromethylphenylboronic acid (0.13 g), to deliver the sub-title compound as a yellow oil (0.18 g). MS (APCI +ve) 388 (M+H) + b) (+/-)-N-[l-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- thiazo!idin-2,4-dione Prepared according to the method of Example 1 with (+/-)- 1 -(3' - trifluoromethylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.175g), from step a) and 2,4-thiazolinedione (0.106 g). Purification of the resulting residue by silica gel chromatography (eluting with 2% methanol in dichloromethane) and super critical fluid chromatography (eluting with 0% - 45% methanol/liquid carbon dioxide) followed by crystallisation from an ethanol/ethyl acetateΛso-hexane mixture, gave the title compound as a colourless solid (0.1 Og). Melting point: 95-96 °C MS (APCI +ve) 487 (M+H) + l H NMR (DMSO-d ) δ 8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m), 7.23 (2H, d), 7.01 (2H, m), 4.56 (IH, m), 4.46 (IH, t), 4.30 (IH, dd), 4.18 (2H, s), 2.65 (2H, t), 2.32 (IH, m), 2.10 (lH, m) Example 22 (+/-)-N-[l-(2'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione a) (+/-)-l-(2'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) using l-(4-bromophenoxy)-4-(4- pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 2-methoxyphenylboronic acid (0.104g), to deliver the sub-title compound as a colourless solid (0.18g). MS (APCI +ve) 350 (M+H) + b) (+/-)-N-[l-(2 , -(Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazoUdin-2,4- dione Prepared according to the method of Example 1 above with (+/-)- 1 -(3'- methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.17g), prepared in step a) above, and 2,4-thiazolinedione (0.114 g). Purification of the resulting residue by silica gel chromatography (eluting with 2% methanol/dichloromethane) and super critical fluid chromatography (eluting with 0% - 45% methanol/liquid carbon dioxide) then crystallisation from an ethanol/ethyl acetateΛso-hexane mixture, gave the title compound as a colourless solid (0.055g). Melting point: 128-130 °C MS (APCI +ve) 487 (M+H) + H NMR (DMSO-d 6 ) δ 8.46 (2H, d), 7.38 (2H, d), 7.33 - 7.22 (4H, m), 7.08 (IH, d), 6.99 (IH, m), 6.91 (2H, d), 4.55 (IH, m), 4.44 (IH, t), 4.26 (IH, dd), 4.18 (2H, s), 3.75 (3H, s), 2.65 (2H, t), 2.31 (IH, m), 2.10 (IH, m) Example 23 (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)^-(4-pyridyl)-2-butyl] iperidin-2,6-dione Prepared according to the method of Example 1 above with (+/-)- 1 -(3 '-nitrobiphenyl- 4-yloxy)-4-(4-pyridyl)-2-butanol (0.25 g) prepared as described in Example 1 la) and glutarimide (0.16 g) to give the title compound as a pale yellow foam (0.11 g). Melting point: 53-55°C MS (APCI) 460 (M+H) + H NMR (DMSO-d6) δ 8.45 (2H, d), 8.38(1H, s), 8.17-8.09 (2H, m), 7.75-7.70 (3H, m), 7.21 (2H, d), 7.02 (2H, d), 5.10-5.00 (IH, m), 4.43-4.29 (2H, m), 2.57 (6H, t), 2.36-2.21 (IH, m), 2.16-2.01 (IH, m), 1.74 (2H, t) Example 24 (+/-)-N-[l-(3'-AminobiphenyI-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazoIidin-2,4-dione A yellow suspension of (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- thiazolidin-2,4-dione (0.377 g) prepared as in Example l ib) above, ammonium chloride (0.17 g) and iron powder (0.18g) in a 1:1 ethanol/ water mixture was heated at reflux temperature for 1.5 hours. The cooled reaction mixture was filtered. The colourless filtrate was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulphate (Na 2 SO ) and concentrated under reduced pressure to yield a residue that was purified by normal phase HPLC (0% - 10% ethanol/dichloromethane) followed by precipitation from an ethanol/ethyl acetate iso-hexane mixture which yielded the title compound as a colourless solid (0.34 g). Melting point: 147-148 °C MS (APCI +ve) 434 (M+H) + H NMR (DMSO-d6) δ 8.46 (2H, d), 7.46 (2H, d), 7.23 (2H, d), 7.05 (IH, t), 6.94 (2H, d), 6.77 (IH, s), 6.71 (lH,d), 6.50 (IH, d), 5.10 (2H, s), 4.54 (IH, m), 4.43 (IH, t), 4.26 (IH, dd), 4.17 (2H, s), 2.62 (2H, t), 2.31 (IH, m), 2.12 (IH, m) Example 25 ( + /.).Λr.[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[l,3]-oxazinan-2-one To a solution of phosgene (1.93 M in toluene, 0.31 ml) in toluene (10 ml) was added (+/-)-N-2-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl) 3Utylamine (0.20 g) from Step 19c) and reaction mixture stirred at room temperature for 2 hours. 3-Chloropropanol (0.09 ml) was then added to the mixture and stirred overnight at room temperature. Solvents were removed under reduced pressure and the residue was redissolved in dimethylformamide (10 ml). This solution was added slowly to a suspension of sodium hydride (60% dispersion in oil, 0.09 g) in dimethylformamide (1 ml). The mixture was heated at 70°C for 9 hours. After cooling to room temperature, solvents were removed under reduced pressure. The residue was made alkaline with aqueous sodium hydroxide (2M) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by ΝPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a yellow oil (0.009 g). MS (APCI) 448 (M+Hf H ΝMR (DMSO-dό) δ 8.46 (2H, dd), 8.39 (IH, t), 8.18-8.09 (2H, m), 7.75-7.70 (3H, m); 7.29 (2H, dd), 7.09 (2H, dd), 4.48-4.33 (IH, m), 4.20-4.12 (4H, m), 3.31-3.21 (2H, m), 2.65 (2H, t), 2.07-1.86 (4H, m) Example 26 (25)-N-[l-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyI]-thiazoIidine-2,4-dione To (2R)-l-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5μmol) prepared according to the method described in Example 37 of WO 97/20815, was added triphenylphosphine (50 μl of a 0.2M solution in tetrahydrofuran) followed by 2,4- thiazolidinedione (50 μl of a 0.2M solution in tetrahydrofuran). Diethyl azodicarboxylate (2μl) was added and the reaction mixture was capped and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylsulphoxide to give the title compound as a lOmM solution in dimethylsulphoxide and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 444 (M+H) + Example 27 (25)-N-[l-(3'-Aπιinobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione Prepared according to Example 26) above from (2R)-l-(3'-aminobiphenyl-4-yloxy)- 4-(3-pyridyl)-2-butanol (5 μmol) prepared according to the method described in Example 50 of WO 97/20815, triphenylphosphine (50 μl of a 0.2M solution in tetrahydrofuran), 2,4- thiazolidinedione (50 μl of a 0.2M solution in tetrahydrofuran) and diethyl azodicarboxylate (2μl) to give the title compound as a lOmM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 434 (M+H) + Example 28 (25)-N-[l-(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2- butyl]thiazolidine-2,4-dione Prepared according to Example 26) above from (2R)-l-(3'- methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5 μmol) prepared according to the method described in Example 98 of WO 97/20815, triphenylphosphine (50 μl of a 0.2M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 μl of a 0.2M solution in tetrahydrofuran) and diethyl azodicarboxylate (2μl) to give the title compound as a lOmM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 512 (M+H) + Example 29 (25,35)-N-[l-(3'-(PyrroUdine-l-suIfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]- pyrrolidine-2,5-dione Prepared according to the method described in Example 26) using (3R,4S)-l-pyridin- 3-yl-4-[3'-(pyrrolidine-l-sulfonyl)biphenyl-4-yl-oxy]pentan-3-ol (6.67 μmol), prepared according to the method of Example 72 of WO 98/42670, triphenylphosphine (50 μl of a 0.27M solution in tetrahydrofuran), succinimide (50 μl of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μl) to give the title compound as a lOmM solution in dimethyl sulphoxide and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 548 (M+H) + Example 30 (25,35)-N-[l-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]- pyrrolidine-2,5-dione Prepared according to the method described in Example 26) using (lS,2R)-4-fluoro- 4'-(2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy)biphenyl-3-carbonitrile (6.67μmol), prepared according to the method of Example 36 of WO 98/42670, triphenylphosphine (50 μl of a 0.27M solution in tetrahydrofuran), succinimide (50 μl of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μl) to give the title compound as a lOmM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate. MS (APCI +ve) 458 (M+H) + Example 31 (25)-N-[l-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine- 2,4-dione Prepared according to the method described in Example 26) using (2R)-l-(3'-cyano- 4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (6.67 μmol), triphenylphosphine (50 μl of a 0.27M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 μl of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μl) to give the title compound as a lOmM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5μm particle size Waters Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate. MS (APCI +ve) 462 (M+H) + Example 32 (+/-)-N-[l-(4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- oxazolidin-2-one a) (+/-)-N-[l-(4-Bromophenoxy)-4-(4-pyridyl)-2-butyl]- oxazolidin-2-one Prepared according to the method described in Example 15c) using (+/-)-N-2-(4- bromophenoxy)-4-(4-pyridyl)-butylamine (Example 19b), 1.08 g), 2-chloroethyl chloroformate (0.521 ml) and sodium hydride (60% dispersion in mineral oil) (0.408 g). After 10 hours at 70°C, water (100 ml) was added and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Residue obtained was purified by column chromatography over silica gel eluting with dichloromethane : ethanol (95: 5) to give the sub-title compound as an oil (0.651 g). MS (APCI +ve) 391/393 (M+H) + L H ΝMR (DMSO-d< $ ) δ 8.46 (2H, dd), 7.44 (2H, dd), 7.28 (2H, dd), 6.92 (2H, dd), 4.29-4.19 (2H, m), 4.07 (2H, d), 4.04-3.96 (IH, m), 3.59-3.41 (2H, m), 2.70-2.56 (2H, m), 1.90 (2H, q). b) (+/-)-[4-(4-Pyridyl)-2-(oxazolidin-2-one-l-yI)butoxy]benzeneboronic acid Prepared according to the method described in Example 18b) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (0.20 g), from step a),tert- butyllithium (1.7 M solution in hexanes, 0.60 ml) and tri-wopropylborate (0.17 ml) to give the sub-title compound as a foam (0.09 g). MS (APCI +ve) 313 (M-B(OH) 2 ) + *H NMR (DMSO-dδ) δ 8.56 (2H, d), 7.82 (2H, d), 7.39 (2H, d), 6.91 (2H, d), 4.25-4.15 (2H, m), 4.07 (2H, d), 4.05-3.94 (IH, m), 3.60-3.46 (2H, m), 2.74-2.62 (2H, m), 1.92 (2H, q). c) (+/-)-N-[l-(4 , -Fluoro-3'-sulfonamidobiphenyI-4-yloxy)-4-(4-pyridyl)-2-butyl]- oxazolidin-2-one Prepared according to the method described in Example 6c) using (+/-)- [4-(4- Pyridyl)-2-(oxazolidin-2-one-l-yl)butoxy]benzeneboronic acid (0.090 g), from step b), 5- bromo-2-fluorophenylsulfonamide (0.097 g) (prepared in Example 35a of WO 98/42670), ethanol (1 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml), tetrakis- (triphenylphosphine)palladium(O) (0.010 g). After work-up, the residue was purified by column chromatography over silica gel eluting with dichloromethane : ethanol (95 : 5) then dichloromethane : ethanol (90 : 10) to give the title compound as a solid (0.034 g). Melting point: 89-91°C MS (APCI +ve) 486 (M+H) + H ΝMR (DMSO-d6) δ 8.46 (2H, d), 7.95 (IH, dd), 7.91-7.86 (IH, m), 7.72 (2H, s), 7.60 (2H, d), 7.48 (IH, t), 7.29 (2H, d), 7.07 (2H, d), 4.29-4.19 (2H, m), 4.14 (2H, d), 4.08-4.00 (IH, m), 3.63-3.47 (2H, m), 2.72-2.60 (2H, m), 1.99-1.90 (2H,m). Example 33 (+/-)-N-[l-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazoIidin-2- one Prepared according to the method described in Example 6c) using (+/-)-[4-(4- Pyridyl)-2-(oxazolidin-2-one-l-yl)butoxy]benzeneboronic acid (Example 32b, 0.100 g), 2- bromo-6-methoxypyridine (J. Org. Chem., 55, (1990), 69-73, 0.079 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis- (triphenylphosphine)palladium(O) (0.010 g). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the tide compound as an oil (0.082 g). MS (APCI +ve) 420 (M+H) + ! H NMR (DMSO-dό) δ 8.46 (2H, dd), 8.04 (2H, d), 7.73(1H, t), 7.48 (IH, d), 7.30 (2H, dd), 7.04 (2H, d), 6.70 (IH, d), 4.29-4.22 (2H, m), 4.15 (2H, d), 4.09-4.02 (IH, m), 3.94 (3H, s), 3.60-3.50 (2H, m), 2.73-2.59 (2H, m), 1.94 (2H, q). Example 34 (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), phenylboronic acid (0.047 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g). After work-up, the residue was purified by ΝPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the tide compound as a solid (0.012 g). Melting point: 116-117°C MS (APCI +ve) 389 (M+H) + ! H NMR (DMSO-dό) δ 8.46 (2H, d), 7.60 (4H, t), 7.43 (2H, t), 7.30 (3H, d), 7.03 (2H, d), 4.31-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 (IH, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q) Example 35 (+/-)-N-[l-(4'-Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazoIidin-2-one Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4-chlorobenzeneboronic acid (0.060 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g). After work-up, the residue was purified by ΝPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.038 g). Melting point: 103-105°C MS (APCI +ve) 423 (M+H) + H ΝMR (DMSO-dό) δ 8.46 (2H, d), 7.62 (4H, q), 7.47 (2H, d), 7.29 (2H, d), 7.03 (2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 (IH, m), 3.62-3.48 (2H, m), 2.70-2.58 (2H, m), 1.94 (2H, q). Example 36 (+/-)-N-[l-(4'-Methylbiphenyl-4-yIoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4-methylbenzeneboronic acid (0.052 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g). After work-up, the residue was purified by ΝPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.033 g). Melting point: 109-110°C MS (APCI +ve) 403 (M+H) + ! H ΝMR (DMSO-dό) δ 8.46 (2H, d), 7.56 (2H, d), 7.50 (2H, d), 7.29 (2H, d), 7.23 (2H, d), 7.01 (2H, d), 4.30-4.20 (2H, m), 4.12 (2H, d), 4.07-4.01 (IH, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q). Example 37 (+/-)-N-[l-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4- methoxybenzeneboronic acid (0.059 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.026 g). Melting point: 114-115°C MS (APCI +ve) 419 (M+H) + H NMR (DMSO-d 6 ) δ 8.46 (2H, d), 7.53 (4H, dd), 7.29 (2H, d), 6.99 (4H, dd), 4.30-4.20 (2H, m), 4.11 (2H, d), 4.06-4.01 (IH, m), 3.32 (3H, s), 3.61-3.48 (2H, m), 2.70-2.59 (2H, m), 1.94 (2H, q). Example 38 (+/-)-N-[l-(3 , ,4'-Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one Prepared according to the method described in Example 6c) using ((+/-)-[4-(4- Pyridyl)-2-(oxazolidin-2-one-l-yl)butoxy]benzeneboronic acid (Example 32b), 0.050 g), 1- bromo-3,4-dichlorobenzene (0.048 g), ethanol (2 ml), aqueous sodium bicarbonate solution (2M, 0.1 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.006 g). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the tide compound as a solid (0.010 g). Melting point: 92-93°C MS (APCI +ve) 457/459/461 (M+H) + H NMR (DMSO-dό) δ 8.46 (2H, d), 7.89 (IH, d), 7.68-7.62 (4H, m), 7.29 (2H, d), 7.04 (2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4.01 (IH, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q). Example 39 (+/-)-N-[l-(4-(6-Methoxypyridin-2-yI)-phenoxy)-4-(4-pyridyI)-2-butyI]-piperidin-2,6- dione a) (+/-)-l-(4-Bromophenoxy)-4-(4-pyridyl)-2-(te/ -butyldimethylsilyloxy)butane tert-Butyldimethylsilyl chloride (20.53 g) andimidazole (9.25 g) were added to a solution of (+/-)- l-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (Example 6b), 14.60g) in dry dichloromethane (500 ml). The solution was stirred overnight at room temperature. The solid was filtered off and the filtrate concentrated under reduced pressure, The residue was purified by chromatography over silica gel eluting with dichloromethane : ethyl acetate (5 : 1) to give the sub-title compound as a solid (19.34 g). Melting point: 73-75°C MS (APCI +ve) 436/438 (M+H) + H NMR (DMSO-dό) δ 8.50 (2H, dd), 7.49 (2H, dd), 7.27 (2H, d), 6.94 (2H, dd), 4.13-4.02 (2H, m), 3.93-3.86 (IH, m), 2.82-2.68 (2H, m), 1.97-1.79 (2H, m), 0.91 (9H, s), 0.12 (3H, s), 0.09 (3H, s). b) (+/-)-4-[4-(4-Pyridyl)-2-(fert-butyldimethylsayloxy)butoxy]benzeneboronic acid Prepared according to the method described in Example 18b) using (+/-)- 1 -(4- bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (lO.Og), from step a), tert-butyllithium (1.7 M solution in hexanes, 27 ml) and tri-wopropylborate (6 ml) in dry tetrahydrofuran (200 ml). After work-up, the residue was purified by column chromatography over silica gel eluting with ethyl acetate : hexane (2 : 1) then ethyl acetate to give the sub-title compound as a foam (4.38 g). MS (APCI +ve) 402 (M+H) + H NMR (DMSO-d6+D 2 O) δ 8.45 (2H, dd), 7.71 (2H, d), 7.24 (2H, q), 6.87 (2H, d), 4.04-3.82 (3H, m), 2.79-2.66 (2H, m), 1.97-1.75 (2H, m), 0.87 (9H, s), 0.14 (3H, s), 0.08 (3H, s). c) (+/-)-4-[4-(4-Pyridyl)-2-butoxy]benzeneboronic acid Dilute hydrochloric acid (2M, 65 ml) was added to (+/-)- l-(4-bromophenoxy)-4-(4- pyridyl)-2-(tert-butyldimethylsilyloxy)butane (4.38 g) from step b) in methanol (200ml). The mixture was stirred for 2 hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The aqueous layer was basified with aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a powder. MS (APCI +ve) 288 (M+H) + l K NMR (DMSO-d6+ D 2 O) δ 8.43 (2H, d), 7.71 (2H, d), 7.31 (2H, d), 6.92 (2H, d), 3.92 (2H, d), 3.84-3.78 (IH, m), 2.87-2.64 (2H, m), 1.89-1.74 (2H, m). d) (+/-)-l-[4-(6-Methoxypyridin-2-yl)phenoxy]-4-(4-pyridyl)-2-butanoI Prepared according to the method described in Example 6c) using (+/-)-4-[4-(4- pyridyl)-2-butoxy]benzeneboronic acid (0.20 g) from step c), 2-bromo-6-methoxypyridine (J. Org. Chem., 55, (1990), 69-73, 0.26 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.7 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.020 g). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the sub-title compound as an oil (0.15 g). MS (APCI +ve) 351 (M+H) + *H NMR (DMSO-dό) δ 8.45 (2H, d), 8.03 (2H, dd), 7.73 (IH, t), 7.47 (IH, d), 7.26 (2H, dd), 7.03 (2H, dd), 6.70 (IH, d), 5.08 (IH, d), 3.95 (2H, d), 3.83-3.78 (IH, m), 3.32 (3H, s), 2.85-2.77 (IH, m), 2.72-2.64 (IH, m), 1.91-1.83 (IH, m), 1.78-1.70 (IH, m) e) (+/-)-N-[l-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]- piperidin-2,6-dione Prepared according to the method of Example 1 using (+/-)- l-[4-(6-methoxypyridin- 2-yl)phenoxy]-4-(4-pyridyl)-2-butanol (0.15 g) from step d), glutarimide (0.1 g), triphenylphosphine (0.22 g) and diethyl azodicarboxylate (0.14 ml). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.10 g). MS (APCI +ve) 446 (M+H) + H NMR (DMSO-dό) δ 8.44 (2H, dd), 8.01 (2H, dd), 7.73 (IH, t), 7.47 (IH, d), 7.21 (2H, dd), 6.97 (2H, d), 6.70 (IH, d), 5.07-5.02 (IH, m), 4.42-4.28 (2H, m), 3.94 (3H, s), 2.62-2.51 (6H, m), 2.35-2.24 (IH, m), 2.12-2.01 (IH, m), 1.78-1.70 (2H, m). Example 40 (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4 yridyl)-2-butyl]-in_ddazoUdine-2,4-dione Prepared according to the method of Example 1 using (+/-)-N-l-(3'-nitrobiphenyl-4- yloxy)-4-(4-pyridyl)-2-butanol (Example 15a), 0.20 g), hydantoin (0.11 g), triphenylphosphine (0.29 g) and diethyl azodicarboxylate (0.17 ml) in dry tetrahydrofuran (10 ml) and dimethylformamide (2 ml). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.03 g). Melting point: 143-145°C MS (APCI +ve) 447 (M+H) + *H NMR (DMSO-d6) δ 8.45 (2H, d), 8.38 (IH, s), 8.17-8.07 (3H, m), 7.74-7.70 (3H, m), 7.24 (2H, d), 7.03 (2H, d), 4.51-4.45 (IH, m), 4.38-4.23 (2H, m), 3.87 (2H, s), 2.69-2.60 (2H, m), 2.38-2.22 (IH, m), 2.16-2.00 (IH, m). Example 41 (+/.).Λt.[l-(3'-Nitrobiphenyl-4-yIoxy)-4-(4-pyridyI)-2-butyl]-piperidin-2-one 5-Chlorovalerylchloride (0.07 ml) was added slowly to a solution of (+/-)N-2-(3'- nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (Example 19c), 0.20 g) in dry dichloromethane (10 ml), in presence of triethylamine (1 ml). The mixture was stirred for 15 minutes at room temperature, then concentrated under reduced pressure. Potassium tert-butoxide solution (1M in tetrathydrofuran, 1.5 ml) was added to the residue redissolved in anhydrous tetrahydrofuran (10 ml). After 30 minutes at room temperature, the mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the tide compound as an oil (0.03 g). MS (APCI +ve) 446 (M+H) + l U NMR (DMSO-dό) δ 8.45 (2H, d), 8.38 (IH, t), 8.18-8.09 (2H, m), 7.75-7.69 (3H, m), 7.26 (2H, d), 7.07 (2H, d), 4.86-4.76 (IH, m), 4.19-4.07 (2H, m), 3.25-3.14 (2H, m), 2.73 (2H, t), 2.28-2.22 (2H, m), 2.00-1.87 (2H, m), 1.64 (4H, bd). Example 42 (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one Prepared according to the method of Example 41 above with (+/-)-N-2-(3'- nitrobiphenyl-4-yloxy)-4-(4-pyridyl) 3utylamine (Example 19c), 0.20 g), triethylamine (1 ml), 4-chlorobutyrylchloride (0.06 ml) and potassium te/t-butoxide solution (1M in tetrathydrofuran, 1.5 ml). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the tide compound as an oil (0.035 g). MS (APCI +ve) 432 (M+H) + H NMR (DMSO-d ) δ 8.45 (2H, dd), 8.38 (IH, t), 8.18-8.09 (2H, m), 7.75-7.69 (3H, m), 7.28 (2H, dd), 7.07 (2H, dd), 4.34-4.27 (IH, m), 4.11 (2H, d), 3.38-3.26 (2H, m), 2.61-2.55 (2H, m), 2.24 (2H, t), 1.97-1.85 (4H, m). Example 43 Pharmacological Analysis Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are known to be agonists of the P2Xγ receptor, effecting the formation of pores in the plasma membrane (Drug Development Research (1996), 37(3). p.126). Consequently, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ediidium bromide is observed. The increase in fluorescence can be used as a measure of P2Xγ receptor activation and therefore to quantify the effect of a compound on die P2Xγ receptor. In this manner, each of the tide compounds of Examples 1 to 42 were tested for antagonist activity at the P2X7 receptor. Thus, the test was performed in 96-well flat bottomed microtitre plates, the wells being filled with 250 μl of test solution comprising 6 -4 200 μl of a suspension of THP-1 cells (2.5 x 10 cells/ml) containing 10 M ethidium bromide, 25 μl of a high potassium buffer solution containing 10 " M bbATP, and 25 μl of the high potassium buffer solution containing 3 x 10 M test compound. The plate was covered with a plastics sheet and incubated at 37 °C for one hour. The plate was then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X receptor agonist) and pyridoxal 5-phosphate (a P2Xγ receptor antagonist) were used separately in the test as controls. From the readings obtained, a PIC5 0 figure was calculated for each test compound, this figure being the negative logarithm of the concentration of test compound necessary to reduce the bbATP agonist activity by 50%. Each of the compounds of Examples 1 to 42 demonstrated antagonist activity, having a PIC50 figure > 4.50.

Claims: C L A I M S 1. A compound of general formula wherein X represents an oxygen or sulphur atom or a group NH, CH2, CH2CH2 or OCH2; Y represents a group CH2 or C=O; R represents a pyridyl or pyrimidinyl group; 2 R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or more substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, Ci-Cg-alkyl, halo-Ci-Cg-alkyl, -Cό-alkoxy, Cι-C6-alkylthio, (di)Cι-C6-alkylamino, Ci-Cό-alkylcarbonyl, -Cό-alkoxycarbonyl, -Cό-alkylsulphinyl, Ci-Cό-alkylsulphonyl, -NR 3 SO 2 R 4 or -SO 2 NR 5 R 6 group, or a group -Z-(CH2)p-Z-(CH2)q-H wherein each Z independently represents a nitrogen or oxygen atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5; R 3 and R 4 each independently represent a hydrogen atom or a Q-Cg-alkyl group; and R and R each independentiy represent a hydrogen atom or a -Cg-alkyl group, or together with the nitrogen atom to which they are attached form apyrrolidinyl or piperidinyl group; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to claim 1 , wherein X represents a sulphur atom or a group CH 2 . 3. A compound according to claim 1 or claim 2, wherein Y represents a group C=O. 4. A compound according to any one of claims 1 to 3, wherein R represents a pyridyl group. 2 5. A compound according to any one of claims 1 to 4, wherein R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one, two or three substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, Cι-C4-alkyl, halo-Cι-C 4 -alkyl, Cι-C4-alkoxy, Cι-C4-alkylthio, (di)Cι-C4-alkylamino, Cι-C 4 -alkylcarbonyl, Cι-C4-alkoxycarbonyl, Cι-C 4 -alkylsulphinyl, Cι-C 4 -alkylsulphonyl, -NR 3 SO 2 R 4 or -SO2NR 5 R 6 group. 2 6. A compound according to any one of claims 1 to 5, wherein R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or two substituents independently selected from a halogen atom or an amino, cyano, nitro, Cι-C -alkyl, halo-Cι-C 4 -alkyl, Cι-C 4 -alkoxy or -SO 2 NR 5 R 6 group. 7. A compound according to claim 1 being: (+/-M-V- [ 1 -(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- (3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- (Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (+/-)-N- (3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- (3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- (3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- (3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N- (3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N- (3'-Nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (2K)-N- (3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N- (3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- (3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyιτolidin-2,5-dione, (+/-)-N- (4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N- (4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- (Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one, (2R)-N- (3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4- dione, (2R)-N-[l-(3'-Chloro-4'-fluorobiρhenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5- dione, (2R)-N- [ 1 -(3 ' ,5 ' -Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (2R)-N-[l-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1 -(3 ' -(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4- dione, (+/-)-N-[l-(2'-Medιoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-dione, (+/-)-N-[l-(3'-Ajτιinobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[l-(3'-Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[l,3]-oxazinan-2-one, (2S)-N-[l-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2S)-N-[l-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-duazolidin-2,4-dione, (2S)-N-[l-(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine- 2,4-dione, (2S,3S)-N-[ 1 -(3'-(PyττoKdine- 1 -sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]- pyrrolidine-2,5-dione, (2S,3S)-N-[l-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]-pyrrolidine-2,5- dione, (2S)-N- [ 1 -(3 ' -Cyano-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4- dione, (+/-)-N- [ 1 -(4' -Fluoro-3 ' -sulfonamidobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin- 2-one, (+/-)-N- [ 1 -(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Med ylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N-[l-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [ 1 -(3 ' ,4' -Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [ 1 -(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6- dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione, (+/-)-N- [ 1 -(3 ' -Νitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one, or (+/-)-N-[l-(3'-NiuObiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one. 8. A process for preparing a compound of formula (I) as defined in claim 1 which comprises (a) reacting a compound of general formula 1 2 wherein L represents a leaving group and R and R are as defined in formula (I), witii a compound of general formula wherein X and Y are as defined in formula (I) except that when X is an oxygen atom or OCH 2 group, then Y is not a CH 2 group; or (b) when X is an oxygen atom and Y is a CH 2 group, reacting a compound of general formula 1 2 wherein R and R are as defined in formula (I), with 2-chloroethyl chloroformate; or (c) when X is an OCH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, with 3-chloropropanol in the presence of phosgene; or (d) when X is a CH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, with 4-chlorobutyryl chloride; or (e) when X is a CH 2 CH 2 group and Y is a CH 2 group, reacting a compound of formula (IV) as defined in (b) above, witii 5-valerylchloride; or (f) when X is an oxygen atom or OCH 2 group, reacting a compound of general formula wherein X represents an oxygen atom or OCH 2 group and Y and R 1 are as defined in formula (I), with a compound of general formula (VI), R 2 -B(OH) 2 , wherein R 2 is as defined in formula (I); or (g) when X is an oxygen atom or OCH group, reacting a compound of general formula wherein X represents an oxygen atom or OCH 2 group and Y and R 1 are as defined in formula (I), with a compound of general formula (VtU), R?-Br, wherein R 2 is as defined in formula (I); ι and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I). 9. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. 10. A process for the preparation of a pharmaceutical composition as claimed in claim 9 which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as defined in any one of claims 1 to 7 with a pharmaceutically- acceptable adjuvant, diluent or carrier. 11. A compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 for use in therapy. 12. Use of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in therapy. 13. A method of effecting immunosuppression which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7.

Inventors: BAXTER ANDREW, CHESHIRE DAVID, CLADINGBOEL DAVID, MCINALLY THOMAS, MORTIMORE MICHAEL, BAXTER, ANDREW, CHESHIRE, DAVID, CLADINGBOEL, DAVID, MCINALLY, THOMAS, MORTIMORE, MICHAEL
Applicants: ASTRA AB, ASTRA PHARMA PROD, BAXTER ANDREW, CHESHIRE DAVID, CLADINGBOEL DAVID, MCINALLY THOMAS, MORTIMORE MICHAEL, ASTRA AKTIEBOLAG, ASTRA PHARMACEUTICALS LTD., BAXTER, ANDREW, CHESHIRE, DAVID, CLADINGBOEL, DAVID, MCINALLY, THOMAS, MORTIMORE, MICHAEL
Application year: 1998
Main classification: C07D405
IPC codes: A61K31, A61P37, A61P43, C07D401, C07D413, C07D417