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AU1791599A - Novel compounds - Google Patents

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Publication number
AU1791599A
AU1791599A AU17915/99A AU1791599A AU1791599A AU 1791599 A AU1791599 A AU 1791599A AU 17915/99 A AU17915/99 A AU 17915/99A AU 1791599 A AU1791599 A AU 1791599A AU 1791599 A AU1791599 A AU 1791599A
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AU
Australia
Prior art keywords
pyridyl
yloxy
butyl
dione
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU17915/99A
Inventor
David Cheshire
David Cladingboel
Thomas Mcinally
Michael Mortimore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
Original Assignee
AstraZeneca UK Ltd
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
Application filed by AstraZeneca UK Ltd filed Critical AstraZeneca UK Ltd
Publication of AU1791599A publication Critical patent/AU1791599A/en
Abandoned legal-status Critical Current

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    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

WO 99/29686 PCT/SE98/02190 1 NOVEL COMPOUNDS The present invention relates to novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical 5 compositions, and their use in therapy. The P2X 7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatoryl/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X 7 receptor by extracellular nucleotides, in particular 10 adenosine triphosphate, leads to the release of interleukin-1 P (IL-1) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X 7 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 7 receptor antagonists for 15is use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X 7 receptor may play a role. In accordance with the present invention, there is therefore provided a compound of general formula O N 0--4 N R 2(i) 20 wherein X represents an oxygen or sulphur atom or a group NH, CH 2 , CH 2
CH
2 or OCH 2 ; Y represents a group CH 2 or C=O;
R
1 represents a pyridyl (especially 3-pyridyl or 4-pyridyl) orpyrimidinyl group;
R
2 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 25 amino, cyano, hydroxyl, nitro, C 1
-C
6 -alkyl, halo-C 1
-C
6 -alkyl, C 1
-C
6 -alkoxy,
C
1
-C
6 -alkylthio, (di)C 1
-C
6 -alkylamino, C 1
-C
6 -alkylcarbonyl, C 1
-C
6 -alkoxycarbonyl,
C
1
-C
6 -alkylsulphinyl, C 1 -C6-alkylsulphonyl, -NR3SO 2
R
4 or -SO 2 NR5 R 6 group, or a WO 99/29686 PCT/SE98/02190 2 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 C 1
-C
6 -alkyl group; and 5 6 R and R each independently represent a hydrogen atom or a C 1
-C
6 -alkyl group, or 5 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. 10 Furthermore, when X represents a group OCH 2 , the oxygen atom is positioned adjacent the carbonyl group in the ring. The group R 2 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, 15 cyano, hydroxyl, nitro, C 1
-C
6 -alkyl (e.g. methyl, ethyl, propyl, butyl,pentyl or hexyl), halo-C 1
-C
6 -alkyl (e.g. trifluoromethyl), C 1
-C
6 -alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C 1
-C
6 -alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-,pentyl or hexylthio),, (di)C 1
-C
6 -alkylamino (e.g. methylamino, dimethylamino, ethylamino or diethylamino), C 1
-C
6 -alkylcarbonyl (e.g. methyl-, ethyl-, propyl-, butyl-,pentyl- or 20 hexylcarbonyl), C 1
-C
6 -alkoxycarbonyl (e.g. methoxy-, ethoxy-,propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C 1
-C
6 -alkylsulphinyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphinyl), C 1
-C
6 -alkylsulphonyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphonyl), -NR3SO 2
R
4 or -SO 2 NR 5R group, or a group
-Z-(CH
2 )p-Z-(CH 2 )q-H wherein each Z independently represents a nitrogen or oxygen 25 atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5. More preferably R 2 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, C 1
-C
4 -alkyl, halo-C 1
-C
4 -alkyl,
CI
1
-C
4 -alkoxy, C 1
-C
4 -alkylthio, (di)C 1
-C
4 -alkylamino, C 1
-C
4 -alkylcarbonyl, WO 99/29686 PCT/SE98/02190 3
C
1
-C
4 -alkoxycarbonyl, Cl-C 4 -alkylsulphinyl, C1-C4-alkylsulphonyl, -NR 3
SO
2
R
4 or
-SO
2
NR
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 5 from a halogen atom or an amino, cyano, nitro, C 1
-C
4 -alkyl, halo-C 1
-C
4 -alkyl,
C
1
-C
4 -alkoxy or -SO 2 NR5R 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 -SO 2 NR5R 6 group. 10 Preferably, R 3 and R 4 each independently represent a hydrogen atom or a
C
1
-C
4 -alkyl group (e.g. methyl or ethyl group). 5 6 Preferably, R and R each independently represent a hydrogen atom or a
C
1
-C
4 -alkyl group (e.g. methyl or ethyl group), or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, especially a pyrrolidinyl group. 15 Preferred compounds of the invention include: (+/-)-(N- [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- [1 -(3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N- [1 -(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (+/-)-N-[1-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, 20 (+/-)-N- [1-(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-[1-(3 '-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, 25 (2R)-N-[1-(3' -Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N- [1 -(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[1 -(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N- [1 -(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N- [1 -(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, 30 (+/-)-N- [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one, WO 99/29686 PCT/SE98/02 190 4 (2R)-N- [1-(3' -Chloro-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4 dione, (2R)-N-[l1-(3'-Chloro-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5 dione, 5 (2R)-N- [1-(3' ,5' -Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [1-(3' -Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (2R)-N- [1-(3' -Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+I-)-N-[ 1-(3' -(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4 dione, 10 (+/-)-N- [1-(2' -Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+I-)-N- [1-(3' -Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-dione, (+/-)-N-[l1-(3' -Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [1-(3' -Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[ 1,3]-oxazinan-2-one, (2S)-N- [1-(3' -Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, 15 (2S)-N- [1-(3' -Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (2S)-N-[1 -(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine 2,4-dione, (2S,3S)-N-[ 1 -(3'-(Pyrrolidine- 1 -sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyll pyrrolidine-2,5-dione, 20 (2S,3S)-N-[ 1 -(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 25 2-one, (+/-)-N- [1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [1-(B iphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [1-(4' -Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [1 -(4' -Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, 30 (+/-)-N-[ 1-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, WO 99/29686 PCT/SE98/02190 5 (+/-)-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'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione, 5 (+/-)-N- [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one, and (+/-)-N- [1-(3'-Nitrobiphenyl-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: 10 (a) reacting a compound of general formula L R1i / O _R2 (LI) R~ 2 wherein L represents a leaving group (e.g. a hydroxyl group) and RI and R 2 are as hereinbefore defined, with a compound of general formula 0O " N H (B) 15is 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
NH
2 R' 1 ' R2 (IV) 20 wherein R 1 and R 2 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 WO 99/29686 PCT/SE98/02190 6 (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 X 0 't; RIO 0 Br (V) 5 wherein X represents an oxygen atom or OCH 2 group and Y and R' 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 O N R 1 IO
-B(OH)
2 (VII) o10 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 (VIII), R 2 -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 15 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). 20 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. SThe compounds of formula (III), (VI) and (VIII) are known or commercially available compounds, or may be prepared by processes known in the art.
WO 99/29686 PCT/SE98/02190 7 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 5 formula (II) or (IV). 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 10 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). 15 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. 20 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 or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt. 25 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 30 pharmacological activity. They are therefore indicated as pharmaceuticals for use in the WO 99/29686 PCT/SE98/02190 8 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, 5 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. 10 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) 15is 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 20 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. 25 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.
WO 99/29686 PCT/SE98/02190 9 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. 5 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 plharmaceutically-acceptable adjuvant, diluent or carrier. The pharmaceutical composition of the invention may be administered topically to (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. s15 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 20 (+/-)-(N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione o o 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 25 continued for a further 5 minutes before addition of (±)- 1-(biphenyl-4-yloxy)-4-(3-pyridyl) 2-butanol (0.10 g) prepared as described in Example 25 of WO 97/20815. After stirring for WO 99/29686 PCT/SE98/02190 10 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). 5 Melting point: 150-151 °C MS (APCI +ve) 401 (M+H) + H NMR (DMSO-d 6 ) 8 8.42-8.40 (2H, m), 7.64 -7.55 (5H, m), 7.43 (2H, t), 7.33-7.28 (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 (lH, m) 10 Example 2 (+/-)-N-[1-(3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione N O Prepared according to the method of Example 1 above with succinimide (0.30 g) and 15 (±)-1-(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 oC MS (EI) 430 (M+H) + 20 1H NMR (DMSO-d 6 ) 8 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) WO 99/29686 PCT/SE98/02190 11 Example 3 (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione O O Prepared according to the method of Example 1 above with (+)-1-(biphenyl-4-yloxy) 5 4-(3-pyridyl)-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) + 10o H NMR (DMSO-d 6 ) 8 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 (1H, m), 4.52 (1H, t), 4.16 (1H, dd), 3.83 (2H, s), 2.73-2.60 (2H, m), 2.55-2.49 (1H, m), 2.15-2.06 (1H, m) Example 4 15is (+/-)-N-[1-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione o O NN CI \ / CI Prepared according to the method of Example 1 above with (±)-1-(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 20 (0.21 g). Melting point: 154 oC WO 99/29686 PCT/SE98/02190 12 MS (APCI +ve) 436/438 (M+H) + H NMR (DMSO-d 6 ) 8 8.47-8.45 (2H, m), 7.53 -7.23 (8H, m), 6.92 (2H, d), 4.63 (1H, m), 4.50 (1H, t), 4.16 (1H, dd), 2.73 (1H, m), 2.62-2.57 (6H, m), 2.11-2.02 (1H, m) 5 Example 5 (+/-)-N-[1-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione N o X / F Prepared according to the method of Example 1 above with (±)-1-(3'-fluorobiphenyl 4-yloxy)-4-(3-pyridyl)-2-butanol (0.05 g) prepared as described in Example 43 of 10 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) 15 1H NMR (DMSO-d 6 ) 8 8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7.38-7.20 (4H, m), 7.01 (1H, m), 6.91 (2H, d), 4.62 (1H, m), 4.50 (1H, t), 4.16 (1H, dd), 2.75-2.47 (2H, m), 2.56 (4H, s), 2.53 (1H, m), 2.11-2.02 (1H, m) WO 99/29686 PCT/SE98/02190 13 Example 6 (+/-)-N-[1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-dione N a) (+/-)-4-Bromophenyloxymethyloxirane 5 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 (MgSO 4 ) and concentrated io 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 oC (oil pump) MS (gems) 228/230 M 15 b) (+/-)-1-(4-Bromophenyloxy)-4-(4-pyridyl)-2-butanol To a solution of 4-methylpyridine (1.2 g) in tetrahydrofuran (10 ml) cooled to -78 oC 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 20 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 (MgSO4) and concentrated 25 under reduced pressure to yield a residue. Purification of the residue by silica gel WO 99/29686 PCT/SE98/02190 14 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)
+ 5 c) (+/-)-1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol A mixture of 1-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (1.8 g) prepared as described in step b) above, 3-methoxyphenylboronic acid (0.90 g), tetrakis (triphenylphosphine)palladium(0) (0.16 g), aqueous sodium carbonate (3.5 ml of a 2M o10 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 (MgSO 4 ) 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 15is title compound as a white solid (1.0 g). Melting point: 74-76 oC MS (APCI +ve) 350 (M+H) 20 d) (+/-)-N-[1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl] pyrrolidine-2,5-dione Prepared according to the method of Example 1 with (+/-)- 1-(3'-methoxybiphenyl-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). 25 Melting point: 111-113 'C MS (EI) 431 (M+H) + 1H NMR (DMSO-d6) 8 8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H, min), 7.06 (1H, min), 6.88 (2H, d), 6.84 (1H, min), 4.61 (IH, min), 4.47 (1H, t), 4.16 (1H, dd), 30 3.83 (3H, s), 2.78 (1H, min), 2.61-2.50 (2H, min), 2.46 (4H, s), 2.11-2.02 (1H, m) WO 99/29686 PCT/SE98/02190 15 Example 7 (+/-)-N-[1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-dione Prepared according to the method of Example 1 above with (+/-)-1-(3' 5 methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.10 g) 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 oC 10 MS (EI) 449 (M+H) + H NMR (DMSO-d 6 ) 5 8.46 (2H, d), 7.58 (2H, d), 7.34 (1H, t), 7.23 (2H, d), 7.17 (2H, d), 7.12 (1H, d), 6.88 (2H, d), 4.53 (1H, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s), 3.81 (3H, s), 2.62 (2H, t), 2.37-2.24 (1H, m), 2.16-2.06 (1H, m) 15 Example 8 (2R)-N-[1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione O O CN NoO Prepared according to the method of Example 1 above with (2S)-1-(3' cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.20g) prepared as described in Example 20 38 of WO 97/20815 and 2,4-thiazolinedione (0.13 g) to give the title compound as a white solid (0.14 g).
WO 99/29686 PCT/SE98/02190 16 Melting point: 110-112 'C MS (EI) 444 (M+H) + H NMR (DMSO-d 6 ) 8 8.43 (2H, m), 8.10 (1H, s), 7.97 (1H, d), 7.76 (1H, d), 7.70-7.60 (4H, m), 7.32 (1H, dd), 7.01 (2H, d), 4.56 (1H, m), 4.46 (1H, t), 4.30 (1H, dd), 5 4.19 (2H, s), 2.65 (2H, t), 2.30 (1H, m), 2.09 (1H, m) Example 9 (2R)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione O O N- \ / NO 2 N-- O N02 0 Prepared according to the method of Example 1 above with (2S)-1-(3'-nitrobiphenyl 4-yloxy)-4-(3-pyridyl)-2-butanol (0.10 g) 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). 15is Melting point: 115-117 'C MS (EI) 446 (M+H) 1H NMR (DMSO-d 6 ) 8 8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7.63 (1H, d), 7.32 (1H, ddd), 7.03 (2H, d), 4.42 (2H, m), 4.28 (1H, dd), 2.61 (6H, m), 2.28 (1H, m), 2.07 (1H, m) 20 WO 99/29686 PCT/SE98/02190 17 Example 10 (2R)-N-[1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione 0 2w N O \1/ CN Prepared according to the method of Example 1 above with (2S)-1-(3' 5 cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.15 g) 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 10 MS (EI) 426 (M+H) + 1H NMR (DMSO-d 6 ) 8 8.41 (2H, m), 8.11 (1H, s), 7.97 (1H, d), 7.77 (1H, d), 7.69-7.60 (4H, m), 7.32 (1H, dd), 6.99 (2H, d), 4.39 (2H, m), 4.28 (1H, dd), 2.60 (6H, m), 2.27 (1H, m), 2.02 (1H, m) 15 Example 11 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione O O ONo 2 a) (+/-)-1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) above using 1-(4 20 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).
WO 99/29686 PCT/SE98/02190 18 MS (APCI +ve) 365 (M+H) + b) (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4 dione 5 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 10 MS (EI) 446 (M+H) + 1H NMR (DMSO-d 6 ) 8 8.47 (2H, d), 8.38 (1H, s), 8.17 (1H, d), 8.11 (1H, d), 7.75 -7.70 (3H, m), 7.23 (2H, dd), 7.04 (2H, d), 4.60-4.44 (2H, m), 4.31 (1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.32 (1H, m), 2.09 (1H, m) 15 Example 12 (+/-)-N- 1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione No
\/NO
2 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 11 a) and 20 succinimide (0.05 g) to give the title compound as a yellow solid (0.03 g). Melting point: 116-118 oC MS (EI) 426 (M+H) + 1H NMR (DMSO-d6) 8 8.46 (2H, m), 8.38 (1H, s), 8.16 (1H, d), 8.11 (1H, d), 25 7.75-7.70 (3H, m), 7.22 (2H, d), 7.03 (2H, d), 4.76-4.34 (2H, m), 4.28 (1H, dd), 2.65-2.60 (6H, m), 2.29 (1H, m), 2.08 (1H, m) WO 99/29686 PCT/SE98/02190 19 Example 13 (+/-)-N-[1-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione o o - \/F a) (+/-)-1-(4'Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol 5 Prepared according to the method of Example 6c) using 1-(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) 10 b) (+/-)-N-[1-(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 (0.10 g) prepared in 15 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 (EI) 419 (M+H) + 1H NMR (DMSO-d 6 ) 8 8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d), 7.28-7.21 (4H, m), 20 6.87 (2H, d), 4.45-4.33 (2H, m), 4.26 (1H, m), 2.59 (6H, m), 2.28 (1H, m), 2.08 (1H, m) WO 99/29686 PCT/SE98/02190 20 Example 14 (+/-)-N-[1-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione - \/ ON" Prepared according to the method of Example 1 above with 5 (+/-)- 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 oC 10 MS (EI) 437 (M+H) + H NMR (DMSO-d 6 ) 8 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7.23 (4H, m), 6.97 (2H, d),.-4.50 (lH, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s), 2.65 (2H, t), 2.30 (1H, m), 2.12 (1H, m) 15 Example 15 (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2.-one OO ON N a) (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-1,3.-dione Prepared according to the method described in Example 1 from (±)-1-(biphenyl-4 20 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 WO 99/29686 PCT/SE98/02190 21 chromatography, eluting with hexane:ethyl acetate (3:2) gave the sub-title compound as a colourless solid (3.9g). Melting point: 132-133 °C s MS (EI) 448 (M+H) 1H NMR (DMSO-d 6 ) 8 8.40 (1H, d), 8.25 (1H, d), 7.85 (4H, m), 7.62-7.51 (5H, m), 7.41(2H, t), 7.29 (1H, t), 7.23(1H, dd); 6.93 (2H, d), 4.52 (2H, min), 4.38 (1H, dd), 2.70 (2H, t), 2.40 (1H, m), 2.20 (1H, m). 10 b) (±)-1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylamine (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-1,3-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 15 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 20 MS (EI) 318 (M+H) + 1 H NMR (CDCl 3 ) 8 8.51(1H, d); 8.45(1H, d); 7.56-7.51(5H, m); 7.42(2H, t); 7.32-7.31(1H, m); 7.24-7.22(1H, m); 6.96(2H, d); 4.00-3.96(1H, m); 3.82(1H, t); 3.25-3.15(1H, m); 2.89-2.82(1H, min); 2.78-2.72(1H, m); 1.92-1.88(1H, m); 1.80-1.72(3H, m). 25 c) (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one 2-Chloroethyl chloroformate (0.516ml) was added, drop-wise, to a solution of (±)-1 (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 30 reduced pressure, the residue dissolved in tetrahydrofuran (5ml) and dimethylformamide WO 99/29686 PCT/SE98/02190 22 (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 5 chromatography eluting with 3% methanol in dichloromethane, then recrystallisation from diethylether gave the title compound as a white solid (0.093g). Melting point: 58-59 'C MS (FAB) 389 (M+H) + 10 1H NMR (CDC1 3 ) 8 8.50-8.49(2H, m); 7.58-7.52(5H, m); 7.42(2H, t); 7.31(1H, t); 7.29-7.23(1H, 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 15 (2R)-N-[1-(3'-Chloro-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin 2,4-dione Cl Chiral / F a) (2S)-1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol Prepared according to the method of Example 1 with (2R)-1-(4-bromophenoxy)-4-(3 20 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)
+ 25 WO 99/29686 PCT/SE98/02190 23 b) (2R)-N-[1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl] thiazolidin-2,4-dione Prepared according to the method of Example 1 with (2S)-1-(3'-Chloro-4' fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.14g), prepared from step a) and 5 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) 10 NMR (DMSO-d 6 ) 8 8.43-8.40 (2H, min), 7.81 (1H, dd), 7.65 -7.60 (4H, min), 7.46 (1H, t), 7.32 (1H, dd), 6.97 (2H, d), 4.50 (1H, m), 4.45 (1H, t), 4.28 (1H, dd), 4.19 (2H, d), 2.64 (2H, t), 2.39-2.26 (1H, m), 2.18-2.03 (1H, m) Example 17 15 (2R)-N-[1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5 dione FChiral O CI -0 Prepared according to the method of Example 7 above with (2S)- 1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.10g), from 20 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)
+ 25 H NMR (DMSO-d 6 ) 8 8.41 (1H, s), 8.39 (1H, m), 7.81 (1H, dd), 7.65 -7.59 (4H, m), 7.56 (111, t), 7.32 (1H, dd), 6.97 (2H, d), 4.45-4.32 (2H, m), 4.26 (1H, m), 2.51 (6H, m), 2.25 (1H, m), 2.07 (1H, m) WO 99/29686 PCT/SE98/02190 24 Example 18 (2R)-N-[1-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione S Chiral 0 ON N N a) (2S)-1l-(4-Bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane 5 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 10 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 5is 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) and tert 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 20 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) WO 99/29686 PCT/SE98/02190 25 b) (2S)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)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)-1-(4-bromophenoxy) -4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (5.0 g) prepared as described in step a) 5 above, and triisopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at -78 0 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 10 ethyl acetate/methanol to yield the sub-title compound as a foam (4.06 g). MS (APCI +ve) 402 (M + H) c) (2S)-1-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol A mixture of (2S)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy] 15 benzeneboronic acid (0.479 g), prepared as described in step b), 5-bromo-1,3 benzenedicarbonitrile (0.371 g, see Ref. J. Het. Chem. (1994), 31(6), p1417-1420, 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 0 C for 2 hours. The reaction mixture was partitioned between diethyl ether and 2N 20 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 25 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 WO 99/29686 PCT/SE98/02190 26 with 2:1 dichloromethane/acetone followed by re-crystallisation from ethyl acetateAso hexane gave the sub-title compound as a white solid. MS (APCI +ve) 370 (M+H) + 5 d) (2R)-N-[1-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4 dione Prepared according to the method of Example 1 with (2S)-1-(3',5'-dicyanobiphenyl 4-yloxy)-4-(3-pyridyl)-2-butanol (0.05 g), prepared in step c) and 2,4-thiazolinedione 10 (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) + 1H NMR (DMSO-d 6 ) 8 8.49 (2H, m), 8.41 (2H, m), 8.36 (1H, s), 7.80 (2H, d), 15is 7.63 (1H, d), 7.32 (1H, dd), 7.03 (2H, m), 4.47 (2H, m), 4.31 (1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.30 (1H, m), 2.20 (1H, m) Example 19 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one 0O 0 20 O a) (+/-)-N-2-[1-(4-Bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-dione Prepared according to the method of Example 15a) with 1-(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).
WO 99/29686 PCT/SE98/02190 27 MS (APCI) 451/453 (M+H) + b) (+/-)-N-2-(4-Bromophenoxy)-4-(4-pyridyl)-butylamine Prepared according to the method of Example 15b) with (+/-)-N-2-[1-(4 5 bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-dione (9.78 g) to give the sub-title compound as a yellow solid (3.04 g). Melting point: 168-169 0 C MS (APCI) 321/323 (M+H) 10 c) (+/-)-N-2-(3'-Nitrobiphenyl-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(0) (0.03 g), aqueous sodium carbonate (2M solution, 0.93 5is 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. 20 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) + 25 d) (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-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). 30 WO 99/29686 PCT/SE98/02190 28 Melting point: 67-69 0 C MS (APCI) 434 (M+H) + 1 H NMR (DMSO-d 6 ) 8 8.46 (2H, dd), 8.39 (1H, 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 (1H, m), 3.63-3.47 5 (2H, m), 2.72-2.58 (2H, m), 1.95 (2H, q) Example 20 (2R)-N41-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione O S Chiral 0 o10 a) (2S)-1-(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 1-bromo-3-fluorobenzene (0.15 ml), to yield the subtitled compound as a colourless oil (0.21 g). 15 MS (APCI +ve) 338 (M+H) + b) (2R)-N-[1-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4 dione 20 Prepared according to the method of Example 1 with (2S)-1-(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). 25 WO 99/29686 PCT/SE98/02190 29 Melting point: 117-118 oC MS (APCI +ve) 437 (M+H) + H NMR (DMSO-d 6 ) 8 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m), 7.33 (1H, dd), 7.13 (1H, m), 6.98 (2H, d), 4.54 (1H, min), 4.45 (1H, t), 4.27 (1H, dd), 4.19 (2H, s), 2.62 (2H, t), 5 2.30 (1H, min), 2.10 (1H, m) Example 21 (+/-)-N-[1-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin 2,4-dione O No_ 0 ,I - F FF 10 a) (+/-)-1-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) using 1-(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 15is oil (0.18 g). MS (APCI +ve) 388 (M+H) + b) (+/-)-N-[1-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl] thiazolidin-2,4-dione 20 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 WO 99/29686 PCT/SE98/02190 30 crystallisation from an ethanol/ethyl acetateAiso-hexane mixture, gave the title compound as a colourless solid (0.10g). Melting point: 95-96 'C 5 MS (APCI +ve) 487 (M+H) + H NMR (DMSO-d 6 ) 5 8.46 (2H, min), 7.92 (2H, min), 7.67 (4H, m), 7.23 (2H, d), 7.01 (2H, m), 4.56 (1H, min), 4.46 (1H, t), 4.30 (1H, dd), 4.18 (2H, s), 2.65 (2H, t), 2.32 (1H, min), 2.10 (lII, m) 10 Example 22 (+/-)-N-[l-(2'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione O 0 0 a) (+/-)-1-(2'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol Prepared according to the method of Example 6c) using 1-(4-bromophenoxy)-4-(4 15 pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 2-methoxyphenylboronic acid (0.104 g), to deliver the sub-title compound as a colourless solid (0.18g). MS (APCI +ve) 350 (M+H) + 20 b) (+/-)-N-[1-(2'-(Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4 dione Prepared according to the method of Example 1 above with (+/-)-l-(3' methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.17 g), prepared in step a) above, and 25 2,4-thiazolinedione (0.114 g). Purification of the resulting residue by silica gel WO 99/29686 PCT/SE98/02190 31 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 acetateAiso-hexane mixture, gave the title compound as a colourless solid (0.055g). 5 Melting point: 128-130 oC MS (APCI +ve) 487 (M+H) + H NMR (DMSO-d 6 ) 5 8.46 (2H, d), 7.38 (2H, d), 7.33 - 7.22 (4H, m), 7.08 (1H, d), 6.99 (1H, m), 6.91 (2H, d), 4.55 (1H, m), 4.44 (1H, t), 4.26 (1H, dd), 4.18 (2H, s), 3.75 (3H, s), 10to 2.65 (2H, t), 2.31 (1H, m), 2.10 (1H, m) Example 23 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-dione N N~ 0 0. .N 6 s15 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 11 a) and glutarimide (0.16 g) to give the title compound as a pale yellow foam (0.11 g). Melting point: 53-55 0 C 20 MS (APCI) 460 (M+H) + H NMR (DMSO-d 6 ) 8 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 (1H, m), 4.43-4.29 (2H, m), 2.57 (6H, t), 2.36-2.21 (1H, m), 2.16-2.01 (1H, m), 1.74 (2H, t) WO 99/29686 PCT/SE98/02190 32 Example 24 (+/-)-N-[1-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione NIV or s, N' S 1 NH 2 A yellow suspension of (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl] 5 thiazolidin-2,4-dione (0.377 g) prepared as in Example 1 lb) 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 10 (Na 2
SO
4 ) 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 acetateliso-hexane mixture which yielded the title compound as a colourless solid (0.34 g). is Melting point: 147-148 °C MS (APCI +ve) 434 (M+H) 1H NMR (DMSO-d6) 8 8.46 (2H, d), 7.46 (2H, d), 7.23 (2H, d), 7.05 (1H, t), 6.94 (2H, d), 6.77 (1H, s), 6.71 (1H,d), 6.50 (1H, d), 5.10 (2H, s), 4.54 (1H, m), 4.43 (1H, t), 4.26 (1H, dd), 4.17 (2H, s), 2.62 (2H, t), 2.31 (1H, m), 2.12 (1H, m) 20 WO 99/29686 PCT/SE98/02190 33 Example 25 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl-[1,3]-oxazinan-2-one 0 00 NO To a solution of phosgene (1.93 M in toluene, 0.31 ml) in toluene (10 ml) was added s (+/-)-N-2-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (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% 10 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 5is NPHPLC 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+H) 1H NMR (DMSO-d 6 ) 8 8.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H, m), 7.75-7.70 (3H, m); 20 7.29 (2H, dd), 7.09 (2H, dd), 4.48-4.33 (1H, m), 4.20-4.12 (4H, m), 3.31-3.21 (2H, m), 2.65 (2H, t), 2.07-1.86 (4H, m) WO 99/29686 PCT/SE98/02190 34 Example 26 (2S)-N-[1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione O'N N o CN o o To (2R)-l1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5pmol) prepared 5 according to the method described in Example 37 of WO 97/20815, was added triphenylphosphine (50 l of a 0.2M solution in tetrahydrofuran) followed by 2,4 thiazolidinedione (50 [l of a 0.2M solution in tetrahydrofuran). Diethyl azodicarboxylate (2pl) 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 10 residue was dissolved in dimethylsulphoxide to give the title compound as a 10mM solution in dimethylsulphoxide and analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 444 (M+H) + 15 Example 27 (2S)-N-[1-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione O N - 0
NH
2 Prepared according to Example 26) above from (2R)-1-(3'-aminobiphenyl-4-yloxy) 20 4-(3-pyridyl)-2-butanol (5 pmol) prepared according to the method described in Example 50 of WO 97/20815, triphenylphosphine (50 l of a 0.2M solution in tetrahydrofuran), 2,4 thiazolidinedione (50 l of a 0.2M solution in tetrahydrofuran) and diethyl azodicarboxylate (2pl) to give the title compound as a 10mM solution in DMSO and WO 99/29686 PCT/SE98/02190 35 analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 434 (M+H) + 5 Example 28 (2S)-N-[1-(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2 butyl]thiazolidine-2,4-dione O0 0 H N~ 10 Prepared according to Example 26) above from (2R)-1-(3 methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5pmol) prepared according to the method described in Example 98 of WO 97/20815, triphenylphosphine (50 p1 of a 0.2M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 ll of a 0.2M solution in tetrahydrofuran) and diethyl azodicarboxylate (2pl) to give the title compound. 15 as a 10mM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 512 (M+H)
+
WO 99/29686 PCT/SE98/02190 36 Example 29 (2S,3S)-N-[1-(3'-(Pyrrolidine--sulfonyl)biphenyl-4-y loxy)-4-(3-pyridyl)-3-pentyl] pyrrolidine-2,5-dione 10 ooo 5 Prepared according to the method described in Example 26) using (3R,4S)-1-pyridin 3-yl-4-[3'-(pyrrolidine- 1-sulfonyl)biphenyl-4-yl-oxy]pentan-3-ol (6.67pmol), prepared according to the method of Example 72 of WO 98/42670, triphenylphosphine (50 p1 of a 0.27M solution in tetrahydrofuran), succinimide (50 pl of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 pl) to give the title compound as a 10mM 10 solution in dimethyl sulphoxide and analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate solution. MS (APCI +ve) 548 (M+H) + 15 Example 30 (2S,3S)-N-[1-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl] pyrrolidine-2,5-dione F N O ON NC N 0 o~o Prepared according to the method described in Example 26) using (1S,2R)-4-fluoro 20 4'-(2-hydroxy- 1-methyl-4-pyridin-3-ylbutoxy)biphenyl-3-carbonitrile (6.67pmol), prepared according to the method of Example 36 of WO 98/42670, triphenylphosphine (50 pl of a 0.27M solution in tetrahydrofuran), succinimide (50 pl of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 pl) to give the title compound as a 10mM WO 99/29686 PCT/SE98/02190 37 solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate. MS (APCI +ve) 458 (M+H) + 5 Example 31 (2S)-N-[1-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine 2,4-dione OO XoN-o 1o Prepared according to the method described in Example 26) using (2R)-1-(3'-cyano 4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (6.67npmol), triphenylphosphine (50 pl of a 0.27M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 p1 of a 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 pl) to give the title compound as a 10mM solution in DMSO and analysed by HPLC on a 50mm x 3.9mm, 5pm particle size Waters 15is Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate. MS (APCI +ve) 462 (M+H) WO 99/29686 PCT/SE98/02190 38 Example 32 (+/-)-N-[1-(4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl] oxazolidin-2-one VN 0 N 5 a) (+/-)-N-[1-(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 10 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). 15 MS (APCI +ve) 391/393 (M+H) 1H NMR (DMSO-d 6 ) 8 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 (1H, m), 3.59-3.41 (2H, m), 2.70-2.56 (2H, m), 1.90 (2H, q). 20 b) (+/-)-[4-(4-Pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy]benzeneboronic acid Prepared according to the method described in Example 18b) using (+/-)-N-[1-(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-isopropylborate (0.17 ml) to give the sub-title compound as a foam (0.09 g). 25 MS (APCI +ve) 313 (M-B(OH) 2
)
+
WO 99/29686 PCT/SE98/02190 39 H NMR (DMSO-d 6 ) 8 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 (1H, min), 3.60-3.46 (2H, m), 2.74-2.62 (2H, m), 1.92 (2H, q). 5 c) (+/-)-N-[1-(4'-Fluoro-3'-sulfonamidobiphenyl-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-1-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), 10 ethanol (1 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml), tetrakis (triphenylphosphine)palladium(0) (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). 15 Melting point: 89-91°C MS (APCI +ve) 486 (M+H) 1 H NMR (DMSO-d 6 ) 8 8.46 (2H, d), 7.95 (1H, dd), 7.91-7.86 (1H, m), 7.72 (2H, s), 7.60 (2H, d), 7.48 (1H, t), 7.29 (2H, d), 7.07 (2H, d), 4.29-4.19 (2H, m), 4.14 (2H, d), 4.08-4.00 20 (1H, m), 3.63-3.47 (2H, m), 2.72-2.60 (2H, m), 1.99-1.90 (2H,m). Example 33 (+/-)-N-[1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2 one o 0 N/ N 0. 25 WO 99/29686 PCT/SE98/02190 40 Prepared according to the method described in Example 6c) using (+/-)-[4-(4 Pyridyl)-2-(oxazolidin-2-one-1-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 5 (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 an oil (0.082 g). MS (APCI +ve) 420 (M+H) 0 1H NMR (DMSO-d 6 ) 8 8.46 (2H, dd), 8.04 (2H, d), 7.73(1H, t), 7.48 (1H, d), 7.30 (2H, dd), 7.04 (2H, d), 6.70 (1H, d), 4.29-4.22 (2H, m), 4.15 (2H, d), 4.09-4.02 (1H, m), 3.94 (3H, s), 3.60-3.50 (2H, m), 2.73-2.59 (2H, m), 1.94 (2H, q). Example 34 15 (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one NN Prepared according to the method described in Example 6c) using (+/-)-N-[1-(4 bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g), phenylboronic acid (0.047 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 20 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 (0.012 g). Melting point: 116-117°C 25 MS (APCI +ve) 389 (M+H) WO 99/29686 PCT/SE98/02190 41 H NMR (DMSO-d6) 8 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 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q) 5 Example 35 (+I-)-N-[1-(4'-Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one 0II NN Prepared according to the method described in Example 6c) using (+/-)-N-[1-(4 bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100g), 10 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 NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.038 g). 15 Melting point: 103-105*C MS (APCI +ve) 423 (M+H) + 1H NMR (DMSO-d 6 ) 8 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 (1H, m), 3.62-3.48 (2H, m), 2.70-2.58 (2H, m), 1.94 (2H, q). 20 WO 99/29686 PCT/SE98/02190 42 Example 36 (+/-)-N-[1-(4'-Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one 0 N -1 Prepared according to the method described in Example 6c) using (+/-)-N-[1-(4 5 bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g), 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 NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.033 g). 10 Melting point: 109-110°C MS (APCI +ve) 403 (M+H) + 1H NMR (DMSO-d 6 ) 8 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, min), 4.12 (2H, d), 4.07-4.01 (1H, min), 3.62-3.48 (2H, min), 15 2.72-2.59 (2H, min), 1.94 (2H, q). Example 37 (+/-)-N-[1-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one 0-n o O NI 20 Prepared according to the method described in Example 6c) using (+/-)-N-[1-(4 bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g), 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).
WO 99/29686 PCT/SE98/02190 43 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 0 C 5 MS (APCI +ve) 419 (M+H) + 1H NMR (DMSO-d 6 ) 8 8.46 (2H, d), 7.53 (4H, dd), 7.29 (2H, d), 6.99 (4H, dd), 4.30-4.20 (2H, min), 4.11 (2H, d), 4.06-4.01 (1H, m), 3.32 (3H, s), 3.61-3.48 (2H, m), 2.70-2.59 (2H, m), 1.94 (2H, q). 10 Example 38 (+/-)-N-[1-(3',4'-Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one O 0 - NCI NI I Prepared according to the method described in Example 6c) using ((+/-)-[4-(4 Pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy]benzeneboronic acid (Example 32b), 0.050 g), 1 15 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 title compound as a solid (0.010 g). 20 Melting point: 92-93*C MS (APCI +ve) 457/459/461
(M+H)
+ 1H NMR (DMSO-d 6 ) 8 8.46 (2H, d), 7.89 (lH, 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 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q). 25 WO 99/29686 PCT/SE98/02190 44 Example 39 (+/-)-N-[1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6 dione oNo O 0 N O N 5 a) (+/-)-1-(4-Bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane tert-Butyldimethylsilyl chloride (20.53 g) and imidazole (9.25 g) were added to a solution of (+/-)- 1-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (Example 6b), 14.60 g) 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. o10 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 0 C MS (APCI +ve) 436/438 (M+H) + 15is 1H NMR (DMSO-d 6 ) 8 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 (1H, 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-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic acid 20 Prepared according to the method described in Example 18b) using (+/-)-1-(4 bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (10.0 g), from step a), tert-butyllithium (1.7 M solution in hexanes, 27 ml) and tri-isopropylborate (6 ml) in dry tetrahydrofuran (200 ml). After work-up, the residue was purified by column chromatography over silica gel 25 eluting with ethyl acetate : hexane (2: 1) then ethyl acetate to give the sub-title compound as a foam (4.38 g).
WO 99/29686 PCT/SE98/02190 45 MS (APCI +ve) 402 (M+H) + H NMR (DMSO-d6+D 2 0) 5 8.45 (2H, dd), 7.71 (2H, d), 7.24 (2H, q), 6.87 (2H, d), 4.04-3.82 (3H, min), 2.79-2.66 (2H, min), 1.97-1.75 (2H, min), 0.87 (9H, s), 0.14 (3H, s), 0.08 (3H, s). 5 c) (+/-)-4-[4-(4-Pyridyl)-2-butoxy]benzeneboronic acid Dilute hydrochloric acid (2M, 65 ml) was added to (+/-)-1-(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 o10 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. 15 MS (APCI +ve) 288 (M+H) H NMR (DMSO-d 6 + D 2 0) 8 8.43 (2H, d), 7.71 (2H, d), 7.31 (2H, d), 6.92 (2H, d), 3.92 (2H, d), 3.84-3.78 (1H, min), 2.87-2.64 (2H, min), 1.89-1.74 (2H, min). d) (+/-)-1-[4-(6-Methoxypyridin-2-yl)phenoxy]-4-(4-pyridyl)-2-butanol 20 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% 25 ethanol in dichloromethane to give the sub-title compound as an oil (0.15 g). MS (APCI +ve) 351 (M+H) + 1H NMR (DMSO-d 6 ) 5 8.45 (2H, d), 8.03 (2H, dd), 7.73 (1H, t), 7.47 (1H, d), 7.26 (2H, dd), 7.03 (2H, dd), 6.70 (1H, d), 5.08 (1H, d), 3.95 (2H, d), 3.83-3.78 (1H, min), 30 3.32 (3H, s), 2.85-2.77 (1H, min), 2.72-2.64 (1H, min), 1.91-1.83 (1H, min), 1.78-1.70 (1H, m) WO 99/29686 PCT/SE98/02190 46 e) (+/-)-N-[1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl] piperidin-2,6-dione Prepared according to the method of Example 1 using (+/-)- 1-[4-(6-methoxypyridin 2-yl)phenoxy]-4-(4-pyridyl)-2-butanol (0.15 g) from step d), glutarimide (0.1 g), s 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) 10 1H NMR (DMSO-d6) 8 8.44 (2H, dd), 8.01 (2H, dd), 7.73 (1H, t), 7.47 (1H, d), 7.21 (2H, dd), 6.97 (2H, d), 6.70 (1H, d), 5.07-5.02 (1H, m), 4.42-4.28 (2H, m), 3.94 (3H, s), 2.62-2.51 (6H, m), 2.35-2.24 (1H, m), 2.12-2.01 (1H, m), 1.78-1.70 (2H, m). Example 40 15 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione H N1 / 0 N.0 Prepared according to the method of Example 1 using (+/-)-N-1-(3'-nitrobiphenyl-4 yloxy)-4-(4-pyridyl)-2-butanol (Example 15a), 0.20g), hydantoin (0.11 g), triphenylphosphine (0.29 g) and diethyl azodicarboxylate (0.17 ml) in dry tetrahydrofuran 20 (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 25 MS (APCI +ve) 447 (M+H) WO 99/29686 PCT/SE98/02190 47 H NMR (DMSO-d 6 ) 8 8.45 (2H, d), 8.38 (1H, 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 (1H, m), 4.38-4.23 (2H, m), 3.87 (2H, s), 2.69-2.60 (2H, m), 2.38-2.22 (1H, m), 2.16-2.00 (1H, m). 5 Example 41 (+/-)-N- [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one oC \NN I I 5-Chlorovalerylchloride (0.07 ml) was added slowly to a solution of (+/-)4V-N-2-(3' nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (Example 19c), 0.20 g) in dry to 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 (lM 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 5is 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 title compound as an oil (0.03 g). 20 MS (APCI +ve) 446 (M+H) + H NMR (DMSO-d 6 ) 8 8.45 (2H, d), 8.38 (1H, 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 (1H, 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).
WO 99/29686 PCT/SE98/02190 48 Example 42 (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one \N.0 Prepared according to the method of Example 41 above with (+/-)-N-2-(3' s nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (Example 19c), 0.20 g), triethylamine (1 ml), 4-chlorobutyrylchloride (0.06 ml) and potassium tert-butoxide solution (IM 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 title compound as an oil (0.035 g). 10 MS (APCI +ve) 432 (M+H) + 1H NMR (DMSO-d 6 ) 8 8.45 (2H, dd), 8.38 (1H, 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 (1H, 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, in). 15 Example 43 Pharmacological Analysis Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are known to be agonists of the P2X 7 receptor, effecting the formation of pores in the plasma 20 membrane (Drug Development Research (1996), 37(3), p. 1 2 6 ). Consequently, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed. The increase in fluorescence can be used as a measure of P2X 7 receptor activation and therefore to quantify the effect of a compound on the P2X 7 receptor. 25 In this manner, each of the title compounds of Examples 1 to 42 were tested for antagonist activity at the P2X 7 receptor. Thus, the test was performed in 96-well flat bottomed microtitre plates, the wells being filled with 250 gl of test solution comprising WO 99/29686 PCT/SE98/02190 49 200 gl of a suspension of THP-1 cells (2.5 x 106 cells/ml) containing 10 4M ethidium bromide, 25 gl of a high potassium buffer solution containing 10-5M bbATP, and 25 gl of the high potassium buffer solution containing 3 x 10 -5M test compound. The plate was covered with a plastics sheet and incubated at 37 'C for one hour. The plate was then read 5 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 7 receptor agonist) and pyridoxal 5-phosphate (a P2X 7 receptor antagonist) were used separately in the test as controls. From the readings obtained, a plC 50 figure was calculated for each test compound, this figure being the negative logarithm of the concentration of test compound o10 necessary to reduce the bbATP agonist activity by 50%. Each of the compounds of Examples 1 to 42 demonstrated antagonist activity, having a pICs 50 figure > 4.50.

Claims (13)

1. A compound of general formula NY RT -- O R R (i) 5 wherein X represents an oxygen or sulphur atom or a group NH, CH
2 , CH 2 CH 2 or OCH 2 ; Y represents a group CH 2 or C=O; R 1 represents a pyridyl or pyrimidinyl group; R 2 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 10 amino, cyano, hydroxyl, nitro, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, (di)C 1 -C6-alkylamino, C 1 -C6-alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulphinyl, C 1 -C6-alkylsulphonyl, -NR3SO 2 R 4 or -SO 2 NR5R group, or a group -Z-(CH 2 )p-Z-(CH 2 )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; 15 R 3 and e ach independently represent a hydrogen atom or a C 1 -C 6 -alkyl group; and R 5 and R each independently represent a hydrogen atom or a C1-C6-alkyl group, or R5 and R each independently represent a hydrogen atom or a C 1 -C 6 -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. 20 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. 25
4. A compound according to any one of claims 1 to 3, wherein R 1 represents a pyridyl group. WO 99/29686 PCT/SE98/02190 51
5. A compound according to any one of claims 1 to 4, wherein R 2 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, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, 5 (di)C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C4-alkoxycarbonyl, C 1 -C 4 -alkylsulphinyl, C 1 -C 4 -alkylsulphonyl, -NR3SO 2 R 4 or -SO 2 NR5R 6 group.
6. A compound according to any one of claims 1 to 5, wherein R 2 represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or two 10 substituents independently selected from a halogen atom or an amino, cyano, nitro, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or -SO 2 NR5R 6 group.
7. A compound according to claim 1 being: (+/-)-(N-[ 1 -(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, 15 (+/-)-N-[ 1 -(3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N-[ 1 -(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (+/-)-N-[ 1-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione, (+/-)-N-[1 -(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, 20 (+/-)-N- [ 1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N-[1 -(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2R)-N- [1-(3'-Nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (2R)-N-[1 -(3' -Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[1 -(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, 25 (+/-)-N- [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[1 -(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-dione, (+/-)-N-[1 -(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N-[1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidine-2-one, (2R)-N-[1 -(3'-Chloro-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4 30 dione, WO 99/29686 PCT/SE98/02 190 52 (2R)-N- [1 -(3'-Chloro-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5 dione, (2R)-N- 111-(3' ,5 '-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [1-(3' -Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, 5 (2R)-N- [1-(3' -Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyll-thiazolidin-2,4-dione, (+/-)-N- [ 1-(3' -(Trifluoromethyl)biphenyl-4-yloxy)-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- [ 1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-dione, 10 (+/-)-N- [ 1-(3' -Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (+/-)-N- [ 1-(3 '-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[ 1 ,3]-oxazinan-2-one, (2S)-N-[l1-(3 '-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione, (2S)-N-[ 1-(3' -Amiinobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-dione, (2S)-N-[ 1-(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine 15 2,4-dione, (2S,3S)-N-[ I-(3'-(Pyrrolidine-l1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl] pyrrolidine-2,5-dione, (2S,3S)-N-[ 1 -(3'-Cyano-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]-pyrrolidine-2,5 dione, 20 (2S)-N- [1-(3 '-Cyano-4' -fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4 dione, (+/-)-N- [ 1-(4' -Fluoro-3 '-sulfonainidobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin 2-one, (+/-)-N- [1I -(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, 25 (+/-)-N- I1 -(Biphenyl-4-yloxy)-4-(4-pyridyI)-2-buty1]-oxazolidin-2-one, (+/-)-N-[ [1-(4' -Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [1-(4' -Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one, (+/-)-N- [1-(4' -Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyll-oxazolidin-2-one, (±/-)-N-[ [1-(3' ,4' -Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyll-oxazolidin-2-one, WO 99/29686 PCT/SE98/02190 53 (+/-)-N- [1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6 dione, (+/-)-N-[1 -(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione, (+/-)-N-[1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one, or 5 (+/-)-N- [1 -(3'-Nitrobiphenyl-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 L RI, O / .. R2 l0 (II) 10 wherein L represents a leaving group and R I and R 2 are as defined in formula (I), with a compound of general formula O N H (I1) wherein X and Y are as defined in formula (I) except that when X is an oxygen atom or 15is 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 NH 2 (IV) wherein R 1 and R 2 are as defined in formula (I), with 2-chloroethyl chloroformate; or 20 (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 25 (IV) as defined in (b) above, with 5-valerylchloride; or WO 99/29686 PCT/SE98/02190 54 (f) when X is an oxygen atom or OCH 2 group, reacting a compound of general formula 2Y R OBr (V) 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 s defined in formula (I); or (g) when X is an oxygen atom or OCH 2 group, reacting a compound of general formula O N RO / \ B(OH) 2 (VII) 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 (VIII), lR-Br, wherein R 2 is as defined in 10 formula (I); 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). 15
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 20 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. WO 99/29686 PCT/SE98/02190 55
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 S 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 10 pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7.
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