MXPA00005327A - Novel compounds - Google Patents
Novel compoundsInfo
- Publication number
- MXPA00005327A MXPA00005327A MXPA/A/2000/005327A MXPA00005327A MXPA00005327A MX PA00005327 A MXPA00005327 A MX PA00005327A MX PA00005327 A MXPA00005327 A MX PA00005327A MX PA00005327 A MXPA00005327 A MX PA00005327A
- Authority
- MX
- Mexico
- Prior art keywords
- pyridyl
- yloxy
- butyl
- dione
- group
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 142
- 238000000034 method Methods 0.000 claims abstract description 79
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- -1 cyano, hydroxyl Chemical group 0.000 claims description 68
- 125000004432 carbon atom Chemical group C* 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 27
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- MHPBKBRTYLDOKT-HSZRJFAPSA-N 5-[4-[(2r)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-pyridin-3-ylbutoxy]phenyl]benzene-1,3-dicarbonitrile Chemical compound O=C1CSC(=O)N1[C@@H](COC=1C=CC(=CC=1)C=1C=C(C=C(C=1)C#N)C#N)CCC1=CC=CN=C1 MHPBKBRTYLDOKT-HSZRJFAPSA-N 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- UCRZVOUYEJDUJF-HXUWFJFHSA-N 1-[(2r)-1-[4-(3-chloro-4-fluorophenyl)phenoxy]-4-pyridin-3-ylbutan-2-yl]pyrrolidine-2,5-dione Chemical compound C1=C(Cl)C(F)=CC=C1C(C=C1)=CC=C1OC[C@H](N1C(CCC1=O)=O)CCC1=CC=CN=C1 UCRZVOUYEJDUJF-HXUWFJFHSA-N 0.000 claims description 3
- AZAGLKQKDUJMMX-UHFFFAOYSA-N 1-[1-(4-phenylphenoxy)-4-pyridin-3-ylbutan-2-yl]pyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1C(COC=1C=CC(=CC=1)C=1C=CC=CC=1)CCC1=CC=CN=C1 AZAGLKQKDUJMMX-UHFFFAOYSA-N 0.000 claims description 3
- SOKXBLLWWVPZCM-JOCHJYFZSA-N 3-[4-[(2r)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-pyridin-3-ylbutoxy]phenyl]benzonitrile Chemical compound O=C1CSC(=O)N1[C@@H](COC=1C=CC(=CC=1)C=1C=C(C=CC=1)C#N)CCC1=CC=CN=C1 SOKXBLLWWVPZCM-JOCHJYFZSA-N 0.000 claims description 3
- DKVAJDQCPRHXSA-HSZRJFAPSA-N 3-[4-[(2r)-2-(2,5-dioxopyrrolidin-1-yl)-4-pyridin-3-ylbutoxy]phenyl]benzonitrile Chemical compound O=C1CCC(=O)N1[C@@H](COC=1C=CC(=CC=1)C=1C=C(C=CC=1)C#N)CCC1=CC=CN=C1 DKVAJDQCPRHXSA-HSZRJFAPSA-N 0.000 claims description 3
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 claims description 3
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 claims description 3
- HAOHUIPHEIQXOP-NRFANRHFSA-N Nc1cccc(c1)-c1ccc(OC[C@H](CCc2ccncc2)N2C(=O)CSC2=O)cc1 Chemical compound Nc1cccc(c1)-c1ccc(OC[C@H](CCc2ccncc2)N2C(=O)CSC2=O)cc1 HAOHUIPHEIQXOP-NRFANRHFSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- UVFWGWMMSVQZLI-QFIPXVFZSA-N n-[3-[4-[(2s)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-pyridin-3-ylbutoxy]phenyl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C=2C=CC(OC[C@H](CCC=3C=NC=CC=3)N3C(SCC3=O)=O)=CC=2)=C1 UVFWGWMMSVQZLI-QFIPXVFZSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- YRKNHZJLTKDOHG-JOCHJYFZSA-N 1-[(2r)-1-[4-(3-nitrophenyl)phenoxy]-4-pyridin-3-ylbutan-2-yl]pyrrolidine-2,5-dione Chemical compound [O-][N+](=O)C1=CC=CC(C=2C=CC(OC[C@@H](CCC=3C=NC=CC=3)N3C(CCC3=O)=O)=CC=2)=C1 YRKNHZJLTKDOHG-JOCHJYFZSA-N 0.000 claims description 2
- RQKAJAWLEOSVNY-LJQANCHMSA-N 3-[(2r)-1-[4-(3-chloro-4-fluorophenyl)phenoxy]-4-pyridin-3-ylbutan-2-yl]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(Cl)C(F)=CC=C1C(C=C1)=CC=C1OC[C@H](N1C(SCC1=O)=O)CCC1=CC=CN=C1 RQKAJAWLEOSVNY-LJQANCHMSA-N 0.000 claims description 2
- SOKXBLLWWVPZCM-QFIPXVFZSA-N 3-[4-[(2s)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-pyridin-3-ylbutoxy]phenyl]benzonitrile Chemical compound O=C1CSC(=O)N1[C@H](COC=1C=CC(=CC=1)C=1C=C(C=CC=1)C#N)CCC1=CC=CN=C1 SOKXBLLWWVPZCM-QFIPXVFZSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 206010062016 Immunosuppression Diseases 0.000 claims description 2
- 230000001506 immunosuppresive effect Effects 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- 238000010828 elution Methods 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 36
- 238000002844 melting Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 229960002317 succinimide Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 11
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 10
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- BURJIEWNHIKROD-FWDYTFEUSA-N [[(2r,3r,4r,5s)-5-(6-aminopurin-9-yl)-4,5-dibenzoyl-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C([C@@]1(O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@]1(N1C=2N=CN=C(C=2N=C1)N)C(=O)C=1C=CC=CC=1)C1=CC=CC=C1 BURJIEWNHIKROD-FWDYTFEUSA-N 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- ZMDQVFXSNXQAHC-UHFFFAOYSA-N 1-(4-bromophenoxy)-4-pyridin-4-ylbutan-2-ol Chemical compound C=1C=C(Br)C=CC=1OCC(O)CCC1=CC=NC=C1 ZMDQVFXSNXQAHC-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RLQIIMRUPAUUBX-UHFFFAOYSA-N 1-(4-phenylphenoxy)-4-pyridin-3-ylbutan-2-ol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1OCC(O)CCC1=CC=CN=C1 RLQIIMRUPAUUBX-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 3
- 229960005542 ethidium bromide Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000004808 supercritical fluid chromatography Methods 0.000 description 3
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 3
- CEKZUJSMKIQUHB-SFHVURJKSA-N (2s)-1-[4-(3-chloro-4-fluorophenyl)phenoxy]-4-pyridin-3-ylbutan-2-ol Chemical compound C([C@H](O)COC=1C=CC(=CC=1)C=1C=C(Cl)C(F)=CC=1)CC1=CC=CN=C1 CEKZUJSMKIQUHB-SFHVURJKSA-N 0.000 description 2
- BIYKPXDURAAHNL-FQEVSTJZSA-N (2s)-1-[4-(3-fluorophenyl)phenoxy]-4-pyridin-3-ylbutan-2-ol Chemical compound C([C@H](O)COC=1C=CC(=CC=1)C=1C=C(F)C=CC=1)CC1=CC=CN=C1 BIYKPXDURAAHNL-FQEVSTJZSA-N 0.000 description 2
- UWORNNFYITUECW-UHFFFAOYSA-N 1-(4-phenylphenoxy)-4-pyridin-3-ylbutan-2-amine Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1OCC(N)CCC1=CC=CN=C1 UWORNNFYITUECW-UHFFFAOYSA-N 0.000 description 2
- YHWLBCGXNJUDPA-UHFFFAOYSA-N 1-[4-(3-methoxyphenyl)phenoxy]-4-pyridin-4-ylbutan-2-ol Chemical compound COC1=CC=CC(C=2C=CC(OCC(O)CCC=3C=CN=CC=3)=CC=2)=C1 YHWLBCGXNJUDPA-UHFFFAOYSA-N 0.000 description 2
- KMODISUYWZPVGV-UHFFFAOYSA-N 2-bromo-6-methoxypyridine Chemical compound COC1=CC=CC(Br)=N1 KMODISUYWZPVGV-UHFFFAOYSA-N 0.000 description 2
- XBAHGVPCQKCVQQ-OAQYLSRUSA-N 3-[(2r)-1-[4-(3-fluorophenyl)phenoxy]-4-pyridin-3-ylbutan-2-yl]-1,3-thiazolidine-2,4-dione Chemical compound FC1=CC=CC(C=2C=CC(OC[C@@H](CCC=3C=NC=CC=3)N3C(SCC3=O)=O)=CC=2)=C1 XBAHGVPCQKCVQQ-OAQYLSRUSA-N 0.000 description 2
- OSQLXUHWZLUWOB-NRFANRHFSA-N 3-[4-[(2s)-2-hydroxy-4-pyridin-3-ylbutoxy]phenyl]benzonitrile Chemical compound C([C@H](O)COC=1C=CC(=CC=1)C=1C=C(C=CC=1)C#N)CC1=CC=CN=C1 OSQLXUHWZLUWOB-NRFANRHFSA-N 0.000 description 2
- ZNRGSYUVFVNSAW-UHFFFAOYSA-N 3-nitrophenylboronic acid Chemical compound OB(O)C1=CC=CC([N+]([O-])=O)=C1 ZNRGSYUVFVNSAW-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- YKMPVOXAMQJSAR-NRFANRHFSA-N 5-[4-[(2s)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-pyridin-3-ylbutoxy]phenyl]-2-fluorobenzonitrile Chemical compound C1=C(C#N)C(F)=CC=C1C(C=C1)=CC=C1OC[C@@H](N1C(SCC1=O)=O)CCC1=CC=CN=C1 YKMPVOXAMQJSAR-NRFANRHFSA-N 0.000 description 2
- DTTZJRAEFQOOBU-QFIPXVFZSA-N 5-[4-[(2s)-2-hydroxy-4-pyridin-3-ylbutoxy]phenyl]benzene-1,3-dicarbonitrile Chemical compound C([C@H](O)COC=1C=CC(=CC=1)C=1C=C(C=C(C=1)C#N)C#N)CC1=CC=CN=C1 DTTZJRAEFQOOBU-QFIPXVFZSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
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
NEW COMPOUNDS DESCRIPTION OF THE INVENTION The present invention is concerned with new processes, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions and their use in therapy. The P2X7 receptor (previously known as P2Z receptor) which is an ion channel interrupted by ligand, is present in a variety of cell types, extensively those that are known to be involved in the inflammatory / immune processes, specifically, macrophages, cells barleys 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 (macrophage / microglial cells), degranulation (mast cells) and shedding or shedding of L-selectin (lymphocytes). The P2X7 receptors are also located on cells that present antigen (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes. It would be desirable to develop effective compounds as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the etiologies of which the P2X7 receptor can play a role. According to the present invention, there is accordingly provided a compound of general formula:
wherein X represents an oxygen or sulfur atom or a group NH, CH2, CH2CH2 or OCH2; Y represents a group CH2 or C = 0; R1 represents a pyridyl group (especially 3-pyridyl or 4-pyridyl) or pyrimidinyl; 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 amino group, cyano, hydroxyl, nitro, alkyl of 1-6 carbon atoms , haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkyl (of 1 to 6 carbon atoms) thio, (di) alkyl (of 1-6 carbon atoms) amino, alkyl ( from 1-6 carbon atoms) carbonyl, alkoxy (from 1-6 carbon atoms) carbonyl, alkyl (from 1-6 carbon atoms) sulfinyl, alkyl (from 1 to 6 carbon atoms) sulfonyl, -NR3S02R4 or - S02NR5R6 or a group -Z- (CH2) PZ- (CH2) qH 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; R3 and R4 independently represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms and; R5 and R6 each independently represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group or a pharmaceutically acceptable salt or solvate thereof . In the context of the present specification, unless otherwise indicated, an alkylp substituent or alkyl portion on a substituent group may be linear or branched and also the alkyl portions on the dialkylamino substituent group may be the same or
different. Further, when X represents an OCH2 group, the oxygen atom is positioned adjacent to the carbonyl group in the ring. The group R2 preferably represents a phenyl, pyridyl or pyrimidinyl group, each of which can
is optionally substituted by one, two, three or four substituents independently selected from a halogen atom (eg fluorine, chlorine, bromine or iodine) or an amino, cyano, hydroxyl, nitro, alkyl group (1-6 carbon atoms) carbon) (for example, methyl, ethyl, propyl, butyl,
pentyl or hexyl), haloalkyl of 1-6 carbon atoms (by
example, trifluoromethyl), alkoxy of 1-6 carbon atoms (for example, methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), alkyl (of 1-6 carbon atoms) thio (for example, methyl-, ethyl- , propyl-, butyl-, pentyl- or hexyl-thio), 5 (di) alkyl (of 1-6 carbon atoms) amino (for example, methylamino, dimethylamino, ethylamino or diethylamino), alkyl (of 1-6 atoms) carbon) carbonyl (eg, methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylcarbonyl), alkoxy (1-6 carbon atoms) carbonyl (eg, methoxy-, ethoxy-,
Propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), alkyl (1-6 carbon atoms) sulfinyl (for example, methyl-, ethyl-, propyl-, butyl-, pentyl- or hexyl-sulfinyl), alkyl (1-6 carbon atoms) sulfonyl (for example, methyl-, ethyl-, propyl-, butyl-, pentyl- or hexyl-sulfonyl), -NR3S02R4 or a
Group -S02NR5R6 or a group -Z- (CH2) PZ- (CH2) qH 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 of 1 a 5. More preferably, R2 represents a phenyl group,
Pyridyl or pyrimidinyl, each of which may be optionally substituted by one, two or three substituents independently selected from a halogen atom or an amino group, cyano, hydroxyl, nitro, alkyl of 1-6 carbon atoms, halo- alkyl of 1-4 carbon atoms, alkoxy of
1-4 carbon atoms, alkyl (1-4 carbon atoms) thio,
- "* • * - ** -" tt- - - "-" - ~ t? Tnpimw "- j ^^ Hjg (di) alkyl (of 1-4 carbon atoms) amino, alkyl (of 1-4 carbon atoms) carbonyl, alkoxy (of 1-4 carbon atoms) carbonyl, alkyl (of 1 -4 carbon atoms) sulfinyl, alkyl (1-4 carbon atoms) sulfonyl, -NR3S02R4 or -S02NR5R6 Even more preferably, R2 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 group, cyano, nitro, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or -S02NR5R6 More preferably, R2 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, methoxa or -S02NR5R6 group. and R4 each independently represents a hydrogen atom or an alkyl group of 1-4 carbon atoms (for example, a methyl or ethyl group). Preferably, R5 and R6 each independently represent a hydrogen atom or an alkyl group of 1-4 carbon atoms (eg, a 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. Preferred compounds of the invention include: (+/-) - (N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, ( +/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidm-2, 5-dione, (+/-) -N- [1- (b? Phenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (3'-chlorobiphenyl) 4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [1- (3'-fluorobiphenyl-4-yloxy) -4 - (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) - 2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [l- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolid? n-2, 4-dione, (2R) -N- [1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-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-) iloxi) -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, 5 (+/-) - N- [l- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+ / -) -N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -oxazolidin-2-one, (2R) -N- [1- (3'-chloro 4 '-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2, -dione, (2R) -N- [1- (3'-chloro-4' - fluorobiphenyl-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, 15 (+/-) -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, (+/-) -N- [1- ( 3 '- (trifluoromethyl) biphenyl-4-yloxy) -4-20 (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (2' - methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidm-2,4-dione, (± / -) -N- [l- (3'-nitrobiphenyl-4-yloxy) - 4- (4-pyridyl) -2-butyl] -piperidine-2,6-dione, 25 (+/-) -N- [1- (3'-aminobiphenyl-4-yloxy) -4- (4-pyridyl) ) -
2-butyl] -thiazolidin-2, -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) -1,2-butyl] -thiazolidin-2,4-dione , (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] thiazolidin-2,4-dione, (2S, 3S) -N- [1- (3 '- (pyrrolidin- l-sulfonyl) biphenyl-4-yloxy) -4- (3-pyridyl) -3-pentyl] -pyrrolidin-2, 5-dione, (2S, 3S) -N- [1- (3'-cyano-4 '-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -3-pentyl] -pyrrolidin-2, 5-dione, (2S) -N- [1- (3'-cyano-4'-fluorobiphenyl- 4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (4'-fluoro-3'-sulfonamidobisphenyl-4-) iloxy) -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] - oxazolidi n-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-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'-nitrobiphenyl- 4-yloxy) -4- (4-pyridyl) -2-butyl] -imidazolidin-2, -dione, (+/-) -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: (a) reacting a compound of general formula
wherein L represents a leaving group (eg, a hydroxyl group) and R1 and R2 are as defined above herein, with a compound of the general formula:
¿^ Tá ^^ ym where X and Y are as defined above, except that when X is an oxygen atom or an OCH2 group, then Y is not a CH2 group; or (b) when X is an oxygen atom and Y is a group
CH2, reacting a compound of general formula:
wherein R1 and R2 are as defined above, with 2-chloroethyl chloroformate; or (c) when X is a group OCH2 and Y is a CH2 group, reacting a compound of formula (IV) as defined in (b) above, with 3-chloropropanol in the presence of phosgene;
(d) when X is a CH2 group and Y is a CH2 group, reacting a compound of formula (IV) as defined above in (b), with 4-chlorobutyryl chloride; or (e) when X is a group CH2CH2 and Y is a CH2 group, reacting a compound of formula (IV) as defined above in (b), with 5-valeryl chloride; or (f) when X is an oxygen atom or an OCH2 group, reacting a compound of the general formula:
* ^^^^^^^ where X represents an oxygen atom or a group OCH2 and Y and R1 are as defined above, with a compound of general formula (VI), R2-B (OH) 2, wherein R2 is as defined above; or (g) when X is an oxygen atom or a group OCH2, reacting a compound of the general formula:
wherein X represents an oxygen atom or a group OCH2 and Y and R1 are as defined above, with a compound of
general formula (VIII), R2-Br, wherein R2 is as defined above; 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 form a salt or
Pharmaceutically acceptable solvate of the compound of formula (I) • Processes (a), (b), (c), (d), (e), (f) and (g) can be conveniently carried out in a solvent (for example, dichloromethane, chloroform, acetonitrile, dioxane or tetrahydrofuran) at a temperature in the range of 0 to 100 ° C, preferably in the range of 10 to 80 ° C and especially at room temperature (20 ° C. ).
The compounds of formula (II) are known from WO 97/20815 and WO 98/42670 or can be prepared by processes analogous to those described in WO 97/20815 and WO 98/42670. The compounds of formula (III), (VI) and (VIII) are known or are commercially available compounds or can be prepared by processes known in the art. The compounds of formula (IV) can be prepared by methods known in the art from the compounds of formula (II). The compounds of formula (V) and (VII) can be prepared by processes analogous to (a), (b) or (c) above using the corresponding bromine or boron-containing compound of 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 intermediates may need to be protected by protecting groups. Thus, the final step 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, TW Greene and PGM Wuts, Wiley-Interscience (1991) The compounds of formula (I) can be converted to additional compounds of formula (I) using standard procedures. Formula (I) wherein R2 is a nitrophenyl group, can be converted to compounds of formula (I) wherein R2 is an aminophenyl group by reduction using iron powder and ammonium chloride in ethanol or a mixture of low ethanol / water reflux conditions The compounds of formula (I) above can 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, methanesulfonate or: p-toluenesulfonate 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, in which racemates are included. 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. 'By
.... »> ? eiA «_.._ > . . _ feig - < Thus, they are indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis. , asthma, airway hypersensitivity, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, malignant cell growth and metastasis, myocardial ischemia, cardiac reperfusion damage, cerebral ischemia, cerebrovascular accident, myoblastic leukemia , diabetes, Alzheimer's disease, osteoporosis, burn injuries, stroke, varicose veins! and meningitis. Thus, the present invention provides a compound of formula (I). or a pharmaceutically acceptable salt or solvate thereof, as defined above 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 defined hereinbefore, in the manufacture of a medicament for use in therapy. The invention further provides a method for effecting immunosuppression (for example, in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) comprising administering a
fy ^^ T- ^ V'- 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 therapeutic uses mentioned above, the dose administered will of course vary with the compound employed, the mode of administration, the treatment desired and the indicated disease. The compounds of formula (I) and acceptable salts
Pharmaceutically and solvates of the compounds can be used on their own but in general will be administered in the form of a pharmaceutical composition in which the compound / salt / solvate of formula (I) (active ingredient) is in association with an adjuvant, diluent or carrier
pharmaceutically acceptable. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight (percent by weight), more preferably from 0.10 to 70% by weight of active ingredient and from 1 to 99.95% by weight, more preferably from 30 to 99.90% in
weight, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight are based on the 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 defined above in the present I 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 comprising the mixture of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with an adjuvant , diluent or pharmaceutically acceptable carrier. The pharmaceutical composition of the invention can be administered topically (for example to the lungs and / or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols or dry powder formulations or systemically, for example by
Oral administration or 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 respectively denote mass spectrome nuclear magnetic resonance and dimethylsulfoxide. 25
Example 1 (+/-) - (N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidin-2, 5-dione
To a solution of triphenylphosphine (0.16 g) in tetrahydrofuran (2 ml) is added diethyl azodicarboxylate (0.1 ml); There is a slight heat release. The resulting orange solution was stirred for 5 minutes before the addition of succinimide (0.062 g) and the stirring was continued for an additional 5 minutes before addition! from
(±) -l- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (0.10 g) prepared as described in Example 25 of WO1
97/20815. After stirring for 1.5 hours, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by chromatography on silica igel, elution with ethyl acetate to give the title compound as a colorless solid (0.090 g). Melting point: 150-151 ° C MS (APCI + ve) 401 (M + H) + X NMR (DMSO-dg) 5 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 (1H, m).
Example 2 (+/-) -N- [1-3'-methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidin-2, 5-dione
Prepared according to the method of Example 1 above with succinimide (0.30 g) and (±) -1- (3 '-methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (0.25 g) prepared or is 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) + X NMR (DMSO-de) d 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- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione
^ ^ ^ ^ ^^^^^^^^^^^^ 1 ^^^ ^ ^ ^ ^^
Prepared according to the method of Example 1 above (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (0.32 g) prepared as described in Example 25, of the document 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) + XH NMR (DMSO-de) d 8.42-8.40 (2H, m), 7.55-7.49 (5H,), 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 1 (+/-) -N- [1- (3'-chlorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2,5-dione
Prepared according to the method of example 1
GAfetó¡j. ^^ amt ^^ x ^ Mß ^ previous (±) -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 (0.21 g). Melting point: 154 ° C MS (APCI + ve) 436/438 (M + H) "1 X NMR (DMSO-de) d 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), 2.11-2.49 (1H, m ).
Example 5 (+/-) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2,5-dione
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 the 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) + X NMR (DMSO-de) d 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,), 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).
Example 6 (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidin-2,5-dione
(a) (+/-) -4-bromophenyloxymethyloxirane To a solution of 4-bromophenol (17 g) and epichlorohydrin (25 ml) in acetonitrile (50 ml) is added cesium carbonate (24 g) and the resulting suspension was heated at reflux for 4 hours. Then the reaction was 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 sulfate (MgSO4) and concentrated under reduced pressure to produce another residue. Distillation of the residue under vacuum gives the subtitle compound as a colorless oil (13 g). Boiling point: 140 ° C (oil pump) S (gcms) 228/230 M + (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 ° C was added a solution in hexanes of n-butyl lithium (5.8 ml of a 2.5 M solution) and the reaction mixture was heated to 0 ° C, after which it was slowly added 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 room temperature, the reaction mixture was first quenched by the addition of aqueous ammonium chloride solution and then extracted with ethyl acetate. Then an organic phase was separated, washed with brine, dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to produce a residue. Purification of the residue by chromatography on silica gel (elution with 5% methanol in dichloromethane) gives the subtitle compound as a yellow solid (1.8 g). MS (APCI + ve) 322/324 (M + H) +
(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), tetra ix- (triphenylphosphine) palladium (0) (, 0.16 g), aqueous sodium carbonate (3.5 ml of a 2 M solution), ethanol (2 ml) and toluene
(7.5 ml) was heated at reflux temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water and an organic gas was separated, washed with brine, dried over magnesium sulfate (MgSO) and then concentrated under reduced pressure to produce a residue.
Purification of the residue by chromatography on silica gel (elution with 5% methanol in dichloromethane) gives the subtitle compound as a white solid.
(1.0 g). Melting point: 74-74 ° C MS (APCI + ve) 350 (M + H) +
(d) (+/-) - N- [l- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -pyrrolidin-2,5-dione Prepared in accordance with 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 (0.06 g). Melting point: 111-113 ° C MS (El) 431 (M + H) + X NMR (DMSO-de) d 8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H, m), 7.06 (1H, m), 6.88 (2H, d), 6.84 (1H, m), 4.61 (1H, m), 4.47 (1H, t), 4.16 (1H, dd), 3.83 ( 3H, s), 2.78 (1H, m), 2.61-2.50 (2H, m), 2.46 (4H, s), 2.11-2.02 (1H, m).
Example 7 (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione
Prepared according to the method of Example 1 above with (±) -1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.10 g) prepared as described in the example 6 (c) above and 2, -thiazolindione (0.067 g) to give the title compound as a colorless solid (0.07 g). Melting point: 111-112 ° C MS (El) 449 (M + H) + XH NMR (DMSO-de) d 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).
Example 8 (2R) -N- [1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione Prepared according to the method of the example 1 above with (2S) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (0.20 g) 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) +? Ti NMR (DMSO-de) d 8.43 (2H, m), 8.10 (1H, s), 7.97 (1H, d),
7. 76 (1H, d), 7.70-7.60 (4H,), 7.32 (1H, dd), 7.01 (2H, d), 4.56 (1H, m), 4.46 (1H, t), 4.30 (1H, dd), 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
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 the 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) + XH NMR (DMSO-de) d 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, dd), 2.61 (6H, m), 2.28 (1H , m), 2.07 (1H, m).
Example 10 (2R) -N- [1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2,5-dione
Prepared according to the method of example 1 above with (2S) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (0.15 g) prepared as described in the 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) + X NMR (DMSO -d6) d 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), 4.39 (2H, m), 4.28 (1H, dd), 2.60 (6H, m), 2.27 (1H, m), 2.02 (1H, m).
Example 11 (+/-) -N- [1- (3 '-ni-robiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione
(a) (+/-) -1- (3'-nitrobiphenyl-3-yloxy) -4- (4-pyridyl) -2-butanol Prepared according to the method of example 6 (c) above using 1- ( 4-bromophenyloxy) -4- (4-pyridyl) -2-butanol (3.12 g) as prepared in example 6 (b) and 3-nitrophenylboronic acid (2.59 g) to give the subtitle compound as an orange oil (2.20 g). MS (APCI + ve) 365 (M + H) +
(b) (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione Prepared in accordance with Method of Example 1 above with (+/-) -1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.14 g) prepared as described in step (a) above and 2,4-thiazole dione (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) + X NMR (DMSO -d6) d 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).
Example 12 (+/-) -N- [1- (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 11 (a) 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) + X NMR (DMSO -d6) d 8.46 (2H, d), 8.38 (1H, s), 8.16 (1H, d), 8.11 (1H, d), 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).
Example 13 (+/-) -N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -pyrrolidin-2,5-dione
(a) (+/-) -1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol Prepared according to the method of example 6 (c) using 1- (4 -bromophenyloxy) -4- (4-pyridyl) -2-butanol (0.40 g) prepared as described in example 6 (b) and 4-fluorophenylboronic acid (0.28 g) to give the title compound as a colorless solid ( 0.23 g). MS (APCI + ve) 338 (M + H) +
(b) (+/-) -N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione Prepared in accordance with Method of Example 1 above with (+/-) -1- (4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.10 g) prepared as described 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) + 1 H NMR (DMSO -d6) d 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 (1H, m), 2.59 (6H, m), 2.28 (1H,), 2.08 (1H, m ).
Example 14 (+/-) -N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione
Prepared according to the method of Example 1 above with (+/-) -1- (4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.12 g) prepared as described in Example 13 (a) and 2,4-thiazolinedione (0.08 g) to give the title compound as a pale gray solid (0.06 g). Melting point: 88-90 ° C MS (El) 437 (M + H) + X NMR (DMSO -d6) d 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, dd), 7.23 (4H, m), 6.97 (2H, d), 4.50 (1H, 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).
Example 15 (+/-) -N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] oxazolidin-2-one
(a) (+/-) - N- [l- (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-yloxy) -4- (3-pyridyl) -2-butanol (2.55 g) (prepared as described in Example 25 of WO 97/20815 ), triphenylphosphine (3.62 g), diethyl azodicarboxylate (2.52 ml) and phthalimide (2.36 g) in tetrahydrofuran. The obtained residue was purified by flash column chromatography, elution with hexane: ethyl acetate (3: 2) to give the subtitle compound as a colorless solid (3.9 g). Melting point: 132-133 ° C MS (El) 448 (M + H) + X NMR (DMSO -d6) d 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, m), 4.38 (1H, dd), 2.70 (2H, t), 2.40 (1H, m), 2.20 (1H, m).
(b) (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butylamine Dissolves (±) -N- [1- (biphenyl-4-yloxy) -4- ( 3-pyridyl) -2-butyl] -isoindole-1,3-dione (3.41 g) in a solution of 30% methylamine in methanol (100 ml). The solution was heated at reflux temperature for 3 hours. The solvent was removed at reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by chromatography on neutral alumina, elution with 10% methanol in dichloromethane gives the subtitle compound as a cream solid (1.08 g). Melting point: 52-53 ° C MS (El) 318 (M + H) + X NMR (CDC13) d 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, m); 2.78-2.72 (1H, m); 1.92-1.88 (1H, m); 1.80-1.72 (3H, m).
(c) (+/-) -N- [l- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -oxazolidin-2-one 2-chloroethyl chloroformate (0.561 ml) is added ) dropwise to a solution of (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butylamine (0.318 g) in acetonitrile (30 ml). The solution was stirred for 3 hours at room temperature.
The solvent was removed under reduced pressure, the residue was dissolved in tetrahydrofuran (5 ml) and dimethylformamide (1 ml). Sodium hydride (60% dispersion in mineral oil) (0.12 g) is added to the solution. Stirring is continued for 1 hour at room temperature, water (20 ml) is added to the reaction mixture, the product is extracted into ethyl acetate and the organic extract is dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography and elution with 3% methanol in dichloromethane, then recrystallization from diethyl ether gives the title compound as a white solid (0.093 g). Melting point: 58-59 ° C MS (FAB) 389 (M + H) + X NMR (CDC13) d 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 (2R) -N- [1- (3'-chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2, -dione
(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-pyridyl) -2-butanol (0.214 g), as prepared in Example 40 (a) of WO 97/20815 and 3-chloro-4-fluorophenylboronic acid (0.18 g), to produce the subtitle compound as a yellow gum (0.24 g). MS (APCI + ve) 372/374 (M + H) + (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 (0.14 g), prepared from step (a) and 2,4-thiazolinedione (0.088 g) to give, after purification by silica gel chromatography (elution with 80% ethyl acetate in iso-hexane), the title compound as a colorless gum (0.0077 g). MS (APCI + ve) 471/473 (M + H) + X NMR (DMSO -d6) d 8.43-8.40 (2H, m), 7.81 (1H, dd), 7.65 -7.60 (4H, m), 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 (2R) -N- [1- (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) -1- (3'-chloro-4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.10 g), Example 16 (a) and succinimide (0.053 g) to give, after purification by chromatography on silica gel (elution with 50% acetone in iso-hexane), the title compound as a pale brown foam (0.05 g). MS (APCI + ve) 453/455 (M + H) + X NMR (DMSO -d6) d 8.41 (1H, s), '8.39 (1H, m), 7.81 (1H, dd), 7.65-7.59 (4H , m), 7.56 (4H, 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,), 2.07 (1H, m).
Example 18 (2R) -N- [1- (3 ', 5'-dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione
(a) (2S) -1- (4-bromophenoxy) -4- (3-pyridyl) -2- (tert-butyldimethylsiloxy) butane A solution of (2S) -4- (3-pyridyl) -1, 2-butanediol
(10 g), prepared according to the method described in example 26 (c) of WO 97/20815 and 1, 1-carbonyldi-imidazole (12 g) in chloroform (250 ml) was stirred at room temperature throughout the night. The mixture was partially concentrated under reduced pressure, then filtered through a pad of silica. Evaporation of the filtrate gives a residue which was dissolved in dimethylformamide (100 ml). Then 4-bromophenyl (11.6 g) and cesium carbonate (16.6 g) are added and the mixture is heated at reflux temperature for 18 hours. The cooled reaction mixture was acidified with 2 M hydrochloric acid and extracted with diethyl ether (x3). The aqueous phase was separated and 2 M sodium hydroxide was added until the mixture reached pH 9 and it was extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. Dimethylformamide (10 ml) is added to the residue, followed by imidazole (6 g) and tert-butyldimethylsilyl chloride (8.4 g) and the resulting mixture is stirred at room temperature overnight. Then the reaction mixture is added to water and extracted twice with diethyl ether / hexane 1: 1. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. Purification by chromatography on silica gel, elution with diethyl ether / hexane 1: 1 gives the subtitle compound as an oil (13.27 g). MS (APCI + ve) 436/438 (M + H)
(b) (2S) -4- [4- (3-pyridyl) -2- (tert-butyldimethylsiloxy) -butoxy] benzeneboronic acid A solution of t-butyl lithium (1.7 M in hexanes, 15.0 ml, PIROFORIC CAUTION) was added dropwise 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) ) above and triisopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at -78 ° C. After the addition was complete, the reaction mixture was stirred at a temperature of -70 ° C for 1 hour. Then water (200 ml) and ethyl acetate (200 ml) are added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This was purified by chromatography on silica gel, elution with ethyl acetate / methanol 5: 1 to give the subtitle compound as a foam (4.06 g). MS (APCI + ve) 402 (M + H) +
(c) (2S) -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. . (1994), 31 (6), p 1417-1420, Registration No. 160892-07-9), tetrakis- (triphenylphosphine) palladium (0) (0.035 g), aqueous sodium carbonate (0.9 ml of a solution 2 M), toluene (10 ml) and ethanol (4 ml) was heated at 100 ° C for 2 hours. The reaction mixture was partitioned between diethyl ether and 2N hydrochloric acid and the layers were separated. The aqueous phase was neutralized with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in tetrahydrofuran (25 ml) and tetrabutyl lithium 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 neutralized with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. Purification by chromatography on silica gel, elution with dichloromethane / acetone 2: 1 followed by recrystallization from ethyl acetate / iso-hexane provide the subtitle compound as a white solid. MS (APCI + ve) 370 (M + H) +
(d) (2R) -N- [1- (3 ', 5'-dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione Prepared in accordance with 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 (0.032 g) to give, after purification by supercritical fluid chromatography (elution with 0% -45% methanol / liquid carbon dioxide), the title compound as a glass (0.015 g). MS (APCI + ve) 469 (M + H) + X NMR (DMSO-de) d 8.49 (2H, m), 8.41 (2H, m), 8.36 (1H, s), 7.80 (2H, d), 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,), 2.20 (1H, m).
Example 19 (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one
(a) (+/-) -N-2- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -iso-indole-1,3-dione Prepared according to the method of Example 15 (a) with 1- (4-bromophenoxy) -4- (4-pyridyl) -2-butanol (6.02 g) prepared as described in example 6 (b) and phthalimide (5.49 g) to give the compound of the subtitle as a golden oil (10.13 g). MS (APCI) 451/453 (M + H) +
(b) (+/-) -N-2- (4-bromophenoxy) -4- (4-pyridyl) -butylamine Prepared according to the method of example 15 (b) with (+/-) -N-2- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -isoindole-1,3-dione (9.78 g) to give the subtitle compound as a yellow solid (3.04 g). Melting point: 168-169 ° C MS (APCI) 321/323 (M + H) +
(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 (2 M solution, 0.93 ml) and ethanol (2 ml) was heated at reflux for 4 hours. After cooling to room temperature, the solvents were removed in vacuo. Then dilute hydrochloric acid is added and the mixture is extracted with diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then the residue was purified by column chromatography on neutral alumina gel, elution with dichloromethane: ethanol (98: 2), then ethanol, to give the subtitle compound as a yellow oil (0.28 g). MS (APCI) 364 (M + H) +
(d) (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-bil] -oxazolidin-2-one Prepared according to the method of example 15 (c) with 2-chloroethyl chloroformate (0.030 ml). The final product was purified by NPHPLC, elution with a gradient of 0-10% 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) + XH NMR (DMSO-d6) d 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 (2H, m), 2.72-2.58 (2H, m), 1.95 (2H, q).
Example 20 (2R) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione
(a) (2S) -1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol
Prepared according to the method of example 18 (c) above using (2S) -4- [4- (3-pyridyl) -2- (tert-butyldimethylsilyloxy) butoxy] benzanboronic acid (0.30 g), prepared as described in Example 18 (b) above and 1-bromo-3-fluorobenzene (0.15 ml) to produce the subtitle compound as a colorless oil (0.21 g).
* > aa $. < --g °% - * MS (APCI + ve) 338 (M + H) +
(b) (2R) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione Prepared according to the method of the 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 HPLC in normal phase
(elution with 0% -10% methanol in dichloromethane) and recrystallization from ethanol, the title compound as a colorless solid (0.032 g). Melting point: 117-118 ° C MS (APCI + ve) 437 (M + H) + X NMR (DMSO-de) d 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H,), 7.33 (1H, dd), 7.13 (1H, m), 6.98 (2H, d), 4.54 (1H, m), 4.45 (1H, t), 4.27 (1H, dd), 4.19 (2H, s), 2.62 (2H, t), 2.30 (1H, m), 2.10 (1H, m).
Example 21 (+/-) -N- [1- (3 '- (trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyrid-dil) -2-butyl] -thiazolidin-2,4-dione ( a) (+/-) -1- (3 '- (trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol Prepared according to the method of example 6 (c) using 1- ( 4-bromophenoxy) -4- (4-pyridyl) -2-butanol (0.20 g) prepared as described in example 6 (b) and 3-trifluoromethylphenylboronic acid (0.13 g) to give the subtitle compound as a yellow 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 Prepared from according to the method of Example 1 with (+/-) -1- (3 '- (trifluoromethylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.175 g), from step (a) and 2,4-thiazolinedione (0.106 g) The purification of the resulting residue by chromatography on silica gel (elution with 2% methanol in dichloromethane) and supercritical fluid chromatography (elution with 0% -45% methanol / carbon dioxide) liquid) followed by crystallization of a mixture of ethanol / ethyl acetate / iso-hexane, gives the title compound as a colorless solid (0.10 g) Melting point: 95-96 ° C MS (APCI + ve) 487 ( M + H) + X NMR (DMSO-de) d 8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m), 7.23 (2H, d), 7.01 (2H, m), 4.56 ( 1H, m), 4.46 (1H, t), 4.30 (1H, dd), 4.18 (2H, s), 2.65 (2H, t), 2.32 (1H, m), 2.10 (1H, m).
Example 22 (+/-) -N- [1- (2'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione
(a) (±) -1- (2'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol Prepared according to the method of example 6 (c) using 1- (4-bromophenoxy) -4- (4-pyridyl) -2-butanol (0.20 g) prepared as described in example 6 (b) and 2-methoxyphenylboronic acid (0.104 g) to give the subtitle compound as a colorless solid (0.18 g) . MS (APCI + ve) 350 (M + H) +
(b) (+/-) -N- [1- (2'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione Prepared according to the method from Example 1 above with (+/-) -1- (3 '-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.17 g), prepared in step (a) above and 2 , 4-thiazolinedione (0.114 g). Purification of the resulting residue by chromatography on silica gel (elution with 2% methanol / dichloromethane) and supercritical fluid chromatography (elution with 0% -45% methanol / liquid carbon dioxide), then crystallization of an ethanol mixture ethyl acetate / iso-hexane, gives the title compound as a colorless solid (0.055 g). Melting point: 128-130 ° C MS (APCI + ve) 487 (M + H) + X NMR (DMSO-de) d 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), 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] -thiazolidin-2,4-dione
Prepared according to the method of example 1 above with (+/-) -1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (0.25 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 ° C MS (APCI) 460 (M + H) + 11H NMR (DMSO-de) d 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,), 2.16-2.01 (1H, m), 1.74 (2H, t).
Example 24 (+/-) -N- [1- (3'-aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione
A yellow suspension of (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione (0.377 g) prepared as in example 11 (b) above, ammonium chloride (0.17 g) and iron powder (0.18 g) in a 1: 1 ethanol / water mixture was heated at reflux temperature for 1.5 hours. The reaction mixture was filtered. The colorless filtrate was poured into a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate (Na2SO) and concentrated under reduced pressure to produce a residue which was purified by normal phase HPLC (0% -10% ethanol / dichloromethane) followed by precipitation of a mixture of Ethanol / ethyl acetate / iso-hexane which afforded the title compound as a colorless solid (0.34 g). Melting point: 147-148 ° C MS (APCI + ve) 434 (M + H) + X NMR (DMSO-de) d 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).
Example 25 (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] - [1,3] -oxazinan-2-one To a Phosgene solution (1.93 M in toluene, 0.31 ml) in toluene (10 ml) was added from (+/-) - N-2- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) - butylamine (0.20 g) from step 19 (c) and the reaction mixture was stirred at room temperature for 2 hours. Then add 3-chloropropanol (0.09 ml) to the mixture and stir overnight at room temperature. The solvents are removed under reduced pressure and the residue was redissolved in dimethylformamide (10 ml). This solution was slowly added to a susion of sodium hydride (60% dision in oil, 0.09 g) in dimethylformamide (1 ml). The mixture was heated at 70 ° C for 9 hours. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was made alkaline with aqueous sodium hydroxide (2 M) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC, elution with 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) + X NMR (DMSO-d6) d 8.46 (2H, dd), 8.39 (1H, 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 (1H, 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 (2S) -N- [1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione
A (2R) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (5 μmol) prepared according to the method described in example 37 of WO 97/20815, Triphenylphosphine (50 μl of a 0.2 M solution in tetrahydrofuran) was added followed by 2,4-thiazolinedione (50 μl of a 0.2 M solution in tetrahydrofuran). Diethyl azodicarboxylate (2 μl) 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 dimethylsulfoxide to give the title compound as a 10 mM solution in dimethyl sulfoxide and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with an aqueous solution of 0.1% ammonium acetate. MS (APCI + ve) 444 (M + H) +
Example 27 (2S) -N- [1- (3'-aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -thiazolidin-2,4-dione
Prepared according to Example 26 above from (2R) -1- (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 0.2 M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 μl of a 0.2 M solution in tetrahydrofuran) and diethyl azodicarboxylate (2 μl) to give the compound of the title as a 10 mM solution in DMSO and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with an aqueous solution of 0.1% ammonium acetate. MS (APCI + ve) 434 (M + H) +
Example 28 (2S) -N- [1- (3'-methanesulfonamidobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione Prepared according to example 26 above from (2R) -1- (3 '-metanesulfonamidobiphenyl-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 0.2 M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 μl of a 0.2 M solution in tetrahydrofuran) and diethyl azodicarboxylate (2 μl) to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with an aqueous solution of 0.1% ammonium acetate. MS (APCI + ve) 512 (M + H) +
Example 29 (2S, 3S) -N- [1- (3 '- (pyrrolidin-1-sulfonyl) biphenyl-4-yloxy) -4- (3-pyridyl) -3-pentyl] -pyrrolidin-2, 5- diona
Prepared according to example 26 using (3R, 4S) -1-pyridin-3-yl-4- [3 '- (pyrrolidin-1-sulfonyl) biphenyl-4-yl-oxy] -pentan-3-ol (6.67 μmol) prepared according to the method described in example 72 of WO 97/20815, triphenylphosphine (50 μl of a 0.2 M solution in tetrahydrofuran), succinimide (50 μl of a 0.27 M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μmol). μl) to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with an aqueous solution of ammonium acetate at 0.1%. MS (APCI + ve) 548 (M + H) +
Example 30 (2S, 3S) -N- [1- (3'-cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridinyl) -3-pentyl] -pyrrolidin-2, 5- diona
Prepared according to example 26 using (ÍS,
2R) -4-fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) -biphenyl-3-carbonitrile (6.67 μmol), prepared according to the method of example 36 of WO 97 / 20815, triphenylphosphine (50 μl of a 0.2 M solution in tetrahydrofuran), succinimide (50 μl of a 0.27 M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μl) to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with 5-95% acetonitrile / ammonium acetate. MS (APCI + ve) 458 (M + H) +
Example 31 (2S) -N- [1- (3'-cyano-4'-fluoro-biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione
Prepared according to the method described in example 26 using (2R) -1- (3'-cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol (6.67 μmol), triphenylphosphine
(50 μl of a 0.27 M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 μl of a 0.27 M solution in tetrahydrofuran) and diethyl azodicarboxylate (3 μl) to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a Waters Symmetry C8 column of 50 mm x 3.9 mm, particle size 5 μm, elution with 5-95% acetonitrile / ammonium acetate. S (APCI + ve) 462 (M + H) + Example 32 (+/-) -N- [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4- (4-pyridyl) - 2-butyl] -oxazolidin-2-one
(a) (+/-) -N- [1- (4 '-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one Prepared according to the method described in Example 15 ( c) using (+/-) -N-2- (4-bromophenoxy) -4- (4-pyridyl) -butylamine (example 19 (b), 1.08 g), 2-chloroethyl chloroformate (0.521 ml) and hydride of sodium (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 sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography, elution with dichloromethane: ethanol (95: 5) to give the subtitle compound as an oil (0.651 g). MS (APCI + ve) 391/393 (M + H) + XH NMR (DMS0-d6) d 8.46 (2H, dd), 7.44 (2H, dd), 7.28 (2H, dd), 6.92 (2H, dd) , 4.29-4.19 (2H,), 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) •
(B) (+/-) - [4- (4-pyridyl) -2- (oxazolidin-2-on-l-yl) butoxy] benzeneboronic acid Prepared according to the method described in example 18 (b) using ( +/-) -N- (1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolid? N-2-one (0.20 g), from step (a), ter- butyl lithium (1.7 M solution in hexanes, 0.60 ml) and tri-isopropylborate (0.17 ml) to give the subtitle compound as a foam (0.09 g) MS (APCI + ve) 313 (MB (0H) 2) + X NMR (DMSO-de) d 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, m), 3.60-3.46 (2H, m), 2.74-2.62 (2H, m), 1.92 (2H, q).
(c) (+/-) -N- [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one Prepared from according to the method described in example 6 (c) using (+/-) - [4- (4-pyridyl) -2- (oxazolidin-2-on-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 (2 M, 0.2 ml), tetrakis- (triphenylphosphine) palladium (0) (0.010 g).
After the procedure, the residue was purified by column chromatography on silica gel, elution 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) + X NMR (DMSO-de) d 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 (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
Prepared according to the method described in example 6 (c) using (+/-) - [4- (4-pyridyl) -2- (oxazolidin-2-on-l-yl) butoxy] benzanboronic acid (Example 32 ( b) 0.100 g), 2-bromo-6-methoxypyridine (J. Org. Chem., 55,
(1990), 69-73, 0.079 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2 M, 0.2 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.010 g). After the procedure, the residue was purified by NPHPLC, elution with 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) + X NMR (DMSO-d6) d 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 ), 3.6-3.50 (2H, m), 2.73-2.59 (2H, m), 1.94 (2H, q).
Example 34 (+/-) - (N- [1- (biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one
Prepared according to the method described in Example 6 (c) using (+/-) -N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one ( Example 32 (a), 0.100 g), phenylboronic acid (0.047 g), ethanol (3 ml), aqueous solution of sodium bicarbonate (2 M, 0.2 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.010 g) . After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.012 g). Melting point: 116-117 ° C MS (APCI + ve) 389 (M + H) + X NMR (DMS0-d6) d 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).
Example 35 (+/-) -N- [1- (4'-chlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one
Prepared according to the method described in example 6 (c) using (+/-) -N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one ( Example 32 (a), 0.100 g), 4-chlorobenzanboronic acid (0.060 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2 M, 0.2 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.010) g). After the procedure, the residue was purified by NPHPLC, elution with 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) + X NMR (DMSO-de) d 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), 3.62-348 (2H, m), 2.70 -2.58 (2H, m), 1.94 (2H, q).
Example 36 (+/-) -N- [1- (4'-methylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one
Prepared according to the method described in example 6 (c) using (+/-) -N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolid-n-2- ona (Example 32 (a), 0.100 g), 4-methylbenzeneboronic acid (0.052 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2 M, 0.2 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.010 g). After the procedure, the residue was purified by NPHPLC, elution with 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) + XH NMR (DMSO-de) d 8.46 (2H, d), 7.56 (2H, d), 7.50 (2H, d) , 7.29 (2H, d), 7.23 (2H, d), 7.01 (2H, d), 430-4.20 (2H, m), 4.12 (2H, d), 4.07-4.01 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q).
Example 37 (+/-) -N- [1- (4'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one
Prepared according to the method described in Example 6 (c) using (+/-) -N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one ( Example 32 (a), 0.100 g), 4-methoxybenzeneboronic acid (0.059 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2 M, 0.2 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.010) g). After the procedure, the residue was purified by NPHPLC, elution with 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) + XH NMR (DMSO-de) d 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 (1H, m), 3.32 (3H, s), 3.61-3.48 (2H, m), 2.70 -2.59 (2H, m), 1.94 (2H, q).
Example 38 (+/-) -N- [1- (3 ', 4' -dichlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one
Prepared according to the method described in Example 6 (c) using (+/-) - N- [4- (4-pyridyl) -2- (oxazolidin-2-on-l-yl) butoxy] benzeneboronic acid (Example 32 (b), 0.050 g), l-bromo-3,4-dichlorobenzene (0.048 g), ethanol (2 ml), aqueous solution of sodium bicarbonate (2 M, 0.1 ml) and tetrakis- (triphenylphosphine) palladium ( 0) (0.006 g). After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane 'to give the title compound as a solid (0.010 g). Melting point: 92-93 ° C MS (APCI + ve) 457/459/461 (M + H) + X NMR (DMSO-de) d 8.46 (2H, d), 7.89 (1H, 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).
Example 39 (+/-) -N- [1- (4- (6-methoxypyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] -piperidine-2,6-dione
(a) (+/-) - (4-bromophenoxy) -4- (4-pyridyl) -2- (-tert-butyldimethylsilyloxy) butane Tert-butyldimethylsilyl chloride (20.53 g) and imidazole (9.25 g) are added. ) to a solution of (+/-) - l- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol (example 6 (b), 14.60 g) in anhydrous dichloromethane (500 ml). The solution was stirred overnight at room temperature. The solid was filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel, elution with dichloromethane: ethyl acetate (5: 1) to give the subtitle compound as a solid (19.34 g). Melting point: 73-75 ° C MS (APCI + ve) 436/438 (M + H) "X NMR (DMSO-d6) d 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,), 1.97-1.79 (2K, m), 0.91 (9H, s) ), 0.12 (3H, s), 0.09 (3H, s).
(b) (+/-) -4- [4- (4-pyridyl) -2- (tert-butyldimethylsilyl-xi) b toxy] benzeneboronic acid Prepared according to the method described in example 18 (b) using (- / -) -1- (4-bromophenoxy) -4- (4-pyridyl) -2- (tert-butyldimethylsilyloxy) butane (10.0 g), from the stage
(a), tert-butyl lithium (1.7 M solution, 27 ml) and tri-isopropyl-borate (6 ml) in anhydrous tetrahydrofuran (200 ml). After the procedure, the residue was purified by column chromatography on silica gel, elution with ethyl acetate: hexane (2: 1), then ethyl acetate to give the subtitle compound as a foam (4.38 g). MS (APCI + ve) 402 (M + H) + X NMR (DMSO-d6 + D20) d 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 (2 M, 65 ml) is added to (+/-) -1- (4- bromophenoxy) -4- (4-pyridyl) -2- (tert-butyldimethylsilyloxy) butane (4.38 g) from step (b) in methanol (200 ml). 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 subtitle compound as a powder. MS (APCI + ve) 288 (M + H) + X NMR (DMSO-d6 + D20) d 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, m), 2.87-2.64 (2H, m), 1.89-1.74 (2H, m).
(d) (+/-) -1- [4- (6-methoxypyridin-2-yl) phenoxy] -4- (4-pyridyl) -2-butanol Prepared according to the method described in example 6 (c) 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 (2 M, 0.7 ml) and tetrakis- (triphenylphosphine) palladium (0) (0.020 g). After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane to give the subtitle compound as an oil (0.15 g). MS (APCI + ve) 351 (M + H) + 1 H NMR (DMSO-d 6 + D 20) d 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, m), 3.32 (3H, s ), 2.85-2.77 (1H, m), 2.72-2.64 (1H, m), 1.91-1.83 (1H, m), 1.78-1.70 (1H, 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 (+/-) -1- [4- (6-methoxypyridin-2-yl) phenoxy] -4- (4-pyridyl) -2-butanol (0.15 g) of the stage (d), glutarimide (0.1 g), triphenylphosphine (0.22 g) and diethyl azodicarboxylate (0.14 ml). After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane to give the subtitle compound as an oil (0.10 g). MS (APCI + ve) 446 (M + H) + XH NMR (DMSO-d6 + D20) d 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 (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] imidazolidin-2,4-dione
Prepared according to the method of Example 1 using (+/-) -Nl- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol (Example 15 (a), 0.20 g), hydantoin (0.11 g), triphenylphosphine (0.29 g) and diethyl azodicarboxylate (0.17 ml) in anhydrous tetrahydrofuran (10 ml) and dimethylformamide (2 ml). After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane to give the subtitle compound as a solid (0.03 g). Melting point: 143: 145 ° C MS (APCI + ve) 447 (M + H) + XH NMR (DMSO-de) d 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).
Example 41 (+/-) -N- [1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -piperidin-2-one
-chlorovaleryl chloride is slowly added
(0.07 ml) to a solution of (+/-) -N-2- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -butylamine (example 19 (c), 0.20 g) in dichloromethane anhydrous (10 ml), in the presence of triethylamine
(1 ml). The mixture was stirred for 15 minutes at room temperature, then concentrated under reduced pressure
A solution of potassium tert-butoxide is added
(1M in tetrahydrofuran, 1.5 ml) to the residue redissolved in anhydrous tetrahydrofuran (10 ml). After 30 minutes at room temperature, the mixture was concentrated under reduced pressure. Water is added and the mixture is 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, elution with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.03 g). MS (APCI + ve) 446 (M + H) + XH NMR (DMSO-d6) d 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, broad).
Example 42 (+/-) -N- [1- (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) -butylamine (Example 19 (c), 0.20 g) , triethylamine (1 ml), 4-chlorobutyryl chloride (0.06 ml) and potassium ter-butoxide solution (1 M in tetrahydrofuran, 1.5 ml). After the procedure, the residue was purified by NPHPLC, elution with a gradient of 0-10% ethanol in dichloromethane to give the subtitle compound as an oil (0.035 g). MS (APCI + ve) 432 (M + H) + X NMR (DMSO-de) d 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, m).
Example 43 Pharmacological Analysis It is known that certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are antagonists of the P2X7 receptor, which effect 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 sample), an increase in the fluorescence of the ethidium bromide bound to the intracellular DNA is observed. The increase in fluorescence can be used as a measure of the activation of the P2X7 receptor and therefore to quantify the effect of a compound on the P2X7 receptor. In this manner, each of the title compounds of Examples 1 to 42 were tested for antagonist activity at the P2X7 receptor. Thus, the test was carried out in 96-well flat bottom microtiter plates, the wells were filled with 250 μl of the test solution comprising 200 μl of a THP-1 cell suspension (2.5 x 10 6 cells / ml). ) containing 10"4 M ethidium bromide, 25 μl of a high potassium pH buffer solution containing 10" 5 M bbATP and 25 μl of the high pH phosphate buffer containing 3 × 10"5 M of the compound of The plate was covered with a plastic sheet and incubated at 37 ° C for 1 hour, then the plate was read on a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slot widths: Ex 15 nm, Em 20 nm For comparison purposes, bbATP (a P2X7 receptor agonist) and pyridoxal 5-phosphate (a P2X7 receptor antagonist) were used separately as controls or references in the test. calculated a pICso figure for each test compound, this figure is the negative logarithm of the concentration of the test compound necessary to reduce the agonist activity of bbATP by 50%. Each of the compounds of Examples 1 to 42 demonstrated antagonist activity, have a pICso figure> 4.50.
Claims (13)
- CLAIMS 1. A compound of general formula: characterized in that X represents an oxygen or sulfur atom or a group NH, CH2, CH2CH2 or 0CH2; Y represents a group CH2 or C = 0; R1 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 amino group, cyano, hydroxyl, nitro, alkyl of 1-6 carbon atoms , haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkyl (of 1 to 6 carbon atoms) thio, (di) alkyl (of 1-6 carbon atoms) amino, alkyl ( from 1-6 carbon atoms) carbonyl, alkoxy (from 1-6 carbon atoms) carbonyl, alkyl (from 1-6 carbon atoms) sulfinyl, alkyl (from 1 to 6 carbon atoms) sulfonyl, -NR3S02R4 or - S02NR5R6 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 of 1 to 5; R3 and R4 independently represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms and; R5 and R6 each independently represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group or a pharmaceutically acceptable salt or solvate thereof.
- 2. The compound according to claim 1, characterized in that X represents a sulfur atom or a CH2 group.
- 3. The compound according to claim 1 or claim 2, characterized in that Y represents a group C = 0.
- 4. The compound according to any of claims 1 to 3, characterized in that R1 represents a pyridyl group.
- 5. The compound according to any of claims 1 to 4, characterized in that R2 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 group, cyano, hydroxyl, nitro, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkyl (of 1 to 4 carbon atoms) thio, (di) alkyl (of 1-4 carbon atoms) amino, alkyl (of 1-4 carbon atoms) carbonyl, alkoxy (of 1-4 carbon atoms) carbonyl, alkyl (of 1-4 carbon atoms) ) sulfinyl, alkyl (1 to 4 carbon atoms) sulfonyl, -NR3S02R4 or -S02NR5R6.
- 6. The compound according to any of claims 1 to 5, characterized in that R2 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 a amino group, cyano, nitro, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or a group -S02NR5R6.
- The compound according to claim 1, characterized in that it is: (+/-) - (N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin- 2, 5-dione, (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, ( +/-) -N- [1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2, -dione, (+/-) -N- [1- ( 3'-chlorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [1- (3'-fluorobiphenyl-4- iloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (4 -pyridyl) -2-butyl] -pyrrolidin-2, 5-dione, (+/-) -N- [1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl ] -thiazolidin-2, -dione, (2R) -N- [1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-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, -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, (+/-) -N- [1- (biphenyl-4-yloxy) -4- (3 -pyridyl) -2-butyl] -oxazolidin-2-one, (2R) -N- [1- (3'-chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2- butyl] -thiazolidin-2,4-dione, (2R) -N- [1- (3'-chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine -2, 5-dione, (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, (+/-) -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, (+/-) -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- [ 1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (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] thiazolidin-2,4-dione, (2S, 3S) -N- [1- (3 '- (pyrrolidin-1-sulfonyl) biphenyl-4-yloxy) -4- (3-pyridyl) ) -3-pentyl] -pyrrolidin-2, 5-dione, (2S, 3S) -N- [1- (3'-cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) - 3-pentyl] -pyrrolidin-2, 5-dione, (2S) -N- [l- (3'-cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidi n-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- [1- (biphenyl-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'-methyl-biphenyl-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'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -imidazolidin-2,4-dione, (+/- ) -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] -pirro lidin-2-one.
- 8. A process for the preparation of a compound of formula (I) "as defined in claim 1, characterized in that it comprises: (a) reacting a compound of the general formula: wherein L represents a leaving group and R1 and R2 are as defined in formula (I), with a compound of general formula: wherein X and Y are as defined in formula (I), except that when X is an oxygen atom or a group 0CH2, then Y is not a CH2 group; or (b) when X is an oxygen atom and Y is a CH2 group, reacting a compound of the general formula: wherein R1 and R2 are as defined in formula (I), with 2-chloroethyl chloroformate; or (c) when X is a group 0CH2 and Y is a CH2 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 group CH2 and Y is a CH2 group, reacting a compound of formula (IV) as defined above in (b), with 4-chlorobutyryl chloride; or (e) when X is a group CH2CH2 and Y is a CH2 group, reacting a compound of formula (IV) as defined above in (b), with 5-valeryl chloride; or (f) when X is an oxygen atom or a group 0CH2, reacting a compound of the general formula: wherein X represents an oxygen atom or a group 0CH2 and Y and R1 are as defined above in formula (I), with a compound of general formula (VI), R2-B (0H) 2, wherein R2 is as defined in formula (I); or (g) when X is an oxygen atom or a group 0CH2, reacting a compound of the general formula: wherein X represents an oxygen atom or a group OCH2 and Y and R1 are as defined in formula (I), with a compound of general formula (VIII), R2-Br, wherein R2 is as defined in 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) •
- 9. A pharmaceutical composition characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to 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 according to claim 9, characterized in that it comprises the mixture of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 7, with a pharmaceutically acceptable adjuvant, diluent or carrier.
- 11. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 7, characterized in that it is used in therapy.
- The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 7, characterized in that it is used in the manufacture of a medicament for use in therapy.
- 13. A method for effecting immunosuppression, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 7.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9704546-2 | 1997-12-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00005327A true MXPA00005327A (en) | 2001-11-21 |
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