EP0530207A1 - Imidazopyridine paf antagonists - Google Patents
Imidazopyridine paf antagonistsInfo
- Publication number
- EP0530207A1 EP0530207A1 EP91907827A EP91907827A EP0530207A1 EP 0530207 A1 EP0530207 A1 EP 0530207A1 EP 91907827 A EP91907827 A EP 91907827A EP 91907827 A EP91907827 A EP 91907827A EP 0530207 A1 EP0530207 A1 EP 0530207A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- alkyl
- group
- phenyl
- chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000005557 antagonist Substances 0.000 title abstract description 6
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 125000003118 aryl group Chemical group 0.000 claims abstract description 35
- 125000005647 linker group Chemical group 0.000 claims abstract description 27
- 150000001412 amines Chemical class 0.000 claims abstract description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 17
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 7
- 230000000172 allergic effect Effects 0.000 claims abstract description 7
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 7
- 125000003368 amide group Chemical group 0.000 claims abstract description 5
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 150000003568 thioethers Chemical class 0.000 claims abstract description 5
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 78
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- -1 piperidino, 4-ketopiperidino,morpholino Chemical group 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims 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 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 9
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 9
- 150000002009 diols Chemical class 0.000 claims description 8
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 7
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000002148 esters Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical class CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000001174 sulfone group Chemical group 0.000 claims description 3
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000004292 cyclic ethers Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 98
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 abstract description 3
- 108010003541 Platelet Activating Factor Proteins 0.000 abstract description 3
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 345
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 258
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 251
- 239000000243 solution Substances 0.000 description 127
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 110
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 110
- 229910001868 water Inorganic materials 0.000 description 101
- 239000000203 mixture Substances 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 83
- 229940093499 ethyl acetate Drugs 0.000 description 83
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
- 239000000047 product Substances 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 55
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000007787 solid Substances 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- 230000002829 reductive effect Effects 0.000 description 40
- 239000000284 extract Substances 0.000 description 38
- 239000000377 silicon dioxide Substances 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 239000003921 oil Substances 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 24
- 235000017557 sodium bicarbonate Nutrition 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
- 239000000725 suspension Substances 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 19
- 238000010992 reflux Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 239000006260 foam Substances 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 238000001665 trituration Methods 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 9
- UKCSAXPHHJMCFW-UHFFFAOYSA-N 4-(2-methylimidazo[4,5-c]pyridin-1-yl)benzaldehyde Chemical compound CC1=NC2=CN=CC=C2N1C1=CC=C(C=O)C=C1 UKCSAXPHHJMCFW-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CTMUBXCBEVXPBQ-UHFFFAOYSA-N [4-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl]methanol Chemical compound CC1=NC2=CN=CC=C2N1C1=CC=C(CO)C=C1 CTMUBXCBEVXPBQ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 4
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 4
- WTDGMNNLENRTOT-UHFFFAOYSA-N 2,2,3,3,4,4,4-heptafluoro-1-[4-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl]butan-1-one Chemical compound CC1=NC2=CN=CC=C2N1C1=CC=C(C(=O)C(F)(F)C(F)(F)C(F)(F)F)C=C1 WTDGMNNLENRTOT-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- ATOORGXSQVVVFW-UHFFFAOYSA-N 4-(2-methylimidazo[4,5-c]pyridin-1-yl)benzamide Chemical compound CC1=NC2=CN=CC=C2N1C1=CC=C(C(N)=O)C=C1 ATOORGXSQVVVFW-UHFFFAOYSA-N 0.000 description 3
- FLZZNCMRFDMVDR-UHFFFAOYSA-N 4-(2-methylimidazo[4,5-c]pyridin-1-yl)benzonitrile Chemical compound CC1=NC2=CN=CC=C2N1C1=CC=C(C#N)C=C1 FLZZNCMRFDMVDR-UHFFFAOYSA-N 0.000 description 3
- JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 3
- 230000004931 aggregating effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
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- 150000003608 titanium Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- NGEDYVJWBRCEEM-UHFFFAOYSA-N trimethyl(pyridin-2-ylmethyl)silane Chemical compound C[Si](C)(C)CC1=CC=CC=N1 NGEDYVJWBRCEEM-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Definitions
- This invention relates to imidazopyridines specifically to certain 4-substituted-1-(2-methylimidazo[4,5-c]pyrid-1-yl)-benzene derivatives.
- the compounds are potent and selective antagonists of platelet activating factor having clinical utility in the treatment of allergic and inflammatory conditions in humans and animals.
- Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-sn- glyceryl-3-phosphorylcholine) is an ether phopholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney.
- PAF In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A 2 or the leukotrienes, which make PAF inhib'itors of potential value in the treatment of a variety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, the treatment of circulatory shock, gastric ulceration, psoriasis and cardiovascular conditions , including angina , thrombosis and stroke.
- other powerful mediators such as thromboxane A 2 or the leukotrienes
- PAF antagonists having the formula: and pharmaceutically acceptable salts thereof,
- A is a C 1 -C 8 alkyl, perfluoro(C 1 -C 8 )alkyl, C 3 -C 8 cycloalkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group may be unsubstituted or substituted with from one to three substituents each independently chosen from C 1 -C 4 alkyl, halo, oxo, CO 2 R 4 , CONR 5 R 6 , OH, C 1 -C 4 alkoxy, NH 2 , NO 2 , CN and (CH 3 ) 3 SiCH 2 ;
- substituents and, in the case where the group A is an aryl or heterocyclic group, the ring may optionally be fused to said aryl or heterocyclic group;
- each of R 1 , R 2 and R 3 is independently H or CH 3 ;
- R 4 is H, C 1 -C 4 alkyl or aryl(C 1 -C 4 )alkyl;
- R 5 and R 6 are each independently H or C 1 -C 4 alkyl, or R 5 is H and
- R 6 is C 3 -C 8 cycloalkyl or aryl, or the two groups R 5 and R 6 together with the nitrogen atom to which they are attached, form a piperidino, 4-ketopiperidino, morpholino or piperazinyl group;
- R 7 is H, C 1 -C 4 alkyl, CO 2 (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl or heteroaryl(C 1 -C 4 )alkyl;
- A-B is not C 2 H 5 OCOCH 2 CO- or CH 3 COCH 2 CO 2 CH 2 -.
- aryl includes phenyl, naphthyl, tetrahydronaphthyl and indanyl, each of said groups being optionally substituted as defined in A above; alkyl groups having 3 or more carbon atoms may be straight or branched-chain; and halo means fluoro, chloro, bromo or iodo.
- heterocyclic group means a 5 or 6 membered ring containing up to four nitrogen atoms, or one or two nitrogen atoms together with a further oxygen or sulphur atom, or up to two oxygen atoms or a sulphur atom, as heteroatom, and said ring may be saturated or unsaturated and substituted with one or more subsitutuents as defined in A above, and may optionally be fused to a phenyl or further 5 or 6 membered heterocyclic ring.
- heterocyclic groups examples include pyridyl, quinolyl, benzimidazolyl, benzthiazolyl, benzdioxolanyl,
- benzothienyl triazolyl, imidazolyl, indazolyl, indolinyl, piperidyl and morpholinyl.
- heteroaryl used in relation to R 7 means a 5 or 6 membered aromatic heterocyclic group including, for example, pyridyl, thienyl and imidazolyl.
- linking groups B are possible and as well as simple straight-chain or branched alkylene and alkenylene groups, the invention includes groups containing an ether, thioether, amine or amide group and various cyclic variations thereof:
- the linking group, B is an ether group having an oxygen atom and up to four carbon atoms in the chain linking the group A to the phenyl ring.
- the linking group may optionally have a further oxygen atom in the chain and said chain may optionally be substituted by hydroxy, oxo (to give an. ester group), C 1 -C 4 alkoxy, C 1 -C 4 alkyl or phenyl.
- the linking group may also form part of a 5 to 7 membered cyclic ether group containing one or two oxygen atoms in the ring which may optionally be substituted by C 1 -C 4 alkyl hydroxy, oxo, or C 1 -C 4 alkoxy and which may optionally be fused to a phenyl or tetrahydronaphthalene ring.
- the ring may be for example, a tetrahydropyranyl, dioxolanyl, dioxanyl or dioxepanyl ring.
- the group, A is preferably a phenyl group which may optionally be substituted as defined in A above.
- this type include compounds of the following formulae-:
- R 1 , R 2 and R 3 being preferably H.
- Cyclic diethers are readily prepared by reaction of a diol with the appropriate aldehyde or ketone.
- reaction of a diol with the appropriate aldehyde or ketone.
- ester-linked derivatives may be prepared by reaction of the carboxylic acid of formula HO 2 C-D 1 -X with an alkanol of formula A-D 1 -OH or by reaction of an alkanol of formula HO-D 1 -X with an acid of formula A-D 1 -CO 2 H wherein A, and X are as previously defined and D 1 is as previously defined for D or it may be a direct bond.
- the linking group B contains an amide group together with up to three further carbon atoms in the chain linking A to the phenyl ring.
- the nitrogen atom may optionally be substituted by C 1 -C 4 alkyl and the chain may optionally be substituted by C 1 -C 4 alkyl or phenyl, or include a further oxo substituent.
- the group A may be phenyl, optionally substituted as defined in A above or it may be naphthyl, indanyl, or a heterocyclic group, for example a pyridyl, quinolyl, indazolyl, benzimidazolyl or benzthiazolyl group.
- this type include:
- reaction may conveniently be achieved via the acid chloride which may be prepared by reaction of the acid with, for example, oxalyl chloride in accordance with normal practice.
- the amino substituent R 7 is preferably H, C 1 -C 4 alkyl, CO 2 (C 1 -C 4 )alkyl or aryl(C 1 -C 4 )alkyl.
- the linking group in this case may optionally be cyclised to form a pyrrolidinyl group or piperidino group, which may optionally be fused to a benzene ring, or it may be an oxazoline ring.
- group A is preferably phenyl, optionally substituted as previously defined.
- group A is preferably phenyl, optionally substituted as previously defined.
- particular and preferred examples include :
- Further reactions include, for example, reaction of the amine products with n-butyl lithium followed by reaction with a C 1 -C 4 alkylchloroformate to give the N-alkoxycarbonyl derivatives, or alkylation to give the products where R 7 is C 1 -C 4 alkyl, aryl(C 1 -C 4 alkyl) or heteroaryl(C 1 -C 4 )- alkyl.
- the linking group B is a 7 membered saturated or mono-unsaturated ring containing -NR 7 - wherein R 7 is as previously defined.
- The. ring may optionally be substituted as previously defined under B; preferred substituents include oxo and CO 2 R 4 , particularly when R 4 is methyl.
- R 7 is preferably H, C 1 -C 4 alkyl, aryl(C 1 -C 4 ) alkyl or heteroaryl(C 1 -C 4 )- alkyl.
- A is preferably phenyl or substituted phenyl and said phenyl ring is benzofused to the 7-membered ring
- R 21 is H, methyl, 4-chlorobenzyl or 2-pyridylmethyl and X is as previously defined.
- each R 22 is independently H or an aryl group substituent as defined in A above, to give the 3-methoxycarbonyl-tetrahydro- benzazepin-2-one (VIII).
- a strong base e.g. sodium hydride
- R 22 is preferably H.
- the linking group B contains a S(O) m group together with up to four carbon atoms where m is 0-2 .
- the sulphur atom may be present as a thioether, sulphone or sulphoxide group.
- the chain may optionally be substituted by C 1 -C 4 alkyl or hydroxy.
- the group A is preferably phenyl optionally substituted as previously defined in A above. Particular and preferred examples of this type include:
- the linking group B is a C 1 -C 4 alkylene or alkenylene group which may optionally be substituted by one or more OH, oxo, CO 2 R 4 or perfluoroalkyl groups.
- the group A is preferably phenyl optionally substituted as defined in A above or is
- heptafluoropropyl examples include:
- R 4 is C 1 -C 4 alkyl and X is as previously defined, yields the 3-aryl-2-alkoxycarbonylprop-2-ene-1-one derivative. Reduction gives the 3-aryl-2-alkoxycarbonyl-1-hydroxypropyl derivative where the linking group is-:
- R 4 is C 1 -C 4 alkyl and D and X are as previously defined, by reaction with, for example, a perfluoroalkyl magnesium iodide, gives the corresponding perfluoroalkyl-carbonyl derivative.
- the ketone may be further reacted, for example with a further Grignard addition to give further disubstituted-methanol derivatives.
- the compounds may be purified using conventional methods such as recrystallisation or column chromatography as appropriate, and compounds having acidic or basic centres may be isolated as the free acid or base or in salt form. Compounds having asymmetric centres may be isolated as the racemic mixtures or resolved to give the individual enantiomers.
- the invention includes all enantiomers whether resolved or not.
- the pharmaceutically acceptable acid addition salts of the compounds of the formula (I) which form such salts are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate,
- the activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro . Testing is performed as follows:
- Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma.
- the plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH 2 PO 4 , 6mM Na 2 HPO 4 , 100 mM
- the activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF.
- a mixture of PAF (50 ⁇ g/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice.
- the compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier.
- the compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD 50 value.
- the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of
- ком ⁇ онентs for example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg).
- individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
- administration would typically be within the range 1 to 10 mg per single dose as required.
- inhalation via a nebuliser or aerosol may be the preferred route of drug administration.
- Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required.
- the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
- the invention provides a
- composition comprising a compound of the formula (I), without proviso, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
- the invention also includes a compound of the formula (I), without proviso, or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic, inflammatory and hypersecretory conditions in a human being.
- Methyl 2-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzyloxy]- benzoate (3.73 g, 10 mmol) was dissolved in ethanol (100 ml), 2N sodium hydroxide (20 ml) added and the solution stirred at room temperature for 2 hours. The solvent volume was reduced to 30 ml under reduced pressure and the residue poured into water (100 ml). The aqueous phase was washed with dichloromethane (2 x 50 ml) and acidified with glacial acetic acid.
- Butyllithium (1.6M in hexane; 0.91 ml, 1.46 mmol) was added in drops to a stirred suspension of 1-[4-(1,3-dihydroxypropyl)- phenyl]-2-methylimidazo[4,5-c]pyridine (0.2 g, 0.7 mmol) in anhydrous tetrahydrofuran. The mixture was heated to reflux for 30 minutes, then cooled and treated with chlorotrimethylsilane (0.22 ml, 1.7 mmol). After stirring for 16 hours, the solvent was evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate, ihe organic layer was dried over magnesium sulphate and concentrated to an oil.
- 1,2-Bistrimethylsilyloxy-1-phenylethane (from Preparation 6) (0.34 g, 1.2 mmol) was added to a cold (-70°C), stirred solution of trimethylsilyl trifluoromethane-sulphonate (0.23 ml, 1.2 mmol) in dry dichloromethane (2 ml). After 5 minutes, a solution of 4-(2-methylimidazo[4,5-c]-pyrid-1-yl)benzaldehyde (0.24 g, 1 mmol) in 2 ml of dichloromethane was added. The mixture was allowed to warm to 22.24°C then stirred at this temperature for 22 hours.
- step (a) The above procedure was followed using the appropriate amine in step (a) to yield the following products
- Glacial acetic acid was added to a stirred solution of
- diethylazodicarboxylate (6.283 ml, 1.8 mmol). The solution was stirred at ambient temperature for 16 hours then evaporated to dryness and the residual gum chromatographed on silica (230-400 mesh), eluting with 10% - 20% methanol in ethyl acetate.
- n-Butyl lithium (1.6M in hexane) (1.19 ml, 1.9 mmol) was added dropwise to a stirred solution of l-[4-(2-chlorobenzyl- aminomethyl)phenyl]-2-methylimidazo[4,5-c]pyridine (0.61 g, 1.7 mmol) in anhydrous tetrahydrofuran, under nitrogen, at -30°C.
- Oxalyl chloride (0.7 ml, 8 mmol) was added to a stirred solution of 2-chlorophenylacetic acid (340 mg, 2 mmol) in anhydrous dichloromethane (6 ml) under nitrogen. Anhydrous dimethylformamide (2 drops) was added and the solution stirred at ambient temperature for 2 hours. The solution was concentrated under high vacuum, then re-dissolved in dichloromethane (10 ml) and a solution of 4-(2-methylimidazo[4,5-c]-pyrid-1-yl)benzylamine (0.6 g, 2.5 mmol) in anhydrous dichloromethane (10 ml) added over 5 minutes.
- N-Methylmorpholine (1.6 ml, 16 mmol) was added to a stirred suspension of the product from c) above (0.7 g, 1.8 mmol),
- Example 118 using the appropriate aromatic aldehyde as starting material.
- Bis(trimethylsilyl)acetamide (5 mmol, 1.24 ml) was dissolved in tetrahydrofuran (15 ml) and cooled to -78°C in a CO 2 /acetone bath.
- Butyllithium (2.2M, in hexane, 5 mmol, 2.27 ml) was added dropwise over 5 minutes and the solution stirred at -78°C for a further 15 minutes.
- the aqueous phase was basified with 2N sodium hydroxide then extracted with dichloromethane (3 x 100 ml). The combined organic extracts were dried over Na 2 SO 4 , filtered and evaporated to dryness. Purification was effected by column chromatography on silica eluting with dichloromethane/ methanol/ ammonia 94:6:0.1 and the product-containing fractions evaporated to dryness. The resulting oil was dissolved in a little dichloromethane and the product precipitated with cold ether, (0.24 g, 37%). M.p. 126-128°C. Found: C,63.52; H.4.61; N.13.19. C 22 H 19 ClN 4 O 2 . 0.5 H 2 O requires C.63.54; H,4.81; N,13.47%.
- Examples 148-151 were prepared by the method of Example 1 using 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzyl alcohol and the appropriate phenol.
- Example 152 was prepared similarly using the procedure of Example 147 but isolating the product as the free basee
- Example 153 The product from Example 153 (2.43 g, 6.54 mmol) was dissolved in a mixture of methanol (60 ml), water (40 ml) and aqueous sodium hydroxide (1M, 3.27 ml, 3.27 mmol) at room temperature with stirring, and then sodium borohydride (254 mg, 6.54 mmol) was added. The mixture was stirred for 18 hours at room temperature, and then parlitioned between dichloromethane (3 x 50 ml) and 0.1M aqueous sodium hydroxide (200 ml).
- Example 154 was cyclised following the method of Example 157 to give the title compound, m.p. 219-220°C (from methanol). Found: C,70.50; H,4.73; N.11.21. C 22 H 18 FN 3 O 2 requires C,70.38; H,4.83; N,11.19%.
- Example 155 was cyclised following the method of Example 157 to give the title compound, m.p. 243-246°C (from methanol/dichloromethane). Found: C, 74.94; H.6.05; N.10.90.
- Example 157 The compound from Example 157 (371 mg, 1.0 mmol) was dissolved in dry dimethylformamide (8 ml) and sodium hydride (48 mg, 60% dispersion, 1.2 mmol) was added at room temperature.
- Example 37 The method of Example 37 was followed using 4-fluoro-(1,3- dihydroxypropyl)benzene to give the title compound, m.p. 70°C.
- step (c) The product from step (b) above, (240 mg, 0.76 mmol) was added to a mixture of trifluoroacetic acid (8 ml) and triethyl- silane (145 ⁇ l, 0.91 mmol), and the mixture was stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 ml) and rendered basic by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was separated, extracted with dichloromethane (2 x 15 ml), and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure.
- Butyllithium (1.6M in hexane; 19 ml, 30 mmol) was added dropwise to a cold (-20°C), stirred solution of phenylethanediol (2 g, 14.5 uuuol) in tetrahydrofuran (80 ml). After 10 minutes, neat chlorotrimethyl-silane (4.5 ml, 35 mmol) was added. After 30 minutes, all voiatiles were removed under vacuum and the residue was partitioned between hexane and saturated sodium bicarbonate solution. The hexane layer was dried over magnesium sulphate and evaporated to give the title product as a pale-yellow oil (4g, 97%).
- the creamy coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator.
- Nickel-aluminium alloy (1 g) was added to a stirred solution of 4-(2-methylimidazof4,5-c]pyrid-1-yl)benzonitrile (1 g, 4.3 mmol) in 90% formic acid (13 ml) and water (3 ml). The mixture was heated to 120°C when an exothermic reaction initiated, then heated under reflux for an additional 1 hour. The solution was cooled and filtered using a filter aid, washing the filter cake with methanol. The filtrate was concentrated and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to dryness.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB909010404A GB9010404D0 (en) | 1990-05-09 | 1990-05-09 | Therapeutic agents |
GB9010404 | 1990-05-09 |
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EP0530207A1 true EP0530207A1 (en) | 1993-03-10 |
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EP91907827A Withdrawn EP0530207A1 (en) | 1990-05-09 | 1991-04-17 | Imidazopyridine paf antagonists |
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EP (1) | EP0530207A1 (fi) |
JP (1) | JPH05505199A (fi) |
CA (1) | CA2078007A1 (fi) |
FI (1) | FI925054A0 (fi) |
GB (1) | GB9010404D0 (fi) |
IE (1) | IE911552A1 (fi) |
PT (1) | PT97587A (fi) |
WO (1) | WO1991017162A1 (fi) |
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GB9200245D0 (en) * | 1992-01-07 | 1992-02-26 | British Bio Technology | Compounds |
WO2001035964A1 (en) | 1999-11-18 | 2001-05-25 | Antexpharma, Inc. | Substituted 1-benzazepines and derivatives thereof |
US6242461B1 (en) * | 2000-01-25 | 2001-06-05 | Pfizer Inc. | Use of aryl substituted azabenzimidazoles in the treatment of HIV and AIDS related diseases |
HN2001000224A (es) * | 2000-10-19 | 2002-06-13 | Pfizer | Compuestos de imidazol condensado con arilo o heteroarilo como agentes anti - inflamatorios y analgesicos. |
TWI243164B (en) | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
US20040192728A1 (en) | 2003-02-03 | 2004-09-30 | Ellen Codd | Quinoline-derived amide modulators of vanilloid VR1 receptor |
US7449481B2 (en) | 2004-04-13 | 2008-11-11 | Cephalon, Inc. | Thio-substituted biaryl-methanesulfinyl derivatives |
TW200538453A (en) * | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
CA2580852A1 (en) | 2004-09-21 | 2006-03-30 | Synta Pharmaceutical Corp. | Compounds for inflammation and immune-related uses |
GB0507575D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
WO2007034277A1 (en) * | 2005-09-19 | 2007-03-29 | Pfizer Products Inc. | Aryl substituted imidazo [4,5-c] pyridine compounds as c3a receptor antagonists |
AU2007312310A1 (en) | 2006-10-16 | 2008-04-24 | Novartis Ag | Phenylacetamides useful as protein kinase inhibitors |
EP2651930B1 (en) * | 2010-12-16 | 2015-10-28 | Boehringer Ingelheim International GmbH | Biarylamide inhibitors of leukotriene production |
CA2877474A1 (en) * | 2011-06-20 | 2012-12-27 | Myrexis, Inc. | Compounds and therapeutic uses thereof |
CN106632107A (zh) | 2012-12-19 | 2017-05-10 | 巴斯夫欧洲公司 | 取代[1,2,4]三唑及其作为杀真菌剂的用途 |
JP7485502B2 (ja) * | 2016-05-04 | 2024-05-16 | ベ.セ.イ. ファルマ | プロテインキナーゼ阻害剤としてのアデニン誘導体 |
CN114262322A (zh) * | 2020-09-16 | 2022-04-01 | 中国科学院上海有机化学研究所 | 一类细胞程序性坏死抑制剂及其制备方法和用途 |
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MY104933A (en) * | 1987-09-30 | 1994-07-30 | Pfizer Ltd | Platelet activating factor antagonists |
GB8804439D0 (en) * | 1988-02-25 | 1988-03-23 | Pfizer Ltd | Dihydropyridines |
GB8905130D0 (en) * | 1989-03-07 | 1989-04-19 | Pfizer Ltd | Therapeutic agents |
DE69008906T2 (de) * | 1989-03-23 | 1994-08-25 | Pfizer | Antiallergische Mittel auf der Basis von Diazepin. |
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1990
- 1990-05-09 GB GB909010404A patent/GB9010404D0/en active Pending
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1991
- 1991-04-17 WO PCT/EP1991/000737 patent/WO1991017162A1/en not_active Application Discontinuation
- 1991-04-17 JP JP3507697A patent/JPH05505199A/ja active Pending
- 1991-04-17 CA CA002078007A patent/CA2078007A1/en not_active Abandoned
- 1991-04-17 EP EP91907827A patent/EP0530207A1/en not_active Withdrawn
- 1991-05-07 PT PT97587A patent/PT97587A/pt not_active Application Discontinuation
- 1991-05-08 IE IE155291A patent/IE911552A1/en unknown
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1992
- 1992-11-06 FI FI925054A patent/FI925054A0/fi unknown
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Publication number | Publication date |
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WO1991017162A1 (en) | 1991-11-14 |
GB9010404D0 (en) | 1990-06-27 |
PT97587A (pt) | 1992-02-28 |
FI925054A (fi) | 1992-11-06 |
JPH05505199A (ja) | 1993-08-05 |
CA2078007A1 (en) | 1991-11-10 |
FI925054A0 (fi) | 1992-11-06 |
IE911552A1 (en) | 1991-11-20 |
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