CN1298404A - Inhibitors of phospholipase A2 - Google Patents
Inhibitors of phospholipase A2 Download PDFInfo
- Publication number
- CN1298404A CN1298404A CN99805379A CN99805379A CN1298404A CN 1298404 A CN1298404 A CN 1298404A CN 99805379 A CN99805379 A CN 99805379A CN 99805379 A CN99805379 A CN 99805379A CN 1298404 A CN1298404 A CN 1298404A
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- CN
- China
- Prior art keywords
- alkyl
- cooh
- group
- phenyl
- compound
- 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.)
- Pending
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- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 102100037611 Lysophospholipase Human genes 0.000 title 1
- 108010058864 Phospholipases A2 Proteins 0.000 title 1
- 230000000694 effects Effects 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims description 247
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 201
- 238000000034 method Methods 0.000 claims description 115
- -1 xylylenimine Chemical compound 0.000 claims description 109
- 229910052736 halogen Inorganic materials 0.000 claims description 107
- 150000002367 halogens Chemical class 0.000 claims description 107
- 150000003839 salts Chemical class 0.000 claims description 91
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 87
- 239000000203 mixture Substances 0.000 claims description 72
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 150000002475 indoles Chemical class 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 26
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 150000002460 imidazoles Chemical class 0.000 claims description 19
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 16
- 150000002240 furans Chemical class 0.000 claims description 16
- 150000003217 pyrazoles Chemical class 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- 150000003233 pyrroles Chemical class 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 15
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 14
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 14
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 14
- 229930192474 thiophene Natural products 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 12
- 108090000790 Enzymes Proteins 0.000 claims description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 12
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 125000001041 indolyl group Chemical group 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- 150000003053 piperidines Chemical class 0.000 claims description 11
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 10
- 229940073608 benzyl chloride Drugs 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 7
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 7
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 7
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 7
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 7
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 claims description 7
- 108090000604 Hydrolases Proteins 0.000 claims description 7
- 102000004157 Hydrolases Human genes 0.000 claims description 7
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 7
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 7
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 claims description 7
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 claims description 7
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 7
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 claims description 7
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 7
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 claims description 7
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 7
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 7
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 7
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 7
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical compound C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 claims description 5
- 108010064785 Phospholipases Proteins 0.000 claims description 5
- 102000015439 Phospholipases Human genes 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- JJLZPNRRWPACDZ-UHFFFAOYSA-N 1-benzyl-5-(4-fluorophenyl)indole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(C=3C=CC(F)=CC=3)=CC=C2N1CC1=CC=CC=C1 JJLZPNRRWPACDZ-UHFFFAOYSA-N 0.000 claims description 2
- DANPCKAHXFNYDT-UHFFFAOYSA-N 1-benzyl-5-phenylindole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(C=3C=CC=CC=3)=CC=C2N1CC1=CC=CC=C1 DANPCKAHXFNYDT-UHFFFAOYSA-N 0.000 claims description 2
- KCJOYERDJPJBOI-UHFFFAOYSA-N 1-benzyl-5-thiophen-2-ylindole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(C=3SC=CC=3)=CC=C2N1CC1=CC=CC=C1 KCJOYERDJPJBOI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 2
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 claims description 2
- 150000001735 carboxylic acids Chemical group 0.000 claims 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 102100022893 Histone acetyltransferase KAT5 Human genes 0.000 abstract description 3
- 108020002496 Lysophospholipase Proteins 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 381
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 267
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 216
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 188
- 239000000243 solution Substances 0.000 description 185
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 131
- 235000019439 ethyl acetate Nutrition 0.000 description 130
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 121
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 117
- 238000002360 preparation method Methods 0.000 description 114
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 107
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 104
- 239000002904 solvent Substances 0.000 description 89
- 239000000047 product Substances 0.000 description 87
- 239000000376 reactant Substances 0.000 description 86
- 239000011541 reaction mixture Substances 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 57
- 238000003756 stirring Methods 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 238000005406 washing Methods 0.000 description 46
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 44
- 150000002148 esters Chemical class 0.000 description 39
- 238000003810 ethyl acetate extraction Methods 0.000 description 38
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 37
- 239000007788 liquid Substances 0.000 description 36
- 238000000605 extraction Methods 0.000 description 35
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 34
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 34
- 239000007787 solid Substances 0.000 description 34
- 239000012141 concentrate Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 239000003513 alkali Substances 0.000 description 32
- 229910000104 sodium hydride Inorganic materials 0.000 description 32
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- 239000000284 extract Substances 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- 238000000746 purification Methods 0.000 description 28
- 238000001914 filtration Methods 0.000 description 27
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 27
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000002253 acid Substances 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- 238000000643 oven drying Methods 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- 239000013058 crude material Substances 0.000 description 23
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 23
- 238000012856 packing Methods 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 150000001299 aldehydes Chemical class 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 18
- 239000012312 sodium hydride Substances 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 229960001866 silicon dioxide Drugs 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 239000012280 lithium aluminium hydride Substances 0.000 description 15
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 150000001263 acyl chlorides Chemical class 0.000 description 14
- 230000029936 alkylation Effects 0.000 description 14
- 238000005804 alkylation reaction Methods 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000012266 salt solution Substances 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 230000007062 hydrolysis Effects 0.000 description 13
- 238000006460 hydrolysis reaction Methods 0.000 description 13
- 229940095102 methyl benzoate Drugs 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 12
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 12
- 150000002617 leukotrienes Chemical class 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 235000015320 potassium carbonate Nutrition 0.000 description 12
- 150000003180 prostaglandins Chemical class 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 10
- 239000002168 alkylating agent Substances 0.000 description 10
- 229940100198 alkylating agent Drugs 0.000 description 10
- 125000003368 amide group Chemical group 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 10
- 238000011097 chromatography purification Methods 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
Inhibitors of cPLA2 activity are disclosed, having a chemical formula selected from the group consisting of (I), (II), and (III), (IV), (V) or (VI).
Description
The application is that the part of the patent application serial numbers 08/918,400 of application on August 26th, 1997 continues, and back one application is the continuation of the patent application serial numbers 80/703,115 of application on August 26th, 1996.Background of invention
The present invention relates to various Phospholipid hydrolases, particularly phospholipase A
2Active chemical inhibitor.
Leukotriene and prostaglandin(PG) are the important medium of inflammation.Leukotriene raises inflammatory cell such as neutrophilic granulocyte to inflamed sites, promotes these cells to exosmose and stimulates the infringement superoxide of this tissue and the release of proteolytic enzyme.Leukotriene also plays pathology physiological action [referring to B.Samuelson etc., Science, 237:1171-76 (1987)] in the anaphylaxis of asthma experience.Prostaglandin(PG) by increasing blood flow and therefore leukocyte increasing soak into inflamed sites and exacerbate inflammation.Prostaglandin(PG) also increases the weight of by stimulator inductive pain reaction.
The Prostaglandins and Leukotrienes instability is not preserved in cell, but stimulator is replied and by arachidonic acid synthetic [W.L.Smith, Biochem.J., 259:315-324 (1989)].Prostaglandin(PG) is produced by arachidonic acid by the effect of COX-1 and COX-2 enzyme.Arachidonic acid also is the substrate that causes producing the different enzymatic pathway of leukotriene.
Phospholipase A
2Enzyme (hereinafter is PLA
2) discharge the arachidonic acid send into these two kinds of different pathways of inflammation by membrane phospholipid sn-2 position.It is believed that PLA
2The inflammatory Prostaglandins and Leukotrienes biosynthesizing of lipid mediation and the rate-limiting step in the production process are represented in catalytic reaction.Work as PLA
2The phosphatide substrate belong to the phosphatidylcholine time-like that the sn-1 position has ehter bond, the lysophospholipid that is produced is the direct precursor of platelet activating factor (hereinafter being PAF), this is the another kind of effectively medium [S.I.Wasserman, Hospital Practice, 15:49-58 (1988)] of inflammation.
The focus of most of anti-inflammatory treatments concentrates on and prevents to produce prostaglandin(PG) or leukotriene by these different approach, but and not all concentrates on this.For example, Ibuprofen BP/EP, Asprin and indomethacin all are to suppress the NSAID that COX-1/COX-2 produces prostaglandin(PG), but do not have effect to producing leukotriene by the arachidonic acid inflammatory in other approach.On the contrary, zileuton only suppresses the approach that arachidonic acid is converted into leukotriene, and does not influence the generation of prostaglandin(PG).None influences the generation of PAF in these widely used antiphlogistons.
Therefore, proposed and promptly to have disturbed described inflammatory reaction to the useful mechanism of the active direct inhibition of PLA2 as therapeutical agent.[referring to for example J.Chang etc., Biochem.Pharmacol., 36:2429-2436 (1987)].
For the secretion signal and the final PLA that are characterised in that existence has been checked order by emiocytosis
2Enzyme family has carried out order-checking and structure and has determined.These excretory PLA
2The about 14kD of molecular weight, contain 7 necessary disulfide linkage of activity.A large amount of these PLA that find in mammalian pancreas, bee venom and various snake venom
2[referring to the reference 13-15 of for example above-mentioned Chang that quotes etc.; And E.A.Dennis, Drug Devel.Res., 10:205-220 (1987)].Yet, it is believed that this pancreas enzyme plays digestion, therefore should be inessential in the generation of the inflammatory mediator that must regulate its generation closely.
Determined first kind of non-pancreas PLA of people
2Primary structure.This non-pancreas PLA
2Being found in thrombocyte, synovia and the spleen, also is a kind of Secretases.This enzyme is a member of above-mentioned family.[referring to J.J.Seilhamer etc., J.Biol.Chem., 264:5335-5338 (1989); R.M.Kramer etc., J.Biol.Chem., 264:5768-5775 (1989); With A.Kando etc., Biochem.Biophys.Res.Comm., 163:42-48 (1989)].Yet, doubtly be that this enzyme is important in prostaglandin(PG), leukotriene and PAF synthetic, because described non-pancreas PLA
2Be a kind of extracellular protein, be difficult to regulate, and the next enzyme in the biosynthetic pathway of these compounds be an intracellular protein.In addition, evidence suggests PLA
2Be subjected to protein kinase C and G albumen to regulate [R.Burch and J.Axelrod, Proc.Natl.Acad.Sci.U.S.A., 84:6374-6378 (1989)], protein kinase C and G albumen are cytoplasmic proteins, must act on intracellular protein.Described non-pancreas PLA
2High reduction potentiality can not in cytosol, work, because will be reduced described disulfide linkage and make described enzyme deactivation.
In the mouse macrophage clone of RAW264.7 by name, identified mouse PLA
2The ratio work of 2 μ mols/min/mg of anti-reductive condition it is reported relevant with the molecule of about 60kD.Yet this albumen is not purified to homogeneous.[referring to C.C.Leslie etc., Biochem.Biophys.Acta., 963:476-492 (1988)].Reference cited above relates to described Phospholipid hydrolase, particularly PLA
2The data of function be attached to herein by reference.
Also identify and cloned cPLA2 A2 and (hereinafter be " cPLA
2").Referring to United States Patent (USP) the 5th, 322,776 and 5,354, No. 677, these patents are attached to herein by reference as whole proposition.The enzyme of these patents is PLA in the born of the same parents
2Enzyme produces by its natural origin purifying or with purified form, works in born of the same parents, and inflammatory stimulus is replied and produced arachidonic acid.
Preferably owing to identified several Phospholipid hydrolases, therefore preferably identify the chemical inhibitor of enzyme effect, described inhibitor can be used for treating the generation of inflammation, particularly prostaglandin(PG), leukotriene and PAF all needs the illness that suppresses.Still need to identify this AID in the art, to be used for the treatment of various disease states.
Summary of the invention
The invention provides and have compound or its pharmacy acceptable salt that is selected from following chemical structural formula:
With
Wherein:
A and any other group are irrelevant, are selected from-CH
2-and-CH
2-CH
2-;
B and any other group are irrelevant, are selected from-(CH
2)
n-,-(CH
2O)
n-,-(CH
2S)
n-,-(OCH
2)
n-,-(SCH
2)
n-,-(CH=CH)
n-,-(C ≡ C)
n-,-CON (R
6)-,-N (R
6) CO-,-O-,-S-and-N (R
6)-;
R
1Irrelevant with any other R group, be selected from-X-R
6,-H ,-OH, halogen ,-CN ,-NO
2, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
2Irrelevant with any other R group, be selected from-H ,-COOH ,-COR
5,-CONR
5R
6,-(CH
2)
n-W-(CH
2)
m-Z-R
5,-(CH
2)
n-W-R
5,-Z-R
5, C
1-C
10The aryl of alkyl, alkenyl and replacement:
R
3Irrelevant with any other R group, be selected from-H ,-COOH ,-COR
5,-CONR
5R
6,-(CH
2)
n-W-(CH
2)
m-Z-R
5,-(CH
2)
n-W-R
5,-Z-R
5, C
1-C
10The aryl of alkyl, alkenyl and replacement;
R
4Irrelevant with any other R group, be selected from-H ,-OH ,-OR
6,-SR
6,-CN ,-COR
6,-NHR
6,-COOH ,-CONR
6R
7,-NO
2,-CONHSO
2R
8, C
1-C
5The aryl of alkyl, alkenyl and replacement;
R
5Irrelevant with any other R group, be selected from-H ,-OH ,-O (CH
2)
nR
6,-SR
6,-CN ,-COR
6,-NHR
6,-COOH ,-NO
2,-COOH ,-CONR
6R
7,-CONHSO
2R
8, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl, replacement ,-CF
3,-CF
2CF
3With
R
6Irrelevant with any other R group, be selected from-H, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
7Irrelevant with any other R group, be selected from-H, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
8Irrelevant with any other R group, be selected from C
1-C
3The aryl of alkyl, aryl and replacement;
R
9Irrelevant with any other R group, be selected from-H ,-OH, halogen ,-CN ,-OR
6,-COOH ,-CONR
6R
7, tetrazolium ,-CONHSO
2R
8,-COR
6,-(CH
2)
nCH (OH) R
6With-(CH
2)
nCHR
6R
5
R
10Irrelevant with any other R group, be selected from-H ,-OH, halogen ,-CN ,-OR
6,-COOH ,-CONR
6R
7, tetrazolium ,-CONHSO
2R
8,-COR
6,-(CH
2)
nCH (OH) R
6With-(CH
2)
nCHR
6R
5
W is each independent use in being included in same compound the time, be selected from-O-,-S-,-CH
2-,-CH=CH-,-C ≡ C-and-N (R
6)-;
X and other any group are irrelevant, each independent use in the time of in being included in same compound, be selected from-O-,-S-and-N (R
6)-;
Z and other any group are irrelevant, and each independent use is selected from-CH in the time of in being included in same compound
2-,-O-,-S-,-N (R
6)-,-CO-,-CON (R
6)-and N (R
6) CO-;
M is each independent use in being included in same compound the time, is the integer of 0-4; And
N and m are irrelevant, and each independent use is the integer of 0-4 in the time of in being included in same compound.
The compounds of this invention preferably has the phosphatide enzyme inhibition activity.Other preferred embodiment comprises the compound with following chemical structural formula:
Compound with following chemical structural formula:
Compound with following chemical structural formula:
In particularly preferred embodiments, A is-CH
2-, and R
2For-(CH
2)
n-W-(CH
2)
m-Z-R
5These preferred compounds comprise that wherein n is 1, and m is 1, and W is-and S-and Z be the compound of-CO-; R wherein
5For-NHR
6Compound; R wherein
6Compound for the aryl that replaces; Independently be selected from the compounds that following substituting group replaces with wherein said aryl with one or more: halogen ,-CF
3,-CF
2CF
3,-(CH
2)
pCOOH ,-(CH
2)
pCH
3,-O (CH
2)
pCH
3,-(CH
2)
pOH ,-(CH
2)
pS (C
6H
6) ,-(CH
2)
pCONH
2With-CHR
11COOH, wherein R
11Be selected from alkyl, alkenyl, alkynyl group ,-(CH
2)
pOH and-O (CH
2)
pCH
3, and wherein p is the integer of 0-4.Other preferred compound comprises wherein R
1Be selected from-H and-OCH
2(C
6H
6), R
3For-COR
5, R
5For-OCH
2R
6, and R
6Compound for the aryl that replaces.In particularly preferred compound, described aryl is selected from following substituting group and replaces with one or more :-CF
3,-CF
2CF
3With-C (CH
3)
2CH
2CH
3
Compound or its pharmacy acceptable salt that following formula is arranged in compound of the present invention:
Wherein:
R
1And R
1, independently be selected from C
1-C
6Alkyl ,-Z-C
1-C
6Alkyl, phenyl ,-(CH
2)
n-Z-(CH
2)
n-phenyl, benzyl ,-(CH
2)
n-Z-(CH
2)
n-benzyl, naphthyl ,-(CH
2)
n-Z-(CH
2)
n-naphthyl, pyrimidyl ,-(CH
2)
n-Z-(CH
2)
n-pyrimidyl, described alkyl, phenyl, benzyl, naphthyl and pyrimidyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
Z is O or S;
N is the integer of 0-3;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6The part of alkyl or following formula:
N independently is chosen to be the integer that is selected from 0-3 in each case;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
1For-COOH or be selected from following part:
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Precursor is: comprise R
3Part or comprise R
3The combination of part comprise an acidic-group that is selected from carboxylic acid or following formula part:
R
5Be selected from:
A) formula L
2-M
2Part;
L
2Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-Z-,-(CH
2)
n-Z-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
2Be selected from-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
R wherein
8And R
9As above definition, and can be substituted any position on described ring or dicyclo; Or
B) part of following formula:
L wherein
3For chemical bond or be selected from following group :-CH
2-,-CH
2-Z-,-C (O)-,-O-,-S-or-(CH
2)
n-Z-(CH
2)
n-;
In the compound of this group that has just defined, a preferred subgroup comprises that wherein core element is the compound of indoles.In this indoles group, another subgroup is arranged, wherein R
1 'And R
2Be hydrogen, part R
3, R
4, R
5, R
8, R
9And R
10, n, L
1, L
2, M
1And M
2As above definition.Another preferred group, wherein R are arranged in this subgroup
15 of indoles.
Following formula: compound or its pharmacy acceptable salt are also arranged in The compounds of this invention:
Wherein:
R
1Be selected from-O-C
1-C
6Alkyl ,-S-C
1-C
6Alkyl ,-the O-phenyl ,-the S-phenyl ,-the O-benzyl ,-the S-benzyl, described alkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6The part of alkyl or following formula:
N independently is chosen to be the integer that is selected from 0-3 in each case;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4The combination of part comprise the part of carboxylic acid or following formula:
R
5Be formula-L
2-M
2Structure;
L
2Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
2Be selected from-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
R wherein
8, R
9And R
10As above definition.
Above-mentioned group the compound or its pharmacy acceptable salt that also preferably have following structure:
Wherein:
R
1Be selected from-O-C
1-C
6Alkyl ,-S-C
1-C
6Alkyl ,-the O-phenyl ,-the O-benzyl ,-the S-benzyl, described alkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
10Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6The part of alkyl or following formula
R wherein
4, R
5, R
8, R
9And R
10Such as claim 19 definition.
Compound or its pharmacy acceptable salt that following formula is also arranged in The compounds of this invention:
Wherein:
R
1And R
1 'Independently be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; Be connected directly to described indole ring or by-S-,-O-or-(CH
2)
n-bridging is connected to described indole ring following a), b) or loop section c):
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) can randomly contain 1-3 the assorted former dicyclo part of giving of ring that is selected from N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine (napthyridine), described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
D) part of following formula:
Z is O or S;
R
6Independently be selected from following relevant member: H ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl or-the S-benzyl, the phenyl of these groups or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Independently be selected from following relevant member :-OH ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NH
2,-(CH
2)
n-NH
2,-NH-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,-(CH
2)
n-NH-(C
1-C
6Alkyl) ,-(CH
2)
n-N (C
1-C
6Alkyl)
2, phenyl ,-O-phenyl, benzyl or-the O-benzyl; Or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
2-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and can randomly contain the dicyclo part that 1-3 is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine, described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3, is preferably 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, benzyloxy-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
6Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N in each case, for independently being selected from the integer of 0-3;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula-L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
1For-COOH or be selected from following part:
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
R
11Be selected from H, C
1-C
6Low alkyl group, C
1-C
6Cycloalkyl ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, preferred 1-3, and more preferably 1-2,
Y is C
3-C
5Cycloalkyl or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and can randomly contain the dicyclo part that 1-3 is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine, described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
D) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
Preferred compound comprises compound or its pharmacy acceptable salt with following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; Be connected directly to described indole ring or by-S-,-O-or-(CH
2)
n-bridging is connected to described indole ring following a), b) or loop section c):
A) furans, pyrroles or thiophene, they can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) pyridine, pyrimidine, piperidines or morpholine, they each can randomly be selected from following substituting group and replace by 1-3: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) cumarone, indoles, naphthalene, purine or quinoline, they can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
Z is O or S;
R
6Independently be selected from following relevant member: H ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl or-the S-benzyl, the phenyl of these groups or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Independently be selected from following relevant member :-OH ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NH
2,-(CH
2)
n-NH
2,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2,-(CH
2)
n-NH-(C
1-C
6Alkyl) ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, phenyl ,-O-phenyl, benzyl or-O-benzyl, furans, pyrroles, thiophene, pyridine, pyrimidine, thiazole, pyrazoles or morpholine, the ring of these groups can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3, is preferably 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, benzyloxy-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3Or-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N is chosen to be the integer that is selected from 0-3 in each case independently;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2-phenyl-C (O)-benzothiazole or formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
Other preferred compound comprises compound or its pharmacy acceptable salt with following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
2-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; By chemical bond-linking be connected to described indole ring or by chemical bonding or-S-,-O-or-(CH
2)
n-bridging is connected to furans, pyrroles or the thiophene of described indole ring, and described phenyl, benzyl, furans, pyrroles or thiphene ring can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
2-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
N is the integer of 0-3, preferred 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, benzyloxy-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3Or-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N is chosen to be the integer that is selected from 0-3 in each case independently;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2-phenyl-C (O)-benzothiazole or formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
The present invention also provides the method for the phospholipase activity of inhibitory enzyme, comprises the The compounds of this invention that gives mammalian subject treatment significant quantity.The method of treatment inflammatory reaction or illness also is provided, has comprised the The compounds of this invention that gives mammalian subject treatment significant quantity, the medicinal compositions that contains The compounds of this invention and pharmaceutically acceptable carrier also is provided.
The pharmacy acceptable salt of compound as herein described also is a part of the present invention, and can be used to implement Compounds and methods for as herein described.The accompanying drawing summary
Fig. 1-13 has described the flow process of synthetic The compounds of this invention.Described flow process is below described in further detail.Detailed description of the preferred embodiments
Term used herein " aryl " and " aryl of replacement " are interpreted as and comprise that monocycle is particularly including 5 yuan and 6 yuan of monocycles, aromatic ring and hetero-aromatic ring part and dicyclo aromatic ring and hetero-aromatic ring parts, particularly including the dicyclo part of 9-10 annular atoms.Wherein, aryl is interpreted as benzyl ring, is included in the benzyl ring of finding in phenoxy group, benzyl, benzyloxy, xenyl and other this class part.Aryl of the present invention and heteroaryl also comprise following group:
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium Huo Evil thiazole; Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine; Or
C) can randomly contain 1-3 dicyclo part that is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or naphthyridine.
" aryl of replacement " of the present invention comprises and can randomly be selected from this class part that following substituting group replaces by 1-3: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-COOH or its ester ,-NO
2,-NH
2,-CN ,-CF
3Or-OH or their combination, such as-CH
2CF
3,-NH (CH
3) etc.
These groups as chosen wantonly the replacement just described of a preferred subgroup comprise the part that is formed by benzene, pyridine, naphthalene or quinoline ring.Further preferred group comprises the group of furans, pyrroles, thiophene, pyrimidine and morpholine ring.One group of preferred aromatics bicyclic radicals comprises cumarone, indoles, naphthalene and quinoline ring.
The alkyl that this paper mentions, alkenyl and alkynyl group are meant this class group with individual, best 1-6 the carbon atom of 1-10, can be straight chain, side chain or ring-type.Except as otherwise noted, otherwise these groups straight or branched preferably.The halogen of this paper is interpreted as and comprises F, Cl, Br and I.
Preferred compound of the present invention is disclosed in following table I-VI.The synthetic method of listed compound in following description list I-VI.Compound number is numbered corresponding to this specific compound synthetic of following description embodiment in the table.
Table I-VI has also been reported the data of listed compound in " LysoPC " mensuration and tonka bean camphor (Coumarine) mensuration (referring to following examples 88).In the field in table, measurement result is with " IC
50" the value report, this value is compound suppresses 50% Phospholipid hydrolase enzymic activity in this mensuration a concentration.When IC not occurring
50During value, " NA " is illustrated in not detect from this compound in the corresponding mensuration and suppresses active, and blank box is illustrated in the application does not test this compound when submitting in this mensuration.
Also, in the experiment of rat palmula oedema, test the activity in vivo of The compounds of this invention according to the method described in the embodiment 89.The result is reported in the table VII.
The table VII
Compound number | Rat carrageenan inductive palmula oedema is suppressed % |
???????8 | ???????????????????29 |
???????10 | ??????????????????8.9 |
???????14 | ??????????????????34.2 |
???????15 | ??????????????????21.8 |
???????16 | ??????????????????26.3 |
???????17 | ??????????????????29.3 |
???????19 | ??????????????????10.5????????? |
???????20 | ??????????????????19.5 |
???????25 | ??????????????????17.5 |
???????26 | ??????????????????10.3 |
???????32 | ??????????????????26.7 |
???????33 | ??????????????????4.2 |
???????46 | ??????????????????12.5 |
???????47 | ??????????????????7.8 |
???????50 | ??????????????????11.7 |
???????67 | ??????????????????17.5 |
???????70 | ??????????????????21.7 |
???????76 | ??????????????????8.2 |
???????77 | ??????????????????13.0 |
" phospholipase activity " used herein is meant that the positive of measuring in (a preferably mensuration described in following examples 88) at phospholipid metabolism is active.When compound suppresses Phospholipid hydrolase (cPLA preferably in any available mensuration (a preferably mensuration described in following examples 88 or 89)
2) when active, then this compound has " phosphatide enzyme inhibition activity ".In preferred embodiments, a kind of compound has (1) IC in LysoPC measures
50Value is lower than about 25 μ M, is preferably lower than about 6 μ M; (2) IC in described vesica is measured
50Value is lower than about 50 μ M; (3) IC in PMN measures
50Value is lower than about 1 μ M; (4) IC in tonka bean camphor (Coumarine) is measured
50Value is lower than about 15 μ M; And/or (5) have detectable activity (preferably oedema reduces at least about 5%, more preferably at least about 10%, more preferably at least about 15%, 20-30% most preferably from about) in rat carrageenan inductive palmula oedema experiment.
The compounds of this invention can be used for suppressing Phospholipid hydrolase (cPLA preferably
2) activity, therefore and can be used for " treatment " (promptly treat, prevent or alleviate) inflammation or inflammation correlated response or illness (for example rheumatoid arthritis, psoriasis, asthma, inflammatory bowel and other disease of mediating by prostaglandin(PG), leukotriene or PAF) and other illness, such as osteoporosis, colitis, myelocytic leukemia, diabetes, become thin and atherosclerosis.
The present invention includes medicinal compositions and methods of treatment or the application of using The compounds of this invention.
Compound of the present invention can be used for medicinal compositions when mixing with pharmaceutically acceptable carrier.This composition also can contain (except that The compounds of this invention and carrier) thinner, weighting agent, salt, buffer reagent, stablizer, solubilizing agent and other material well known in the art.Term " pharmaceutically acceptable " is meant the non-toxic substance that does not disturb described active ingredient biological activity to render a service.The feature of described carrier will depend on route of administration.Described medicinal compositions can also contain other antiphlogiston.The factor that this class is extra or medicine can be included in the described medicinal compositions, producing synergistic effect with The compounds of this invention, or reduce the side effect that The compounds of this invention causes as far as possible.
Medicinal compositions of the present invention can be the liposome form, compound wherein of the present invention also mixes in the aqueous solution such as the lipid that exists with aggregated forms such as micella, insoluble monolayer, liquid crystal or stratiform multilayer with amphiphilic reagent except that with other pharmaceutically acceptable carrier mixes.The suitable lipid that is used for Liposomal formulation includes but not limited to monoglyceride, triglyceride, sulfatide, lysolecithin, phosphatide, saponin(e, bile acide etc.The preparation of this lipoid plastid preparation as is disclosed in United States Patent (USP) the 4th, 235, No. 871, United States Patent (USP) the 4th in the state of the art of this area, No. the 4th, 837,028,501, No. 728, United States Patent (USP) and United States Patent (USP) the 4th, 737, No. 323, all these patents all are attached to herein by reference.
Term used herein " treatment significant quantity " is meant that every kind of active ingredient of described medicinal compositions or method is enough to demonstrate the amount of significant patient's benefit, promptly treats, cures, prevention or amelioration of inflammation reaction or illness or improve the amount of this class treatment of conditions, healing, prevention or remission rate.When each active ingredient of being used for giving separately, this term is meant described independent component.When being used for composition, this term be meant produce described treatment effect, order or unite the combined amount of the described active ingredient that gives simultaneously.
In the enforcement of methods of treatment of the present invention or application, with the Mammals of The compounds of this invention with illness to be treated of treatment significant quantity.According to method of the present invention separately or the associating other therapies such as the therapy of using other antiphlogiston, cytokine, lymphokine or other Hemopoietic factor, give compound of the present invention.When giving jointly, can form the factor with described other antiphlogiston, cytokine, lymphokine, other Hemopoietic factor, thrombolytics or antithrombotic and give compound of the present invention simultaneously or sequentially with one or more other antiphlogistons, cytokine, lymphokine or other Hemopoietic factor.If order gives, then the attending doctor will determine The compounds of this invention to unite the proper order that other antiphlogiston, cytokine, lymphokine, other Hemopoietic factor, thrombolytics or antithrombotic form factor administration.
That use in described medicinal compositions or implement the inventive method the giving and can carry out with multiple ordinary method of The compounds of this invention is such as oral, suction or skin, subcutaneous or intravenous injection.
When the The compounds of this invention per os that will treat significant quantity gave, The compounds of this invention was tablet, capsule, powder, solution or elixir form.When giving with tablet form, medicinal compositions of the present invention can contain solid carrier in addition, such as gelatin or auxiliary.Described tablet, capsule and powder contain the The compounds of this invention of the 5-95% that has an appointment, preferably the The compounds of this invention of about 25-90%.When giving, can add liquid vehicle, such as oil such as peanut oil, mineral oil, soya-bean oil or sesame oil or the synthetic oil in water, oil, animal or plant source with liquid form.The described medicinal compositions of liquid form can also contain normal saline solution, glucose or other sugar soln or glycol such as ethylene glycol, propylene glycol or polyoxyethylene glycol.When giving with liquid form, described medicinal compositions contains the The compounds of this invention of the 0.5-90% that has an appointment (weight), preferably the The compounds of this invention of about 1-50%.
When the The compounds of this invention of significant quantity is treated in intravenously, skin or subcutaneous injection, compound of the present invention will be the acceptable aqueous solution form of pyrogen-free parenteral.The preparation of the protein solution that this class parenteral is acceptable, have suitable pH, isotonicity, stability etc. in the art technology scope interior.Be used for intravenously, skin or hypodermic preferred medicinal compositions except that containing The compounds of this invention, the vadose solution matchmaker such as also should contain, such as sodium chloride injection, RingerShi injection liquid, glucose injection, dextrose ﹠ sodium chloride injection, lactic acid RingerShi injection liquid or other solvent known in the art.Medicinal compositions of the present invention also can contain stablizer, sanitas, buffer reagent, antioxidant or other additive well known by persons skilled in the art.
The amount of the The compounds of this invention in the medicinal compositions of the present invention will depend on the character of the previous therapy of the character of illness to be treated and severity and described patient experience.The attending doctor will finally determine the amount in order to the The compounds of this invention of treatment individual patient.At first, the attending doctor will give the The compounds of this invention of low dosage and observe reaction.Can give more heavy dose of The compounds of this invention until the optimal treatment effect that obtains for described patient, no longer increase dosage this moment.Imagined in order to the various medicinal compositionss of implementing the inventive method and should contain the 0.1 μ g that has an appointment to about 100mg (preferably about 0.1mg is to about 50mg, and more preferably from about 1mg is to about 2mg) The compounds of this invention/kg body weight.
Adopt the time length of the intravenous therapy of medicinal compositions of the present invention to change with the severity of disease to be treated and each patient's illness and potential atopic reaction.The scope of having imagined each application time length of The compounds of this invention is continuous intravenous administration 12-24 hour.The attending doctor finally determines the suitable time length of the intravenous therapy of employing medicinal compositions of the present invention.The synthetic method of embodiment 1-87
Compound of the present invention can be according to method preparation described below.Temperature is degree centigrade.Method A
With two the step Ethyl indole-2-carboxylate is converted into the aldehyde II: in 0 ℃ make its in suitable solvent such as tetrahydrofuran (THF) (THF) with lithium aluminium hydride (LAH) or other hydride reaction, then solvent such as THF in oxygenant such as the Manganse Dioxide oxidation.With highly basic such as hexamethyl dimethyl silanyl ammonification potassium (KHMDS) in THF with the deprotonation of aldehyde II, then alkali such as triethylamine in chloro-formic ester reaction, produce the carbamate III.III is converted into the bromide IV with two steps: react with carbon tetrabromide in such as the dichloromethane solution of two (diphenylphosphino) propane at phosphonate reagent with sodium borohydride reaction and (2) in alcoholic solution (1).With replacing the bromide IV, obtain the ether V by the potassium phenylate that in suitable solvent such as THF or DMF, makes phenol and KHMDS prepared in reaction.Can V be converted into or trifluorumethylketone VII or carboxylic acid IX with different methods.In the presence of Tetrabutylammonium bromide, make V and trifluoromethyl trimethyl silyl (TMSCF
3) reaction, obtain trifluoromethyl alcohol, in methylene dichloride, its oxidation is obtained the ketone VI then with periodo alkane (periodinane) (Dess-Martin reagent).In this stage, can with or trifluoroacetic acid (TFA) or alkali remove carbamate such as sodium hydroxide.Then alkali such as sodium hydride in the presence of with suitable alkyl bromide with the indole nitrogen alkylation, produce VII.Perhaps, can V be gone protection, obtain VII with the alkyl bromide reaction then, in the THF aqueous solution, its oxidation be obtained sour IX with Textone with TFA or alkali aqueous solution.Method B
In THF with highly basic such as sodium hydride (NaH) with the deprotonation of 2-indyl carboxylic acid, ethyl ester I, it is reacted with suitable alkyl bromide obtain X then.With alkali such as aqueous sodium hydroxide solution hydrolysis X, then carbodiimide such as dimethylaminopropyl ethyl-carbodiimide hydrochloride (EDCI) in the presence of, suitable solvent such as methylene dichloride in the aniline reaction of aniline or replacement, obtain the acid amides XI.XI is hydrolyzed to corresponding sour XII at alkali in such as aqueous sodium hydroxide solution.Method C
In suitable solvent such as tetracol phenixin or methylene dichloride, make the reaction of indoles I and bromine or N-bromine succinimide, the indoles I 3 brominations, is obtained bromide X III.Highly basic such as NaH in the presence of, in THF or DMF, make the reaction of X III and suitable alkyl bromide obtain indoles X IV.Carry out palladium mediated X IV and suitable alkene coupling at phosphine and alkali in the presence of such as triethylamine, produce the indoles X V that 3-replaces.The X V can be converted into acid amides X VII with two-step reaction: (1) with alkali such as NaOH aqueous hydrolysis and (2) in the presence of carbodiimide such as EDCI with the amine coupling.By with the alkali aqueous solution hydrolysis then suitable solvent such as ether in the lithium hydroxide reaction, ester X VI can be converted into lithium salts X VIII.With n-Butyl Lithium suitable solvent such as THF in lithiumation, use acyl chlorides acidylate in THF then, obtain ketone X IX.The coupling of catalytic X IX of carbodiimide (EDCI) and suitable amine obtains the acid amides XX.Method D
Can the indoles I be converted into the X XI with two steps: (1) solvent such as THF in LAH reaction and (2) in usefulness tert-butyldimethylsilyl chloride (TBDMSCl) silylanizing in solvent such as methylene dichloride or DMF in the presence of alkali such as the imidazoles.Handle X XI at solvent such as THF in-60 ℃ with Grignard reagent such as ethyl-magnesium-bromide; in ether with the magnesium salts acidylate of suitable acyl chlorides such as Acetyl Chloride 98Min. with gained; highly basic such as NaH in the presence of in DMF with alkylogen such as monobromoethane alkylation on nitrogen, obtain ketone X XII.Remove silyl on the X XII in such as THF with Tetrabutylammonium bromide at solvent, use in such as methylene dichloride carbon tetrabromide and two (diphenylphosphino) ethane that the alcohol of gained is converted into bromide, obtain bromide XX III at solvent.Replace the bromine of XX III with mercaptan compound at alkali in the presence of such as cesium carbonate, or in the presence of highly basic such as NaH in DMF with the bromine of alcohol replacement XX III, obtain XX IV (being respectively sulfide or ether).Method E
In the presence of highly basic such as sodium hydride or KHMDS, solvent such as DMF in suitable alkyl bromide (or iodine) such as bromotoluene or iodoethane, will obtain the XX V with the aldehyde II alkylation of method A preparation.The XX V can be converted into unsaturated acid XX IV by two steps: (1) alkali such as sodium hydride in the presence of solvent such as THF in, carry out with suitable reagent such as phosphine acyl acetic acid trimethyl that Wittig reacts and (2) use the aqueous sodium hydroxide solution hydrolysis.With the coupled reaction of two inferior acid amides such as EDCI (dimethylaminopropyl ethyl-carbodiimide hydrochloride) catalysis XX VI and amine, use alkali such as the aqueous sodium hydroxide solution hydrolysis then, obtain the XX VII.Method F
Make indoles I reduction with LAH at solvent in such as THF.Carry out second time reduction with sodium cyanoborohydride at solvent in such as acetate, obtain pure XX VIII.Alkali such as triethylamine in the presence of with di-tert-butyl dicarbonic acid ester ((BOC)
2O), the nitrogen with tertbutyloxycarbonyl (BOC) protection XX VIII obtains carbamate XX IX.Solvent such as methylene dichloride in methylsulfonyl chloride and triethylamine hydroxyl methylsulfonylization with the XX IX, then as method D described in or mercaptan or alcohol replace generation indoline XXX.Go protection to obtain the XX XI XXX with trichoroacetic acid(TCA),, obtain XX XII or XXX III respectively itself or acidylate (acyl chlorides, triethylamine, methylene dichloride) or alkylation (alkylogen, salt of wormwood, DMF).Method G
Carboxylic acid XXX IV is converted into aldehyde XXX V with two steps: (1) in the presence of the EDCI solvent such as methylene dichloride in N, reduce with diisobutylaluminium hydride (DIBAL) in such as THF at solvent O-dimethyl hydroxylamine reaction and (2).Highly basic such as KHMDS in the presence of solvent such as THF in, handle the XXX V with the phosphine acyl acetic acid trimethyl, cause generating ester XXX VI.In hydrogenchloride with tin reduction XXX VI, then the inert solvent of heating such as toluene in cyclisation, obtain the XXX VII.The condition of describing at method F obtains sour XXX VIII with alkali such as NaOH aqueous hydrolysis ester then with the azanylization of XXX VII.Can by in the presence of EDCI with suitable amine coupling, the XXX VIII is converted into acid amides XXX IX.Method H
In the presence of highly basic such as KHMDS or NaH, solvent such as THF in, make the aldehyde XXX V for preparing among the method G carry out the Wittig reaction with iodate Jia base triphenyl phosphonium, obtain alkene X L.In ammonium chloride solution,, in the presence of alkali such as triethylamine, handle then, produce carbamate X L I with chloroformic acid benzyl ester with the nitro of iron powder reducing X L.Basic solution such as sodium bicarbonate aqueous solution in THF, obtain iodide X L II with iodinate X L I.Replace iodine on the X L II in such as DMF with lithium benzoate at solvent, use the NaOH hydrolysis then, obtain pure X L III.The method I
By the indoline XX VIII acidylate for preparing in method F or method H with acyl chlorides in the presence of such as triethylamine at alkali, perhaps in the presence of salt of wormwood solvent such as DMF in alkylogen with its alkylation, produce pure X L IV.Handle X L IV with methylsulfonyl chloride and triethylamine at solvent in such as methylene dichloride, replacing such as Methyl Thioglycolate with mercaptan at solvent in the presence of alkali such as the cesium carbonate, obtain ester X L V then such as acetonitrile.Obtain sour X L VI with alkali such as NaOH aqueous hydrolysis X L V, can solvent such as methylene dichloride in two inferior acid amides such as EDCI catalysis with itself and amine coupling, obtain acid amides X L VII.By in DMF, handling with alkylogen and highly basic such as NaH, can be with the alkylation on amide nitrogen of X L VII.Acid amides with alkali such as NaOH aqueous hydrolysis gained obtains sour X L IX.Can be sour X L VIII with X L IV direct hydrolysis also with NaOH.Method J
Method J has described aminophenyl acetic ester synthetic of alpha-substitution.Solvent such as THF in can with highly basic such as diisobutyl lithamide (LDA) with ester L deprotonation, use alkylogen such as the methyl-iodide alkylation subsequently, obtain the L I.By using palladium catalyzed hydrogenation in such as ethanol, can finish that the L I is reduced to amine L III at solvent.Can with LDA and oxa-aziridine (oxaziridine) L be oxidized to pure L II in such as THF at solvent.Highly basic such as NaH in the presence of in DMF with alkylating agent such as methyl-iodide with the alkylation of L II, in the presence of palladium, carry out catalytic hydrogenation generation amine L IV then.Method K
Synthesizing of the Aminobenzoate that method K description replaces.By following steps single sour L V is converted into acid amides L VI: (1) generates acyl chlorides with the oxalyl chloride reaction in methylene dichloride and handle such as dimethyl amine with suitable amine (2).As finishing nitroreduction by palladium catalyzed hydrogenation as described in the method J is amine.In THF, the L V can be reduced to pure L VIII with hydrogen borine-THF mixture.In the presence of imidazoles, be silyl ether with hydroxyl protection, then with nitroreduction (H with TBDMSCl
2/ Pd-C) be amine, obtain the L IX.Can with two the step L VIII is converted into secondary alcohol L X: (1) in ethyl acetate with suitable reagent such as Manganse Dioxide (MnO
2) oxidation and (2) add required Grignard reagent such as methylmagnesium-bromide in THF.In THF with the Manganse Dioxide oxidation L X and the nitro (H that reduces
2/ Pd-C), produce ketone L X III.With L VII reduction (H
2/ Pd-C) obtain the L XI.Method L
Solvent such as ethanol in, by the catalytic hydrogenolysis of palladium on carbon, the pure L X IV for preparing in the method I is gone benzylization.In the presence of salt of wormwood, use the alcohol of methoxy-benzyl chlorine being handled gained in such as THF at solvent, obtain L X V.Can pure L X V be converted into ether or sulfide L X VI with the method described in the method D.To methoxy-benzyl go protection with TFA at solvent in such as methylene dichloride, then in the presence of salt of wormwood, in solvent such as THF with suitable reagent such as the alkylation on oxygen of 4-benzyl bromotoluene, obtain L X VII.
The embodiment part
Following examples further describe the present invention.All temperature that propose among the embodiment are degree centigrade.All compounds are all levied by the proton resonance stave of obtaining on Varian Gemini 300 spectrometers or the suitable instrument.Embodiment 12-(2-(1-phenyl methoxycarbonyl-5-phenyl methoxyl group) indyl) methoxybenzoic acid
Step 1:2-(5-phenyl methoxyl group) indyl formaldehyde
2-(5-phenyl methoxyl group) indyl with 12.3g (42mmol)) ethyl formate is dissolved among the 100ml THF, in 0 ℃ to the THF solution that wherein adds 130ml (130mmol) 1M lithium aluminum hydride.Under this temperature, reactant was stirred 2 hours, by the quencher of slow adding 65ml 6N NaOH solution.Use the ethyl acetate extraction product, organic phase is washed with aqueous ammonium chloride solution.Evaporating solvent obtains crude alcohol, and this alcohol need not be further purified, and it is dissolved among the 400ml THF, adds 52g manganese oxide (IV), mixture is stirred under room temperature spend the night.Filter and remove manganese oxide also with 3: 1 hexanes: ethyl acetate is carried out the flash chromatography purifying, obtains the 8.15g title compound.
Step 2:(1-(2-formyl radical-5-phenyl methoxyl group) indyl) benzyl formate
In-35 ℃ of toluene solutions that in the 140ml THF solution of the aldehyde of 6.9g (27.5mmol) step 1, slowly add two (trimethyl silyl) ammonification potassium of 61ml (30.5mmol) 0.5M.After this temperature stirs 10 minutes, add 4.4ml (29.5mmol) chloroformic acid benzyl esters in-35 ℃, then with mixture from-35 ℃ of temperature to 0 ℃ 3.5 hours.By the quencher reaction to the aqueous ammonium chloride solution of inclining.The aqueous solution is handled and used 12: 1 toluene: ethyl acetate is carried out flash chromatography, obtains the 4.8g title compound.
Step 3:(1-(2-methylol-5-phenyl methoxyl group) indyl) benzyl formate
In the solution of 40ml THF solution and 20ml trifluoroethanol, add 760mg (20mmol) sodium borohydride in 0 ℃ of aldehyde to 2.9g (7.5mmol) step 2.Mixture was stirred 30 minutes in 0 ℃, by adding the aqueous ammonium chloride solution quencher.Adopt 2: 1 hexane-ethyl acetate to carry out flash chromatography, obtain the 2.2g title compound.
Step 4:(1-(2-brooethyl-5-phenyl methoxyl group) indyl) benzyl formate
To 1 of the pure and mild 2.05g (5.0mmol) of the step 3 of 2.2g (5.7mmol), in the two solution of (diphenylphosphino) propane in the 60ml methylene dichloride of 3-, in 15 ℃ of 4ml dichloromethane solutions that add 2.0g (6mmol) carbon tetrabromides.Mixture was stirred under room temperature 2 hours, and under room temperature, add 1g (3mmol) 1, two (diphenylphosphino) propane of 3-.Stir after 1 hour, by adding aqueous ammonium chloride solution quencher reaction.The aqueous solution is handled and adopted 4: 1 hexanes: the flash chromatography of ethyl acetate obtains the 1.7g title compound.
Step 5:(1-(2-(2-formyl radical phenoxy group) methyl-5-phenyl methoxyl group) indyl) benzyl formate
In 0 ℃ in the 18ml THF of the 2 hydroxybenzoic acid methyl esters of 439mg (3.6mmol) solution, add the toluene solution of two (trimethyl silyl) ammonification potassium of 6ml (3mmol) 0.5M.Solution was stirred 10 minutes in 0 ℃, in the THF solution of 0 ℃ of bromide of preparation in wherein adding 1.25g (2.8mmol) step 4.The reactant temperature was stirred 2 hours to room temperature and in this temperature.The aqueous solution is collected organic solvent after handling (ammonium chloride/ethyl acetate) processing, through dried over sodium sulfate and evaporation.Product is solidified and use ethyl acetate: hexane washs at 1: 1.Obtain 690mg (51%).
Step 6:
The aldehyde of the step 5 of 120mg (0.24mmol) is dissolved in 5: 1: 5 THF-acetonitriles-2 of 11ml, in the 2-dimethyl ethanol.To the 0.5ml aqueous solution that wherein adds 56mg (0.5mmol) Textone and 1 aqueous hydrogen peroxide solution.After 4 hours, add other 56mg (0.5mmol) Textone.Mixture was stirred under room temperature 3 days.The aqueous solution is handled and with 2.5: 1: 0.5 hexanes: ethyl acetate: acetate obtains the 110mg title compound.Embodiment 24-(2-(1-phenyl methoxycarbonyl-5-phenyl methoxyl group) indyl) methoxybenzoic acid
Prepare title compound according to embodiment 1 described method, but use the 4-hydroxy benzaldehyde.Embodiment 33-(2-(1-phenyl methoxycarbonyl-5-phenyl methoxyl group) indyl) methoxybenzoic acid
Prepare title compound according to embodiment 1 described method, but use the 3-hydroxy benzaldehyde.Embodiment 41-(2-(2-(1-oxo-2,2,2-trifluoroethyl) phenoxy group) methyl-5-phenyl methoxyl group) indyl) benzyl formate
Step 1:1-(2-(2-(1-hydroxyl-2,2,2-trifluoroethyl) phenoxy group) methyl-5-phenyl methoxyl group) indyl) benzyl formate
The solution of aldehyde in 4ml THF of preparation in embodiment 1 step 1 of 0.4g (0.8mmol) is cooled to 0 ℃.To wherein adding 0.24ml (1.6mmol) trifluoromethyl trimethyl silane and 5mg 4-butyl ammonium fluoride trihydrate.Reactant in 0 ℃ of stirring 2.5 hours, is added extra 0.2ml (1.3mmol) trifluoromethyl trimethyl silane and 5mg 4-butyl ammonium fluoride trihydrate.After 2 hours, use aqueous ammonium chloride solution and ethyl acetate processing reaction thing in 0 ℃ of stirring.Carry out the silica gel column chromatography purifying with 4: 1 hexane-ethyl acetate and obtain corresponding TMS ether.1N HCl solution with 1.3ml is handled TMS ether under room temperature, with salt solution and ethyl acetate treating water solution, through chromatography purification, with 3: 1 hexane-eluent ethyl acetates, obtain the 230mg title compound.
Step 2:
In 150mg (0.27mmol) step 1, in the solution of trifluoroethanol in the 5.5ml methylene dichloride of preparation, add 255mg (0.6mmol) Dess-Martin perfluor iodate.Mixture was stirred under room temperature 1 hour, be allocated in then between sodium bicarbonate aqueous solution and the ethyl acetate.Organic phase with 3: 1 hexane-ethyl acetate chromatography purifying, obtains the 150mg title compound with sodium bicarbonate aqueous solution washing 1 time.Embodiment 53-(2-(1-benzyl-5-benzyloxy) indoles formamido group) phenylformic acid
Step 1:2-(1-benzyl-5-benzyloxy) indolecarboxylic acid ethyl ester
In in the 12mlDMF solution of 1g (3.4mmol) 5-benzyloxy indole-2-ethyl formate, add under the room temperature sodium hydride (0.163g, 60% oil dispersion, 4.07mmol).Reactant was stirred 30 minutes.(0.44ml 3.73mmol) and again stirs reactant 1 hour to add bromotoluene this moment.Finish reaction (through TLC monitoring=0.5Rf, at hexane: in the ethyl acetate), water quencher reaction is with ethyl acetate extraction (3 *).Organic phase through dried over mgso, concentrate and be used for next step.
Step 2:2-(1-benzyl-5-benzyloxy) indolecarboxylic acid
The ester (3.4mmol) of preparation in the step 2 is dissolved among the THF (20ml), adds methyl alcohol (20ml), add 1N NaOH then.Reaction mixture stirred under room temperature spend the night, concentrate it this moment, dilute with water, be acidified to pH5 and use ethyl acetate extraction (3 *) with 10%HCl, organic extract liquid obtains described indolic acid (1.14g, 94.2% through dried over mgso and concentrated, TLC=0.5Rf has 1: 1 hexane of 1% acetate: in the ethyl acetate).
Step 3:3-(2-(1-benzyl-5-benzyloxy) indoles formamido group) ethyl benzoate
Acid (0.54g 1.5mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) (0.32g with step 2,1.66mmol), 4-dimethylaminopyridine (DMAP) (0.081g, 0.15mmol) and the 3-subcutin (0.27g 1.66mmol) stirs under room temperature in tetrahydrofuran (THF) and spends the night.Second day, reactant was with ethyl acetate and water dilution, with ethyl acetate extraction (3 *), through dried over mgso and concentrated.Crude material on silica gel with 3: 1 hexanes: the ethyl acetate purifying obtains pure acid amides (0.578g 76%, and TLC=0.4Rf is at 3: 1 hexanes: in the ethyl acetate).
Step 4:
(0.578g 1.15mmol) is dissolved among the THF (13.6ml), adds methyl alcohol (13.6ml), adds 1N NaOH (9.6ml) then with the ester of preparation in the step 3.Reaction mixture stirred under room temperature spend the night, concentrate it this moment, dilute with water, be acidified to pH5 and use ethyl acetate extraction (3 *) with 10%HCl, organic extract liquid obtains title compound (0.437g, 80% through dried over mgso and concentrated, TLC=0.5Rf has 3: 1 hexanes of 1% acetate: in the ethyl acetate).
With the method for embodiment 5, with embodiment 6,7,8,9,10 and 11 in suitable amine and the alkylogen preparation table I.Embodiment 123-(2-(3-(2, two (1, the 1-dimethyl propyl) the phenoxy group ethanoyl of 4-)-5-methoxyl group-1-methyl) indyl) methylthio group acetylaminohydroxyphenylarsonic acid 4-methoxybenzoic acid
Step 1:2-(5-methoxyl group) indyl methyl alcohol
(30g 102mmol) is dissolved among the 250ml THF and is cooled to 0 ℃, adds lithium aluminum hydride (LAH) (255ml1.0M THF solution) by addition funnel in 40 minutes with 5-methoxyl group-2-indolecarboxylic acid ethyl ester.Reactant in 0 ℃ of restir 2 hours, is added 4N NaOH (190ml) then and handles.The salt of gained is filtered, and (3 * 400ml) washings, merging filtrate is also also concentrated through dried over mgso, obtains 24.8g alcohol, and it is directly used in next step reaction with ethyl acetate.
Step 2:2-(5-methoxyl group) indyl methoxyl group-tertiary butyl dimethylsilane
With in the step 1 preparation rough indanol (6.2g 32.6mmol) is dissolved among the DMF (10.5ml).In this solution, add imidazoles (5.5g, 81.5mmol) and tert-butyldimethylsilyl chloride (5.4g, 35.8mmol).Mixture stirred under room temperature spend the night.Incline reactant to water and usefulness ethyl acetate extraction (3 *).Organic layer is through dried over mgso and concentrated.Crude material on silicagel column with 19: 1 hexanes: the ethyl acetate purifying obtains pure product (yield is 94% for 9.5g, 31mmol, and TLC:0.8Rf is at toluene: in the ethyl acetate 2: 1).
Step 3:3-(2-t-butyldimethylsilyloxy ylmethyl-5-methoxyl group) indyl (2, two (1, the 1-dimethyl propyl) phenoxy groups of 4-) methyl ketone
With 2.32g (7.95mmol) 2, the two tert.-amylbenzene ethoxyacetic acids of 4-are dissolved in the methylene dichloride (21ml), and (1.4ml 16.1mmol), adds dimethyl formamide (0.5ml) then under room temperature to add oxalyl chloride.After 1 hour reactant is concentrated also and methylbenzene azeotropic, placed high vacuum following 2 hours.
In another reaction vessel; indoles (2g with the silyl protection of preparation in the step 2; 6.56mmol) ether (20ml) drips of solution add to ethylmagnesium bromide (2.4ml 3M diethyl ether solution, in ether 7.2mmol) (10ml) solution, the latter maintain-78 ℃.Reactant was stirred 2 hours in-60 ℃.The ether (4ml) of the acyl chlorides of preparation more than in this reaction soln, dripping.Reactant was kept 2 hours between-50 ℃ to-60 ℃ again.Reactant saturated sodium bicarbonate quencher then.With ethyl acetate extraction (3 *).Organic layer is through dried over mgso and concentrated.Crude material on silicagel column with 19: 1 hexanes: the ethyl acetate purifying obtains pure product (2.36g, 50%, TLC:0.15Rf is at hexane: in the ethyl acetate 19: 1).
Step 4:3-(2-t-butyldimethylsilyloxy ylmethyl-5-methoxyl group-1-methyl) indyl (2, two (1, the 1-dimethyl propyl) phenoxy groups of 4-) methyl ketone
Under room temperature to the ketone of step 3 (1.97g, add in 12ml DMF solution 3.4mmol) sodium hydride (0.163g, 60% oil dispersion, 4.07mmol).Reactant was stirred 30 minutes.(0.23ml 3.73mmol) and again stirs reactant 1 hour to add methyl-iodide this moment.Water quencher reaction when (by the TLC monitoring) finished in reaction, reactant ethyl acetate extraction (3 *).Organic layer concentrates through dried over mgso, and crude product is used for next step.
Step 5:3-(2-methylol-5-methoxyl group-1-methyl) indyl (2, two (1, the 1-dimethyl propyl) phenoxy groups of 4-) methyl ketone
With in the step 4 preparation the N-skatole (2.01g, 3.4mmol) (8.5ml 1M THF solution, 8.5mmol) mixture in THF (17.9ml) stirred 1 hour under room temperature with tertiary butyl Neutral ammonium fluoride (TBAF).This moment, reactant diluted with ethyl acetate and water, with ethyl acetate extraction (3 *), also concentrated through dried over mgso.The crude material hexane: 2: 1 purifying on silica gel of ethyl acetate obtain pure alcohol (0.82g, 60%, TLC:0.3Rf is at 2: 1 hexanes: in the ethyl acetate).
Step 6:3-(2-(3-(2, two (1, the 1-dimethyl propyl) phenoxy groups of 4-) ethanoyl-5-methoxyl group-1-skatole base) methyl thioacetyl amino)-4-methoxyl methyl benzoate
(0.20g 0.43mmol) is dissolved in the methylene dichloride (0.7ml), with triethylamine (0.1ml with the indanol of preparation in the step 5,0.64mmol) handle and be cooled to 0 ℃, added methylsulfonyl chloride this moment in 5 minutes (0.04ml 0.52mmol), adds 2 DMF then.Reactant again in 0 ℃ of stirring 2 hours, is concentrated it and be directly used in next reaction then.
The methanesulfonates of above preparation is dissolved among the DMF (0.8ml).By feeding nitrogen 10 minutes solution is outgased.Add cesium carbonate (0.25g, 1.29mmol), be added in then the mercaptan for preparing in the intermediate I (0.11g, 0.43mmol).The mixture stirring is spent the night, incline then to saturated ammonium chloride,, concentrate with ethyl acetate extraction (3 *), drying.The crude material hexane: ethyl acetate=2: 1 purifying on silicagel column obtains pure products (0.12g, 40%, TLC:0.3Rf is at hexane: in the ethyl acetate 1: 1).
Step 7:
(0.12g 0.17mmol) is dissolved among the THF (1.0ml), adds methyl alcohol (1.0ml), adds 1N NaOH (0.4ml) then with the ester of step 6.Reaction mixture stirred under room temperature spend the night, concentrate it this moment, dilute with water, be acidified to pH5 with 10%HCl, with ethyl acetate extraction (3 *), organic extract liquid is through dried over mgso and concentrated, obtain title compound (85mg, 72%, TLC=0.3Rf is at the hexane with 1% acetate: in the ethyl acetate 1: 1).
By the method for embodiment 12, with 2-(5-benzyloxy) indolecarboxylic acid ethyl ester, acetylfluoride and suitable alkylogen, the embodiment 13,14,15 and 16 in the preparation table I.Embodiment 173-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio group acetylamino benzoic acid
Step 1:2-(5-benzyloxy) indolinyl methyl alcohol
(30g 102mmol) is dissolved among the 250ml THF and is cooled to 0 ℃, adds lithium aluminum hydride (LAH) (255ml1.0M THF solution) by addition funnel in 40 minutes with 5-benzyloxy-2-indolecarboxylic acid ethyl ester.Reactant in 0 ℃ of stirring 2 hours, is added 4N NaOH (190ml) then and handles.The salt of gained is filtered, and (3 * 400ml) washings, merging filtrate is also also concentrated through dried over mgso, obtains 24.8g with ethyl acetate.Then this crude material is dissolved in the glacial acetic acid (260ml), the yellow solution of gained is cooled to 15 ℃, (18.5g 294mmol), stirs the reaction mixture of gained 3 hours to drip sodium cyanoborohydride in 10 minutes.Reactant is by the quencher to 1.5 liters of almost saturated sodium bicarbonates of slowly inclining, and with ethyl acetate extraction (3 *), through dried over mgso and concentrate, obtains orange solids (29.6g).
Step 2:1-(5-benzyloxy-2-methylol) indolinyl t-butyl formate
With in 25g (85mmol) step 1 preparation crude alcohol and 4-dimethylaminopyridine (DMAP) (1.19g 9.78mmol) is dissolved in the methylene dichloride (180ml).Solution is cooled to 0 ℃, add then triethylamine (13.6ml, 98mmol).Stir after 10 minutes, in 2 hours, add tert-Butyl dicarbonate (21.3ml, 98mmol) solution that is dissolved in methylene dichloride (20ml) by syringe.Stir after 1 hour, by adding 1/2 saturated ammonium chloride solution quencher reactant, with dichloromethane extraction (3 *), through dried over mgso and concentrated, obtain the 36.3g yellow oil, with 9: 1-4: 1-1: 1 hexane: ethyl acetate gradient liquid obtains described product (15.25g, 44%) by column chromatography purification.
Step 3:2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl methylmercaptan ethyl acetoacetic ester
(15.25g 43mmol) is dissolved in the methylene dichloride (180ml) and (9.0ml 64.4mmol) handles with triethylamine with the carbamate of preparation in the step 2.Solution is cooled to-10 ℃, this moment in 5 minutes, add methylsulfonyl chloride (4.3ml, 56mmol).Reactant in-10 ℃ of restir 2 hours, is concentrated and is directly used in next step substitution reaction with it then.
The methanesulfonates of above preparation is dissolved among the DMF (85ml, strong suggestion is with the solvent degassing), add cesium carbonate (35g, 107.3mmol), add then ethyl thioacetate (4.70ml, 42.9mmol).Mixture was stirred 1 day, incline then to 1/2 saturated ammonium chloride and with ethyl acetate extraction (3 *), drying concentrates and chromatographic separation (hexane: ethyl acetate gradient liquid 10: 1-4: 1), obtain the 8.55g yellow oil product.
Step 4:2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl methylthio group acetate
(5g adds entry (10ml) in methyl alcohol (100ml) solution of 1M potassium hydroxide 11mmol) to the indoline ester of preparation in step 3.Reactant was stirred under room temperature 2 hours, this moment dilute with water, be acidified to pH5 with 10%HCl, and with ethyl acetate extraction (3 *), organic extract liquid obtains described indoline acid (4.5g, 95.5% through dried over mgso and concentrated, TLC=0.5Rf has 2: 1 hexanes of 1% acetate: in the ethyl acetate).Described crude material is directly used in next step.
Step 5:3-(2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl methylmercaptan ethyl amido ethyl benzoate
Acid (3g with preparation in the step 4,7mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.6g, 8.4mmol), 4-dimethylaminopyridine (0.85g, 7mmol) and the 3-subcutin (1.27g 7.7mmol) stirs under room temperature in tetrahydrofuran (THF) and spends the night.Second day, reactant was with ethyl acetate and water dilution, with ethyl acetate extraction (3 *), through dried over mgso and concentrated.Crude material was with 3: 1 hexanes: ethyl acetate is purifying on silica gel, obtains described product (3.4g, 85%, TLC=0.3Rf is at 3: 1 hexanes: in the ethyl acetate).
Step 6:3-(2-(5-benzyloxy) indolinyl) methylmercaptan ethyl amido ethyl benzoate
(3.4g adds trifluoroacetic acid (24ml) in 5.9mmol), and reactant was stirred 1 hour in 0 ℃ to the indoline of step 5.By adding entry quencher reaction, by adding in the sodium bicarbonate and described TFA, water layer also concentrates through dried over mgso with ethyl acetate extraction (3 *).Crude material was with 2: 1 hexanes: ethyl acetate is purifying on silica gel, obtains described product (2.7g, 96%, TLC=0.3Rf is at 2: 1 hexanes: in the ethyl acetate).
Step 7:3-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylmercaptan ethyl amido ethyl benzoate
With 2, (0.228g 0.78mmol) is dissolved in the methylene dichloride (2ml) two (1, the 1-dimethyl propyl) phenyliums of 4-, and (0.14ml 1.6mmol), adds dimethyl formamide (0.1ml) then to wherein adding oxalyl chloride under room temperature.After 1 hour, reactant is concentrated also and methylbenzene azeotropic, placed high vacuum following 2 hours.With in the step 6 preparation indoline to (0.308g; 0.65mmol) and 4-dimethylaminopyridine (0.008g; 0.066mmol) be dissolved in the methylene dichloride (1.2ml); methylene dichloride (0.5ml) solution that adds the chloride of acid of above preparation; add then triethylamine (0.28ml, 1.95mmol).Reactant stirred under room temperature spend the night, then with ethyl acetate and water dilution, with ethyl acetate extraction (3 *), through dried over mgso and concentrate.Crude material was with 2: 1 hexanes: ethyl acetate is purifying on silica gel, obtains described product (0.291g, 60%, TLC=0.4Rf is at 2: 1 hexanes: in the ethyl acetate).
Step 8:
(0.231g 0.31mmol) is dissolved among the THF (4.3ml), adds methyl alcohol (4.3ml), adds 1N NaOH (3.2ml) then with the ester of step 7.Reaction mixture stirred under room temperature spend the night, concentrate it this moment, dilute with water, be acidified to pH5 with 10%HCl, with ethyl acetate extraction (3 *), organic extract liquid is through dried over mgso and concentrated, obtain title product (0.207g, 93.2%, TLC=0.3Rf has 2: 1 hexanes of 1.5% acetate: in the ethyl acetate).Embodiment 183-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio group acetylaminohydroxyphenylarsonic acid 4-tolyl acid
Step 1:2-(5-benzyloxy) indolinyl methylmercaptan ethyl acetoacetic ester
(3.0g 6.6mmol) adds in the flask and is cooled to 0 ℃ with the N-tert-butoxy carbonyl dihydro indoles of preparation in embodiment 17 steps 3.In this reaction mixture, add trifluoroacetic acid (35ml), reactant in 0 ℃ of stirring 1 hour, was stirred 1 hour under room temperature then.Reactant is by adding the entry quencher, and by adding in the solid sodium bicarbonate and described TFA, water layer through dried over mgso and simmer down to orange (1.85g, 79%), is directly used in next step with it with ethyl acetate extraction (4 *).
Step 2:2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl methylmercaptan ethyl acetoacetic ester
With 2,4-two (1, the 1-dimethyl) phenylium (2.0g propyl group), 6.8mmol), methylene dichloride (15ml), oxalyl chloride (1.2ml, 13.6mmol), dimethyl formamide (0.1ml) stirred 45 hours in 0 ℃, this moment reactant is concentrated and with methylbenzene azeotropic (1 *), concentrated under high vacuum before using.Indoline ester (1.85g with preparation in the step 1,5.2mmol) and 4-dimethylaminopyridine (0.08g) be dissolved in the methylene dichloride (15ml), add above methylene dichloride (5ml) solution that produces acyl chlorides then, add subsequently triethylamine (0.95ml, 6.8mmol).Reactant was stirred under room temperature 16 hours, handle and concentrated (4.0g, orange), with 9: 1-6: 1 hexane: ethyl acetate gradient chromatography, obtain described product (2.5g, 75%), it is used for next step without being further purified.
Step 3:2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl methylthio group acetate
(2.5g 3.9mmol) is dissolved among the THF (20ml), adds methyl alcohol (6ml), adds 1N NaOH (12ml) then with the ester of step 2.Reaction mixture was stirred 24 hours, and concentrate it this moment, and dilute with water is acidified to pH4 with dense HCl, and with ethyl acetate extraction (4 *), organic extract liquid is through dried over mgso, concentrated and through chromatography purification (3: 1 hexanes with 1% acetate; Ethyl acetate), obtain the described product of 1.17g white solid.
Step 4:3-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio group acetylaminohydroxyphenylarsonic acid methyl 4 methylbenzoate
With the acid of step 3 (0.20g, 0.33mmol), EDCI (0.08g, 0.43mmol), DMAP (4mg, 0.03mmol) and 3-amino-4-hydroxy methyl benzoate (0.06g 0.33mmol) is dissolved among the THF (3ml) and refluxed 16 hours.Carry out the aqueous solution with ammonium chloride and ethyl acetate and handle, and through silica gel column chromatography purifying (hexane: ethyl acetate 3: 1), obtain the described product of 0.13g (52%) white solid.
Step 5:
According to the described method of step 3, the ester that is prepared by step 4 prepares title compound.
According to or embodiment 17 or embodiment 18 described in method, the product of the embodiment 17-36 of preparation in the table 2.Embodiment 372-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylthio group acetate
Step 1:2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methyl alcohol
The 17.0g (59mmol) 3 that in the round-bottomed flask of the 1L oven drying of being furnished with magnetic force splash bar and balanced dropping funnel, packs into, two (trifluoromethyl) benzyloxy acetate of 5-, DMF (5) and anhydrous methylene chloride (300ml).In 10 minutes, drip oxalyl chloride (23ml, 263mmol).After stirring 2.5 hours under the room temperature, vacuum is removed solvent, and promptly excessive oxalyl chloride obtains the acyl chlorides of white solid.It is used for next reaction immediately.
2-(5-benzyloxy) the indolinyl methyl alcohol, DMAP of preparation in 15.3g (60ml) embodiment 17 steps 1 of in the round-bottomed flask of the 1L oven drying of being furnished with magnetic force splash bar and balanced dropping funnel, packing into (0.73g, 6mmol) and anhydrous methylene chloride (300ml).After being cooled to 0 ℃, drip anhydrous methylene chloride (100ml) solution of the acyl chlorides (59mmol) of above preparation, drip NEt then
3(9ml, 64.7mmol).After 1 hour, reaction mixture is with saturated sodium bicarbonate solution (100ml), 1N HCl solution (100ml) and water (100ml) washing, through dried over sodium sulfate and filtration in 0 ℃ of stirring.Vacuum is removed solvent.Hexane solution with 25-40%AcOEt carries out purification by silica gel column chromatography, obtains the product of light yellow solid.Output is 22.0g (71%).
Step 2:2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl acetoacetic ester
(19.0g 36.15mmol), drips anhydrous methylene chloride (300ml) and NEt to the alcohol of preparation in the step 1 of packing in the round-bottomed flask of the 500ml oven drying of being furnished with the magnetic force splash bar
3(7.5ml, 54.23mmol).In 2 minutes, drip MsCl and reaction mixture was stirred 10 minutes under room temperature.Solution is with methylene dichloride (500ml) dilution, with 1N HCl (100ml) and saturated sodium bicarbonate solution (100ml) washing.Dichloromethane solution is through dried over sodium sulfate and filtration.Remove solvent, described methanesulfonates is used for next step without being further purified.
Packing in the round-bottomed flask of the 500ml oven drying of being furnished with the magnetic force splash bar, (4.2ml is 38.5mmol) with anhydrous THF (75ml) for ethyl thioacetate.In dry ice/acetone batch, after the cooling, add NaN (SiMe
3)
2(1M THF solution, 50ml, 50mmol).After 15 minutes, add methanesulfonates (21g, anhydrous THF (60ml) solution 35mmol) of above preparation.The relief mixture was cooled to room temperature in 15 minutes.After stirring 100 minutes under the room temperature, with reactant reflux 4 hours.Allow solution be cooled to room temperature.It with chloroform (500ml) dilution, is washed with saturated sodium bicarbonate solution (200ml) and 1N HCl solution (200ml).Organic solution is through dried over sodium sulfate and filtration.Vacuum is removed solvent.Crude material is through purification by silica gel column chromatography, and the hexane solution wash-out with 15%AcOEt obtains 13.8g (63%) product.
Step 3:
The ester of preparation in the step 2 of in the 250ml round-bottomed flask of being furnished with the magnetic force splash bar, packing into (12.45g, 19.8mmol), THF (100ml), MeOH (33ml) and water (33ml).Add LiOHH
2(1.08g 25.7mmol) and with reaction mixture stirred under room temperature 3 hours O.Vacuum is removed solvent.Residue is absorbed in the 1N HCl solution (200ml) also with AcOEt (2 * 400ml) extractions.The extraction liquid that merges is with 1N HCl solution (100ml) extraction, through dried over sodium sulfate and filtration.Vacuum is removed solvent, obtains title compound.Output is 11.9g (100%).Embodiment 385-(2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1, the 3-dicarboxylic acid
Step 1:5-(2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1, the 3-dicarboxylic acid esters
Acid (the 1.2g of preparation in embodiment 37 steps 3 of in the round-bottomed flask of the 100ml oven drying of being furnished with the magnetic force splash bar, packing into, 2mmol), anhydrous THF (40ml), EDCI (0.544g, 2.8mmol), DMAP (0.024g, 0.2mmol) and 5-amino-1, the 3-phthalic acid (0.46g, 2.2mmol).With the reactant reflux until detect no change through TLC.Vacuum is removed solvent.Residue is dissolved in the methylene dichloride (200ml), with 1N HCl solution (25ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Crude material is through purification by silica gel column chromatography, and the dichloromethane solution wash-out with 1-2%MeOH obtains 1.2g (77%) product.
Step 2:
The ester of preparation in the step 1 of in the 25ml round-bottomed flask of being furnished with the magnetic force splash bar, packing into (0.6g, 0.76mmol), THF (7.5ml), MeOH (2.5ml) and water (2.5ml).Add LiOHH
2(0.084g 2mmol) and with reaction mixture stirred under room temperature 6 hours O.Vacuum is removed solvent.Residue is absorbed in the 1N HCl solution (10ml), and (2 * 50ml) extract, and through the extract that dried over sodium sulfate merges, filter and remove in a vacuum with AcOEt.Crude material is through the purification by silica gel column chromatography (chloroformic solution of elutriant: 5%MeOH+0.5-0.7%AcOH), obtain 0.28g (46%) title compound.
Prepare embodiment 39,40,43 in the table 3 according to the method described in the embodiment 38.Embodiment 415-(2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido)-3-hydroxymethyl-benzoic acid
Step 1:5-(2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido)-3-t-butyldimethylsilyloxy ylmethyl methyl benzoate
Prepare this compound according to the method described in embodiment 38 steps 1.
Step 2:5-(2-(5-benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido)-3-hydroxymethyl-benzoic acid methyl esters
The ester of the silyl protection of preparation in the step 1 of in the round-bottomed flask of the 25ml oven drying of being furnished with the magnetic force splash bar, packing into (1.32g, 1.5mmol), anhydrous THF (10ml) and TBAF (1M THF solution, 2.5 molar equivalents).Reaction mixture was stirred under room temperature 3 hours.Vacuum is removed solvent.The oily residue is through purification by silica gel column chromatography, and the dichloromethane solution wash-out with 0-30%AcOEt obtains 0.94g (92%) product.
Step 3:
Prepare title compound according to the method described in embodiment 38 steps 2.
Prepare embodiment 42 in the table 3 according to the method described in the embodiment 41.Embodiment 445-(2-(5-hydroxyl-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1, the 3-dicarboxylic acid
Step 1:2-(5-hydroxyl-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methyl alcohol
2-(5-benzyloxy-the 1-(3 of preparation in embodiment 37 steps 1 of in 500ml Parr hydrogenation bottle, packing into; two (trifluoromethyl) phenoxy group ethanoyl of 5-) methyl alcohol (10g indolinyl); 19.1mmol), 5% palladium on carbon (1.0g), AcOEt (150ml) and MeOH (100ml), hydrogenation 18 hours under 50psi subsequently.Make reaction mixture pass through diatomite filtration and vacuum concentration, obtain crude product.This product is used for next step reaction without being further purified.
Step 2:2-(5-(4-methoxyl group) benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methyl alcohol
(8.56g 23.6mmol), adds methoxy-benzyl chlorine (3.2ml, 450ml anhydrous acetonitrile 23.6mmol) alcohol of preparation at last in the step 1 of packing in the round-bottomed flask of the 1L oven drying of being furnished with magnetic force splash bar and reflux exchanger.With reaction mixture refluxed heating 4 hours.Reaction mixture is allocated in AcOEt (500ml) and water (200ml).(3 * 500ml) extract water layer with AcOEt.The AcOEt extraction liquid that merges is with salt solution (500ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Residue obtains required product through purification by silica gel column chromatography (hexane solution of elutriant: 40%AcOEt).Output is 8.7g (83%).
Step 3:5-(2-(5-(4-methoxyl group) benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1,3-dioctyl phthalate methyl esters
The alcohol of preparation in the step 2 of in the 100ml round-bottomed flask of being furnished with the magnetic force splash bar, packing into (3.2g, 5.77mmol), anhydrous methylene chloride (44ml).Reaction mixture is cooled to 0 ℃ and add anhydrous Et
3N (1.2ml, 8.61mmol), add then MsCl (0.53ml, 6.84mmol).Reaction mixture was stirred 5 minutes in 0 ℃.Reaction mixture is allocated between methylene dichloride (100ml) and the water (50ml).(3 * 100ml) extract water layer with methylene dichloride.The dichloromethane extraction liquid that merges is with 1N HCl solution (100ml), saturated sodium bicarbonate solution (100ml), water (100ml), salt solution (100ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent, obtains methanesulfonates.It is used for next step reaction without being further purified.
In the 100ml round-bottomed flask of being furnished with the magnetic force splash bar, pack into above preparation methanesulfonates (3.60g, 5.70mmol), the Carbon Dioxide caesium (5.19g, 15.9mmol) and dry DMF (20ml).In reaction soln, fed nitrogen 15 minutes.The 5-thioacetyl amino-1 that once adds preparation in the intermediate 2,3-phthalic acid methyl esters heats reaction mixture 18 hours in 50 ℃.Reaction mixture is allocated between AcOEt (500ml) and the water (200ml).(3 * 100ml) extract water layer with AcOEt.The AcOEt extraction liquid that merges is with saturated sodium bicarbonate solution (100ml), water (100ml), salt solution (500ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Residue obtains product through purification by silica gel column chromatography (dichloromethane solution of elutriant: 5%AcOEt).Output 2.5g (53%).
Step 4:5-(2-(5-hydroxyl-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1, the 3-methyl-formiate
The ester of preparation in the step 3 of in the 100ml round-bottomed flask of being furnished with the magnetic force splash bar, packing into (2.60g, 3.17mmol) and anhydrous methylene chloride (30ml).In 1 hour, in reaction mixture, add TFA (25ml).Reaction mixture is inclined to the 500ml saturated sodium bicarbonate solution, and extract (3 * 100ml) with methylene fluoride.The dichloromethane extraction liquid that merges is with saturated sodium bicarbonate solution (200ml), water (200ml), salt solution (500ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Residue obtains described product through purification by silica gel column chromatography (dichloromethane solution of elutriant: 12.5-20%AcOEt).Output 1.5g (68%).
Step 5:
The ester of preparation in the step 4 of in the 25ml round-bottomed flask of being furnished with the magnetic force splash bar, packing into (270mg, 0.40mmol), LiOH hydrate (3.3 a great deal of), THF (3.6ml), MeOH (1.2ml) and water (1.2ml).Reaction mixture is a homogeneous phase, and white solid is suspended in this solution.Stir after 4 hours, to add more 3: 1: 1=THF: MeOH: the solvent of water, make clear soln.Reaction mixture was stirred under room temperature 18 hours and detect through TLC.With 1NHCl solution reaction mixture is acidified to pH=2, or is acidified with acetic acid to pH=4, its distribution is given between AcOEt (20ml) and the water (20ml) then.(3 * 20ml) extract water layer with AcOEt.The AcOEt extraction liquid water (20ml) that merges, salt solution (20ml) washing, through dried over sodium sulfate and concentrated, vacuum is removed solvent.Residue is through purification by silica gel column chromatography, and recrystallization from acetone/hexane obtains 130mg title compound (50%) then.Embodiment 455-(2-(5-(3, the 5-dibromo) benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1, the 3-dicarboxylic acid
Step 1:5-(2-(5-(3, the 5-dibromo) benzyloxy-1-(3, two (trifluoromethyl) phenoxy group ethanoyl of 5-) indolinyl) methylmercaptan ethyl amido) benzene-1,3-dioctyl phthalate methyl esters
5-(2-(5-hydroxyl-the 1-(3 of preparation in embodiment 4 steps 4 of in the round-bottomed flask of the 25ml oven drying of being furnished with magnetic force splash bar and reflux exchanger, packing into; two (trifluoromethyl) phenoxy group ethanoyl of 5-) benzene-1 methylmercaptan ethyl amido indolinyl)); 3-dioctyl phthalate methyl esters (0.19g; 0.27mmol), 200 order salt of wormwood (2.4 equivalent) and 3, the 7.5ml anhydrous acetonitrile of 5-dibromo-benzyl bromine (1.2 equivalent).Reaction mixture was heated 2 hours in 70 ℃.Reaction mixture is allocated between AcOEt (30ml) and the water (20ml).(3 * 20ml) extract water layer with AcOEt.The AcOEt extraction liquid that merges is with salt solution (50ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Residue is through purification by silica gel column chromatography, and the dichloromethane solution wash-out with 155EtOAc obtains the described product of 0.2g (77%).
Step 2:
According to method described in embodiment 44 steps 5, prepare title compound by the ester of step 1.
According to the method described in the embodiment 44, but prepare embodiment 46-50 in the table 4 with corresponding alkylating agent.Embodiment 513-(2-(5-benzyloxy-1-(4-benzyl benzoyl) indolinyl) methylmercaptan ethyl amido) methyl benzoate
(0.19g 0.91mmol) is dissolved in the methylene dichloride (2.3ml), and (0.16ml 1.82mmol), adds dimethyl formamide (0.5ml) then under room temperature then to add oxalyl chloride with the 4-benzylbenzoic acid.After 1 hour, reactant is concentrated also and methylbenzene azeotropic, placed vacuum following 2 hours.
3-(2-(5-benzyloxy) indolinyl) methylmercaptan ethyl amido ethyl benzoate (0.308g with preparation in embodiment 17 steps 6,0.65mmol, method according to embodiment 17 steps 6 prepares) and 4-dimethylaminopyridine (8mg, 0.066mmol) be dissolved in the methylene dichloride (1.2ml), methylene dichloride (0.5ml) solution that adds the acyl chlorides of above-mentioned preparation then, add then triethylamine (0.28ml, 1.95mmol).Reactant stirred under room temperature spend the night.Reactant is with ethyl acetate and water dilution, with ethyl acetate extraction (3 *), through dried over mgso and concentrated.Crude material is used hexane through silica gel purification: eluent ethyl acetate obtains 0.354g title product (81.7%, TLC=0.4Rf is at 2: 1 hexanes: in the ethyl acetate).Embodiment 523-(2-(5-benzyloxy-1-(4-benzyl benzoyl) indolinyl) methylmercaptan ethyl amido) phenylformic acid
(0.354g 0.53mmol) is dissolved among the THF (5.6ml), adds methyl alcohol (5.6ml), adds 1N NaOH (4.2ml) then with the ester of preparation among the embodiment 51.Reaction mixture stirred under room temperature spend the night, concentrate it this moment, and dilute with water is acidified to pH5 with 10%HCl, with ethyl acetate extraction (3 *).Organic extract liquid is through dried over mgso and concentrate, and obtains title product (0.32g, 94.4%, TLC=0.3Rf has 2: 1 hexanes of 1.5% acetate: in the ethyl acetate).
Prepare embodiment 53-58 in the table 5 according to the method described in embodiment 51 and 52.Embodiment 593-(2-(5-benzyloxy-1-(2-naphthyloxy ethanoyl) indolinyl) methylmercaptan ethyl amido)-4-methoxybenzoic acid
Step 1:3-(2-(5-benzyloxy indolinyl) methylmercaptan ethyl amido)-4-methoxyl methyl benzoate
According to the method described in embodiment 17 steps 6, but prepare title compound with the 4-methoxyl methyl benzoate.
Step 2:3-(2-(5-benzyloxy-1-(2-naphthyloxy ethanoyl) indolinyl) methylmercaptan ethyl amido)-4-methoxyl methyl benzoate
K-281 (0.22g with preparation in the step 1,0.45mmol), 2-naphthoxy acetic acid (0.11g, 0.53mmol), EDCI (0.10g, 0.53mmol) and DMAP (5mg, 0.04mmol) weighing adds and to be furnished with in the flask of condenser, charge into nitrogen, add tetrahydrofuran (THF) (5ml) then, reactant was refluxed 18 hours; Reactant with 1/2 saturated ammonium chloride and ethyl acetate dilution, is used ethyl acetate extraction 3 times,, concentrate, obtain (0.30g, 100% raw product) white solid, its not purified use through dried over mgso.
Step 3:
Ester (0.12g with preparation in the step 2,0.20mmol) be dissolved in the THF/ methyl alcohol, add 1N sodium hydroxide (0.8ml) then, the mixture of gained was stirred under room temperature 16 hours, stirred 5 hours in 45 ℃ again, processing obtains the 0.12g yellow solid, with it by preparation type TLC purifying (1: 1 hexane with 1% acetate: ethyl acetate), obtain 0.12g title product (95%).
According to the method described in embodiment 59 or embodiment 51 and 52, the embodiment 60-63 in the preparation table 5.Embodiment 643-(2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl) methyl sulphonyl acetylamino benzoic acid
Step 1:3-(2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl) methyl sulphonyl acetylamino benzoic acid ethyl ester
3-(2-(5-benzyloxy-1-tertbutyloxycarbonyl) indolinyl) the methylmercaptan ethyl amido ethyl benzoate 0.05g of preparation in embodiment 17 steps 5,0.09mmol) methylene dichloride (0.1ml) solution under room temperature, add the metachloroperbenzoic acid (60%m-cPBA of 0.06g, 0.21mmol), the reactant stirring is spent the night.Second day, reactant sodium bicarbonate aqueous solution quencher was with ethyl acetate extraction (3 *), through dried over mgso and concentrated.Rough sulfone (0.52g, 98%, TLC=0.3RF is at 1: 1 hexane: in the ethyl acetate) is directly used in next reaction.
Step 2:
Prepare title compound according to the method described in embodiment 59 steps 3.
Prepare embodiment 66 and 65 according to the method described in the embodiment 18.Embodiment 673-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio-benzoic acid
Step 1:5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl)-2-methylol indolinyl
With diisopropylethylamine (3.5ml, 20.5mmol), DMAP (0.25g, 2.05mmol) and embodiment 17 steps 1 in the preparation indanol (4.53g, 17.7mmol) weighing adds in the flask, charge into nitrogen and be cooled to 0 ℃, add methylene dichloride (50ml) solution of two tert-pentyl phenoxy group Acetyl Chloride 98Min.s (2.05mmol) this moment by intubate.Allow the solution temperature of gained to ambient temperature overnight, then by adding 1/2 saturated ammonium chloride and methylene dichloride quencher, solution dichloromethane extraction (3 *), the layer that merges is through dried over mgso and concentrated, obtain (10.4g) yellow foam, with gradient (hexane: ethyl acetate 7: 1-3: 1-1:, obtain the described product of 3.62g 1) through chromatography purification.
Step 2:2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl methylmethanesulfonate ester
To the preparation 1 in the preparation alcohol (1.2g, add in methylene dichloride 2.26mmol) (15ml) solution triethylamine (0.44ml, 3.16mmol).Make this solution to-50 ℃, add then methylsulfonyl chloride (0.23ml, 2.93mmol).Mixture was stirred 2 hours in-50 ℃, with the saturated ammonium chloride quencher and allow its temperature to room temperature.Mixture is absorbed in the chloroform (50ml), with saturated sodium bicarbonate (1 * 10ml), (1 * 10ml) washing, dry (sal epsom), filter also and concentrate obtain described product (1.19g, 86%) to salt solution.
Step 3:2-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio-benzoic acid methyl esters
In step 2, add in degassing DMF (2ml) solution of methanesulfonates of preparation cesium carbonate (0.724g, 2.22mmol) and thio-methyl salicylate (0.134ml, 0.98mmol).Mixture was stirred 4 hours, be absorbed in the ethyl acetate (20ml), (3 * 30ml), dry (sal epsom) filters and concentrates with the salt water washing.Chromatographic separation (gradient, hexane: ethyl acetate 15: 1-4: 1) obtain the title compound of 0.53g (86%) yellow oil.
Step 4:
Prepare title compound according to the method described in embodiment 59 steps 3.
Prepare embodiment 68 according to the method described in the embodiment 67.Embodiment 693-(N-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylmercaptoethyl) benzaminic acid
According to the method described in embodiment 59 steps 3, use intermediate 15 preparation title compounds.Embodiment 703-N-methyl-(2-(5-benzyloxy-1-(2, two (1, the 1-dimethyl) propyl group of 4-) phenoxy group ethanoyl) indolinyl) methylthio group acetylaminohydroxyphenylarsonic acid 4-methoxybenzoic acid
3-(2-(5-benzyloxy-the 1-(2 that in the 100ml of the oven drying of being furnished with splash bar and nitrogen inlet 3 neck round-bottomed flasks, packs into and in embodiment 20 synthetic, prepare with the method for embodiment 18; 4-two (1; the 1-dimethyl) methylthio group acetylaminohydroxyphenylarsonic acid 4-methoxyl methyl benzoate (581mg indolinyl phenoxy group ethanoyl propyl group))); 0.757mol), add 10ml THF by syringe.In the yellow solution of gained, add NaH (60% suspension at mineral oil, 39mg, 0.975mmol).Reaction mixture in 25 ℃ of stirrings 1.5 hours, is obtained light color suspension.(161mg 1.14mmol), stirs reaction mixture 2 days in 25 ℃ to add methyl-iodide.After being cooled to 0 ℃, add entry (10ml), add 50ml semi-saturation ammonium chloride and 100mlEtOAc then.Separate each layer, water extracts with EtOAc (50ml).With organic phase drying (sodium sulfate), the filtration and concentrated that merges, obtain the crude product of 0.6g orange.This material is dissolved in 15ml THF and the 10ml methyl alcohol, under nitrogen, adds 7ml 1N NaOH.In 25 ℃ stir 2 hours after, the reaction mixture rotation is concentrated into dried, add 100ml 1N HCl and 100 EtOAc.Separate each layer, with organic phase drying (sal epsom), filtration and concentrated.The crude material that obtains obtains title compound (0.415g, yield is 70%) through purification by silica gel column chromatography (elutriant: chloroform is to the chloroformic solution of 3%MeOH).
According to the method described in the embodiment 70, use allyl bromide 98 to prepare embodiment 71.Embodiment 723-(2-(5-benzyloxy-1-(2-(4-pyridyl) ethyl) indolinyl) methylthio group acetylamino benzoic acid
Step 1:3-(2-(5-benzyloxy-1-(2-(4-pyridyl) ethyl) indolinyl) methylmercaptan ethyl amido ethyl benzoate
3-(2-(5-benzyloxy) indolinyl) the methylmercaptan ethyl amido ethyl benzoate (0.30g of preparation in embodiment 17 steps 6,0.63mmol) in methylene dichloride (3.0ml) and acetate (2.0ml) solution, add 4-vinylpridine (0.08ml, 0.75mmol).Reactant stirred under room temperature spend the night.Reactant is with the quencher of semi-saturation sodium bicarbonate, with ethyl acetate extraction (3 *), through dried over mgso and concentrated.Crude material is through silica gel purification, and with 2: 1 hexanes: the gradient elution of ethyl acetate to 100% ethyl acetate obtained 0.023g product (25%, TLC=0.7Rf is in ethyl acetate).
Step 2:
Prepare title compound according to the method described in embodiment 59 steps 3.Embodiment 733-(2-(5-benzyloxy-1-(2-naphthyl) methyl) indolinyl) methylthio group acetylamino benzoic acid
Step 1:3-(2-(5-benzyloxy-1-(2-naphthyl) methyl) indolinyl) methylmercaptan ethyl amido ethyl benzoate
3-(2-(5-benzyloxy) indolinyl) methylmercaptan ethyl amido benzoic ether (0.2g with preparation in embodiment 17 steps 6,0.42mmol), 2-(brooethyl) naphthalene (0.1g, 0.42mmol) and salt of wormwood (0.17g, 1.26mmol) at N, the mixture in the dinethylformamide (2ml) stirs under room temperature and spends the night.Then reactant, also concentrates through dried over mgso with ethyl acetate extraction (3 *) with ethyl acetate and water dilution.Crude material is through silica gel purification, and with 2: 1 hexanes: eluent ethyl acetate obtained 0.22g product (85%, TLC=0.5Rf is at 2: 1 hexanes: in the ethyl acetate).
Step 2:
Prepare title compound according to the method described in embodiment 59 steps 3.
Prepare embodiment 74 and 75 in the table 6 according to the method described in the embodiment 73.Embodiment 762-(2-(5-benzyloxy-1-(2-naphthyl) methyl) indolinyl) methylthio-benzoic acid
Step 1:2-(2-(5-benzyloxy-1-(1, the 1-dimethyl) ethoxycarbonyl) indolinyl) methanesulfonates
(6.72g 19mmol) is dissolved in the methylene dichloride (80ml, use before through dried over mgso) with 1-(5-benzyloxy-2-methylol) the indolinyl t-butyl formate of preparation in embodiment 17 steps 2.Clear soln is cooled off in the dry ice bath.Add Et then
3N (4.0ml) adds methylsulfonyl chloride (2.0ml) then.Reaction mixture was stirred water quencher then 2 hours in-40 ℃.It is washed water layer dichloromethane extraction 2 times with saturated sodium bicarbonate (300ml).The dichloromethane layer that merges is through dried over mgso, filters and be evaporated to dried, obtains described product (7.30g, 89.1% yield), and it is directly used in next reaction.
Step 2:2-(2-(5-benzyloxy-1-(1, the 1-dimethyl) ethoxycarbonyl) indolinyl) methylthio-benzoic acid methyl esters
With in the step 1 preparation methanesulfonates (7.2g 1.8mmol) is dissolved among the DMF (50ml).Should clarifying light brown solution outgas in 30 minutes by violent feeding argon gas.Add cesium carbonate (13.8g), add thio-methyl salicylate (2.4ml) then.This solution becomes glassy yellow, suspension is stirred spend the night.Add thio acetate (0.15ml) to finish reaction, mixture is stirred spend the night.Then by adding saturated sodium bicarbonate (400ml) quencher reaction.Mixture dichloromethane extraction (3 *), dichloromethane solution water (200ml) back scrubbing of merging.Organic layer is through dried over sodium sulfate, filters and be evaporated to dried, obtains described product (9.71g, 99%).
Step 3:2-(2-(5-benzyloxy) indolinyl) methylthio-benzoic acid methyl esters
Ethyl acetate (75ml uses preceding through dried over mgso) is added in the 500ml round-bottomed flask.Feed HCl gas, EtOAc/HCl solution is cooled off in ice bath.The methyl esters (8.4g) of preparation in the step 2 is dissolved in EtOAc (25ml uses preceding through dried over mgso).This solution is transferred in the HCl/EtOAc solution by syringe.Solution becomes redness, stirs in ice bath.White precipitate occurs in 1 hour, solution stirring is spent the night to finish reaction.Solid collected by filtration is washed with exsiccant EtOAc, it is suspended in the saturated sodium bicarbonate (175ml) and with EtOAc (400ml) stirs.Milky emulsion is dissolved gradually, and mixture becomes settled solution.Separate each layer, water layer is with EtOAc extraction (2 *), and the EtOAc layer that merges is through dried over mgso, filters and be evaporated to dried, obtains described product (6.06g, yield is 90%).
Step 4:2-(2-(5-benzyloxy-1-(4-benzyl) benzyl) indolinyl) methylthio-benzoic acid methyl esters
In the 50ml round-bottomed flask, the ester (1g) for preparing in the step 3 is dissolved among the DMF (6ml).Adding adds salt of wormwood (1eq) then to benzyl bromotoluene (1eq).Reaction mixture stirred under room temperature spend the night.In order to finish reaction, add extra to benzyl bromotoluene (0.5eq), with reactant restir 2 hours.After reaction was finished, the reactant dilute with water was with EtOAc extraction (2 *).Merge organic layer, through dried over mgso.Filter sal epsom and evaporating solvent, obtain oily mater,, obtain described product (1.59g, yield is 109%) its dried overnight under high vacuum.
Step 5:
In the 50ml round-bottomed flask, the ester (1.52g) for preparing in the step 4 is dissolved among the THF (10ml).(1eq 2N), adds MeOH (3ml) then, reaction mixture is stirred spend the night to wherein adding NaOH.Add extra NaOH (0.3eq) to finish reaction, during whole weekend, stir the mixture.Then with its acidifying, dilute with water and with EtOAc extraction (2 *).Organic layer is merged, through dried over mgso.Filter sal epsom and evaporating solvent, dry under high vacuum, obtain rough red solid.Solid is dissolved among the EtOAc, adds hexane with precipitated product.Filter the solid of gained, merge impure filter cake, simultaneously filtrate is evaporated to dried.This material is handled with EtOAc and EtOH.Filter the solid of gained, be suspended in then among the EtOH, stir simultaneously and heating under low temperature.Then it is cooled to room temperature.With suspension filtered,, obtain title product (280mg, 19% yield) with the EtOH washing.
Prepare embodiment 77,78 and 79 in the table 6 according to the method described in the embodiment 76.Embodiment 804-(1-(5-benzyloxy-2-(two-2,4-trifluoromethyl) benzyloxymethyl) indolinyl) tolyl acid
Step 1:1-(5-benzyloxy-2-(methylol) indolinyl) methyl-toluate
2-(5-benzyloxy) indolinyl methyl alcohol (3-21g that will in DMF (20ml), prepare, 12.6mmol), 4-(brooethyl) methyl benzoate (2.88g, 14.5mmol) and salt of wormwood (1.77g is heated to 125 ℃ before the use) mix to be incorporated under the room temperature and stirred 2 hours.Reactant extracts 3 times with the dilution of 100ml water and with EtOAc.The EtOAc layer that merges is evaporated to dried, obtains crude product (5.66g).Crude material is through the silicagel column purifying, with 3: 1 to 2: 1 hexane: eluent ethyl acetate.Merge suitable flow point, it is further dry under high vacuum that it is evaporated to dry doubling, obtains described product (3.00g, 64%).
Step 2:4-(1-(5-benzyloxy-2-(two-2,4-trifluoromethyl) benzyloxymethyl) indolinyl) methyl-toluate
Ester (700mg) and two-(2, the 4-trifluoromethyl) bromotoluene (0.35ml) of preparation in the step 1 are dissolved among the DMF (5ml).The glassy yellow solution of gained is cooled off in ice bath, in 5 minutes, add NaH (85mg) then with aliquot.Suspension was stirred 4 hours in 0 ℃.In order to finish reaction, add extra 0.35ml 2, two (the trifluoromethyl)-bromotoluenes of 4-continue to stir 3 hours 40 minutes again.Reactant dilute with water and with EtOAc extraction 3 times then.EtOAc layer evaporation with merging obtains crude product, uses hexane then: 8: 1 purifying on silica gel of ethyl acetate.Merge suitable flow point and be evaporated to driedly, obtain described product (0.417g, 38.2% yield).
Step 3:
Prepare title compound according to the method described in embodiment 76 steps 5.
Prepare embodiment 81 and 82 in the table 6 according to the method described in the embodiment 80.Embodiment 835-(2-(1-(2, two (trifluoromethyl) benzyls of 4-) indolinyl) formamido group-1,3-phthalic acid
Step 1:2-(1-(2, two (trifluoromethyl) benzyls of 4-) indolinyl) formic acid
(0.43g 2.6mmol) is dissolved among the DMF (5ml), is placed under the nitrogen and is cooled to 0 ℃, and (60% dispersion of 0.26g 6.5mmol), continues to stir 1 hour under this temperature to add sodium hydride with 2-indolinyl formic acid.Then add 2, two (trifluoromethyl) bromotoluenes of 4-(1.22ml, 6.5mmol), with the reactant temperature to ambient temperature overnight.Reactant dilutes with 1/2 saturated ammonium chloride/ethyl acetate then, and water layer also concentrates through dried over mgso with ethyl acetate extraction (3 *), organic layer.Crude product is through chromatography purification (hexane: ethyl acetate 9: 1), obtain the described ester of 0.96g.(0.87g 0.1.41mmol) is dissolved in the THF/ methyl alcohol, adds 1N sodium hydroxide (4.21ml) then, and the mixture of gained was stirred under room temperature 2 hours, handles and through chromatography purification (7: 1 hexanes with 1% acetate with the ester of gained; Ethyl acetate), obtain the described product of 0.58g.
Step 2:
Acid (0.25g with preparation in the step 1,0.64mmol), EDCI (0.16g, 0.83mmol), DMAP (7mg, 0.06mmol) and the amino dimethyl isophthalate (0.16g of 5-, 0.77mmol) be dissolved among the THF (2ml) and refluxed 16 hours, after handling, the aqueous solution obtains the 0.33g crude product.With this ester (0.29g, 0.50mmol) be dissolved in the THF/ methyl alcohol, add 1N sodium hydroxide (1.5ml) then, the mixture of gained was stirred under room temperature 16 hours, handle and through chromatography purification (1: 1 hexane with 1% acetate: ethyl acetate), obtain the 0.22g title compound.Embodiment 84N-methyl sulphonyl-2-(1-(2, two (trifluoromethyl) benzyls of 4-) indolinyl) methane amide
Acid (0.13g 0.32mmol), EDCI (0.07g with preparation in embodiment 83 steps 1; 0.39mmol), DMAP (4mg; 0.03mmol) and methyl sulphonyl aniline (0.04g; 0.39mmol) be dissolved among the THF (5ml) and refluxed 16 hours; obtain (1.6g) after the processing, through chromatography purification (98: 2 methylene dichloride: methyl alcohol) obtain 0.04g title compound (29%).Embodiment 85N-phenyl sulfonyl-2-(1-(2, two (trifluoromethyl) phenyl of 4-) indolinyl) methane amide
According to producing the method described in 84, use phenyl-sulfamide to prepare title compound.Embodiment 865-(2-(5-methoxybenzyl Oxy-1-(2, two (trifluoromethyl) benzyls of 4-) indolinyl) methylamino formamido group-1,3-phthalic acid
Step 1:1-(5-benzyloxy-2-methylol) indolinyl formic acid 2-trimethyl silyl ethyl ester
2-(5-benzyloxy) the indolinyl methyl alcohol of preparation in embodiment 17 steps 1 of in the 1L of the oven drying of being furnished with splash bar round-bottomed flask, packing into (33.2g, 130mmol), 2-(trifluoromethyl silyl) ethyl p-nitrophenyl carbonic ether (36.8g 130mmol), NEt
3(38ml is 273mmol) with the 300ml dry DMF.Reaction mixture in 60 ℃ of stirrings 28 hours, is stirred under room temperature and spends the night.Be concentrated into driedly under the solution for vacuum with gained, add 1L chloroform and 200ml saturated sodium bicarbonate solution.Separate each layer,, filter and concentrate organic phase drying (sodium sulfate).Crude material (55.7g) obtains product (33.5g, 60% yield) through purification by silica gel column chromatography (dichloromethane solution of elutriant: 0-5%MeOH).
Step 2:1-(5-hydroxyl-2-methylol) indolinyl formic acid 2-trimethyl silyl ethyl ester
In the 500ml of oven drying Parr pressure flask, add preparation in the step 1 alcohol (30g75mmol), Pd/C (10%, 2.2g), 100ml MeOH and 300ml EtOAc.Be installed on H at Parr
2After jolting was spent the night in (50psi) under the atmosphere, reaction mixture filtered by Florisil.Be concentrated into the filtrate rotation dried.The crude material (24g) that obtains obtains product (20.9g, 90% yield) through purification by silica gel column chromatography (dichloromethane solution of elutriant: 0-3%MeOH).
Step 3:1-(5-(4-methoxyl group) benzyloxy-2-methylol) indolinyl formic acid 2-trimethyl silyl ethyl ester
Glycol (the 27.1g that in the 1L round-bottomed flask of being furnished with splash bar of oven drying, adds preparation in the step 2,87.7mmol), 4-methoxy-benzyl chlorine (Aldrich, 15ml, 110mmol), salt of wormwood (200 orders, 30.4g, 220mmol), (Aldrich, 18.3g is 110mmol) with the 800ml anhydrous acetonitrile for KI.With reaction mixture refluxed heating 4 hours.Allow solution be cooled to room temperature and add entry (800ml) and chloroform (1.5L).Separate each layer, water extracts with chloroform (800ml).Extraction liquid water (200ml) washing that merges, dry (sodium sulfate) filters and concentrates.The crude material (45g) that obtains is through purification by silica gel column chromatography (hexane solution of elutriant: 20-25%EtOAc), and recrystallization obtains product (22.2g, 59% yield) from the EtOAc/ hexane.
Step 4:1-(5-(4-methoxyl group) benzyloxy-2-brooethyl) indolinyl formic acid 2-trimethyl silyl ethyl ester
In 3.0g (6.4mmol) step 3, add 2.53g (7.6mmol) carbon tetrabromide and 3.15g (7.6mmol) 1 in the 30ml dichloromethane solution of the alcohol of preparation, two (diphenylphosphino) propane of 3-.Reactant was stirred under room temperature 18 hours.Reactant saturated aqueous ammonium chloride quencher, the product dichloromethane extraction.The organic extract liquid that merges is with the salt water washing and through dried over mgso.Crude product is used hexane through the flash chromatography purifying: 3: 2 wash-outs of ethyl acetate obtain the described product of 1.51g.
Step 5:1-(5-(4-methoxyl group) benzyloxy-2-azido methyl) indolinyl formic acid 2-trimethyl silyl ethyl ester
In step 4, add 0.51g (7.9mmol) sodiumazide in the 15ml dimethyl formamide solution of 1.4g (2.6mmol) bromide of preparation.Reactant is heated to 75 ℃ and stirred 18 hours.The quencher of reactant water, described product ethyl acetate extraction.The organic layer water that merges, salt water washing and through dried over mgso.Crude product is used hexane through the flash chromatography purifying: 4: 1 wash-outs of ethyl acetate obtain the described product of 1.08g.
Step 6:1-(5-(4-methoxyl group) benzyloxy-2-amino methyl) indolinyl formic acid 2-trimethyl silyl ethyl ester
In 0.88g (1.9mmol) step 5, add 90mg (10%wt) Pd/ lime carbonate in the 20ml ethanolic soln of the trinitride of preparation.Mixture is placed under the atmosphere of hydrogen, and stirred 18 hours.Reactant spends the night by Celite pad and concentrates mutually orange then.Crude product with 10%MeOH/ methylene dichloride wash-out, obtains the described product of 0.717g through the flash chromatography purifying.
Step 7:5-(2-(5-methoxybenzyl Oxy-1-(2-trimethylsiloxy) ethoxycarbonyl) indolinyl) methylamino formamido group-1,3-phthalic acid methyl esters
In 30 minutes, in the 5ml dichloromethane solution of 0.164g (0.6mmol) triphosgene, add the 20ml dichloromethane solution of amino isophthalic ester of 0.31g (1.5mol) dimethyl-5-and 0.39g (3.0mmol) diisopropylethylamine by syringe pump.After the adding reactant was stirred under room temperature 1 hour, once add the 5ml dichloromethane solution of the amino of preparation in 0.64g (1.5mmol) step 6 then.Reactant was stirred 2 hours water quencher then.The product ethyl acetate extraction, the organic layer water of merging, saturated sodium bicarbonate aqueous solution, salt water washing and through dried over mgso.Crude product with 10%MeOH/ methylene dichloride wash-out, obtains the described product of 0.78g through the flash chromatography purifying.
Step 8:5-(2-(5-methoxyl group benzyloxy base) indolinyl) methylamino formamido group-1,3-phthalic acid methyl esters
The THF solution 2.2ml (2.2mmol) that in 0.485g (0.7mmol) step 7, adds the 1.0M tetrabutyl ammonium fluoride in the 20ml acetonitrile solution of the ester of preparation.Reactant was stirred under room temperature 18 hours.Reactant salt solution quencher, the product ethyl acetate extraction.The organic extract liquid that merges is with saturated aqueous ammonium chloride, salt water washing and through dried over mgso.Crude product with 5%MeOH/ methylene dichloride wash-out, obtains the described product of 0.342g through the flash chromatography purifying.
Step 9:5-(2-(5-methoxybenzyl Oxy-1-(two-2,4-trifluoromethyl) benzyl) indolinyl) methylamino formamido group-1,3-phthalic acid methyl esters
In 0.15g (0.3mmol) step 8, add 0.097g (0.3mmol) 2 in the 5ml dimethyl formamide solution of the indoline diester of preparation, two (trifluoromethyl) bromotoluenes of 4-and 0.12g (0.9mmol) salt of wormwood.Reactant was stirred under room temperature 18 hours.The quencher of reactant water, the product ethyl acetate extraction.The organic extract liquid water that merges, salt water washing and through dried over mgso.Crude product is used hexane through the flash chromatography purifying: 1: 1 wash-out of ethyl acetate obtains the described product of 0.066g.
Step 10:
In the step 9 of 0.063g (0.1mmol), add 0.8ml (0.8mmol) 1.0N NaOH solution and 0.5ml methyl alcohol in the 5ml tetrahydrofuran solution of the diester of preparation.Reactant was stirred under room temperature 18 hours.The evaporation organic solvent is acidified to pH3 with the solid suspension of gained in water and with 10%HCl.The product ethyl acetate extraction, the organic extract liquid water of merging, salt water washing and through dried over mgso.Crude product with 5%MeOH/ methylene dichloride wash-out, obtains the 0.049g title compound through the flash chromatography purifying.
According to the method described in the embodiment 86, prepare embodiment 87 with 4-(3, two (trifluoromethyl) phenoxymethyls of 5-) bromotoluene.Intermediate 14-methoxyl group-3-thioacetyl benzaminic acid methyl esters
Step 1: two (4-methoxyl groups-3-dithio acetyl-amino-benzoic acid methyl ester)
In the round-bottomed flask of being furnished with the magnetic force splash bar of 2L oven drying, pack into methyl-carbithionic acid (10-2-15.5g, 56-85mmol) and anhydrous methylene chloride (50ml).In 10 minutes, drip oxalyl chloride (2.1 molar equivalent).Reaction mixture was stirred under room temperature 4-5 hour.The anhydrous methylene chloride solution (300-500ml) and the DMAP (0.1 molar equivalent) that under room temperature, add 4-methoxyl group-3-amido methyl benzoate (2.1 molar equivalent).In 30 minutes, drip NEt
3(4.2 moles of a great deal oves).After stirring under the room temperature was spent the night, (2 * 300ml) washings were through dried over mgso and filtration with 1N HCl solution for reaction mixture.Vacuum is removed solvent.Residue is used hexane through purification by silica gel column chromatography: ethyl acetate=5: 1 wash-outs, obtain required product, and yield is 56%.
Step 2:
The disulphide of preparation in the step 1 of in the 1L round-bottomed flask of being furnished with the magnetic force splash bar, packing into (15.7-26.3g, 36.6-57.5mmol) and PPh
3(1.1 moles of a great deal oves).With reactant be suspended in diox/water (4/1,375-500ml) in, and add concentrated hydrochloric acid solution (5).Reaction mixture is exhausted until disulphide in 40 ℃ of heating.Vacuum is removed solvent.Residue is used hexane immediately through purification by silica gel column chromatography: 2: 1 wash-outs of ethyl acetate, obtain title compound, and yield is 89%.Intermediate 25-thioacetyl amino-1,3-phthalic acid methyl esters
According to the method described in the intermediate 1, with 5-amino-1,3-phthalic acid ester synthesising title compound.Intermediate 32-(3-amino-4-p-methoxy-phenyl)-2-methoxy menthyl acetate
Step 1:2-(3-nitro-4-p-methoxy-phenyl) methyl acetate
The diacetyl oxide (631ml) of packing in the 2L of the oven drying of being furnished with mechanical stirring motor, low-reading thermometer and balanced dropping funnel 3 neck round-bottomed flasks is cooled to-78 ℃ subsequently.By the dropping funnel with the drying tube protection that is filled with calcium chloride drip nitrosonitric acid (Baker, 90%, 27ml).After being added dropwise to complete, in 1 hour with temperature of reaction temperature to 20 ℃.Reaction mixture is cooled to once more-78 ℃, by dropping funnel drip 4-anisole guanidine-acetic acid (50g, 0.28mmol)., in 20 minutes, allow the reaction mixture temperature to-30 ℃, and then be cooled to-50 ℃ after 1 hour in-50 ℃ of stirrings.Reaction mixture water (500ml) is in-50 ℃ of quenchers, and temperature is to room temperature and stirred 0.5 hour.Reaction mixture is allocated between methylene dichloride (500ml) and the water.Water layer dichloromethane extraction (3 * 500ml).Dichloromethane extraction liquid vacuum concentration with merging obtains yellow oil.Slowly add it in 2M NaOH (2L) solution that is cooled to 0 ℃ and under room temperature, stir and spend the night.Reaction mixture is allocated between methylene dichloride (500ml) and the water.Water layer dichloromethane extraction (3 * 500ml).The dichloromethane extraction liquid that merges was stirred 1 hour with 2M NaOH solution (1L).Separate each layer, organic layer water (500ml), salt solution (500ml) washing are through dried over sodium sulfate and filtration.Vacuum is removed solvent, obtains the crude product (56g) of light yellow solid.Through recrystallization purifying from MeOH (600ml), obtain product.Must measure into 48g (77%).
Step 2:2-(3-nitro-4-p-methoxy-phenyl)-2-hydroxy methyl acetate
(2.3g is 10mmol) with anhydrous THF (100ml) for the ester of preparation in the step 1 of packing in the 25ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask.Reaction mixture is cooled to-78 ℃, in 10 minutes, drips NaN (SiMe
3)
2(10M THF solution, 12ml, 12mmol).In-78 ℃ stir 30 minutes after, to by with commercially available (1S)-(+)-(10-camphor sulfonyl) oxa-aziridine (1.7g) with (1R)-(-)-racemize camphor sulfonyl oxa-aziridine solution that (10-camphor sulfonyl) oxa-aziridine (1.7g) is mixed with in 50mlTHF in this deep purple solution of dropping.After 30 minutes, reaction mixture in-78 ℃ of quenchers, allows its temperature to room temperature with saturated ammonium chloride solution (45ml) then in-78 ℃ of stirrings.Reaction mixture is allocated between ether (250ml) and the water (50ml).Water layer extracted with diethyl ether (3 * 250ml).The ether extraction liquid that merges is with salt solution (250ml) washing, through dried over sodium sulfate and concentrated.Vacuum is removed solvent.Through purification by silica gel column chromatography (hexane solution of elutriant: 50%AcOEt), obtain required product.Output is 2.2g (88%).
Step 3:2-(3-nitro-4-p-methoxy-phenyl)-2-methoxy menthyl acetate
The alcohol of preparation in the step 2 of in the 10ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, packing into (0.30g, 1.24mmol), AgO (0.68g, 3.0mmol) and toluene (3ml).To wherein dripping CH
3I (0.36g 5.75mmol).Reaction flask is tightly closed the lid and place ultrasonic treatment chamber.With reaction mixture supersound process 18 hours, under room temperature, stir simultaneously.Reaction mixture is extremely done by diatomite filtration and vacuum concentration.Residue obtains required product through purification by silica gel column chromatography (hexane solution of elutriant: 30%AcOEt).Output is 0.26g (82%).
Step 4:
To being furnished with the magnetic force splash bar and being connected in the 100ml round-bottomed flask of oven drying of Y-junction of hydrogen capsule and water suction and pumping device, and the nitro-compound of packing into (0.7g, 2.6mmol), 5% palladium on carbon (10% (weight)) and MeOH (20ml).Reaction flask is placed under the vacuum by water suction and pumping device, be full of hydrogen subsequently.It is repeated 3 times.Reaction mixture was stirred 18 hours under positive hydrogen-pressure, all react until all raw material.Reaction mixture is extremely done by diatomite filtration and vacuum concentration.Residue with the dichloromethane solution wash-out of 10% ethyl acetate, obtains title compound (0.57g, 97%) through purification by silica gel column chromatography.Intermediate 42-(3-amino-4-p-methoxy-phenyl)-2-t-butyldimethylsilyloxy guanidine-acetic acid methyl esters
The alcohol of preparation in intermediate 3 steps 2 of in the 25ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, packing into (0.30g, 1.24mmol) and anhydrous methylene chloride (10ml).Reaction mixture is cooled to 0 ℃ and add 2, and (through NaOH sheet drying, 0.36ml 3.11mmol), drips BuMe to the 6-lutidine then
2SiOTf (0.43ml, 1.87mmol).After 0 ℃ of stirring 30, reaction mixture is allocated between methylene dichloride (20ml) and the water (15ml).Water layer dichloromethane extraction (3 * 20ml).The dichloromethane extraction liquid that merges is with salt solution (20ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent.Through purification by silica gel column chromatography (hexane solution of elutriant: 30%AcOEt), obtain described product.Output is 0.42g (95%).
Step 2:
According to the method described in intermediate 3 steps 4, prepare title compound by the nitro-compound of step 1.Intermediate 52-(3-amino-4-p-methoxy-phenyl) methyl acetate
According to the method described in intermediate 3 steps 4, prepare title compound by the nitro-compound for preparing in intermediate 3 steps 1.Intermediate 62-(3-amino-4-p-methoxy-phenyl)-2-methyl acetic acid methyl esters
Step 1:2-(3-nitro-4-p-methoxy-phenyl)-2-methyl acetic acid methyl esters
In the 25ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, pack into heavily steam Diisopropylamine (0.84ml, 6.0mmol) and anhydrous THF (10ml) and be cooled to 0 ℃.In 5 minutes, drip n-BuLi (the 2.5M hexane solution, 2.4ml, 6.0mmol).After 15 minutes, temperature of reaction is cooled to-78 ℃ in 0 ℃ of stirring, and the ester of preparation in dropping intermediate 3 steps 1 (1.13g, 5.0mmol).After 45 minutes, (1.60g 12.5mmol), allows reaction mixture temperature to room temperature and stirring spend the night to drip methyl-sulfate in-78 ℃ of stirrings.Reaction mixture is allocated between methylene dichloride (50ml) and the water (50ml).Water layer dichloromethane extraction (3 * 50ml).The dichloromethane extraction liquid that merges is with salt solution (50ml) washing, through dried over sodium sulfate and concentrated.Vacuum is removed solvent.Through purification by silica gel column chromatography (hexane solution of elutriant: 30%AcOEt), obtain the described product of 0.7g (58%).
Step 2:
According to the method described in intermediate 3 steps 4, the nitro-compound that is prepared by step 1 prepares title compound.Intermediate 72-(3-amino-4-p-methoxy-phenyl)-2-allyl acetic acid methyl esters
Step 1:2-(3-nitro-4-p-methoxy-phenyl)-2-allyl acetic acid methyl esters
According to the method described in intermediate 6 steps 1, use allyl bromide 98, by synthetic this compound of the ester of preparation in intermediate 3 steps 1.
Step 2:
The ester of preparation in the step 1 of in the 25ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, packing into (0.30,1.13mmol), SnCl
22H
2O (1.28g, 5.66mmol) and EtOH (5ml).Reaction mixture was heated 30 minutes in 70 ℃.Reaction mixture is cooled to room temperature, inclines to ice/water (20ml), alkalize to pH=8 with saturated sodium carbonate solution.Add AcOEt (50ml).The emulsion of gained is passed through diatomite filtration.With filtrate distribution between AcOEt (20ml) and water (15ml).Water layer extracts (3 * 50ml) with AcOEt.The AcOEt extraction liquid that merges is with salt solution (50ml) washing, through dried over sodium sulfate and concentrated.Vacuum is removed solvent.Through purification by silica gel column chromatography (dichloromethane solution of elutriant: 10%AcOEt), obtain title compound.Output is 0.16g (60%).Intermediate 82, two (1, the 1-dimethyl propyl) phenyliums of 4-
With 2, two (1, the 1-dimethyl) propylphenol (12g of 4-, 51.2mmol) dimethyl formamide (100ml) solution be cooled to-30 ℃, (12.3g 61.5mmol) handles, and stirs 30 minutes with two (trimethyl silyl) ammonification potassium, add methyl bromoacetate (5.7ml then, 61.5mmol), reactant was stirred 1 hour under this temperature, removed after the cooling bath 5 hours, processing obtains (16.6g, ≈ 100%) yellow oil.Oily matter is dissolved in the THF/ methyl alcohol, handled and stir 48 hours with 1N sodium hydroxide (155ml).Reactant is concentrated, and dilute with water is acidified to pH4 with concentrated hydrochloric acid, with ethyl acetate extraction (4 *), through dried over mgso and concentrated.Crystallization obtains 12.85g title compound (86%) from ethyl acetate and hexane.Intermediate 94-benzyl phenylium
Method according to described in the intermediate 8 prepares title compound by the 4-benzylphenol.Intermediate 102-naphthoxy acetic acid
Method according to described in the intermediate 8 prepares title compound by beta naphthal.Intermediate 113, two (trifluoromethyl) phenyliums of 5-
According to the method described in the intermediate 8, by 3, two (trifluoromethyl) phenol of 5-prepare title compound.Intermediate 125-amino-3-(N, N-dimethyl) formamyl methyl benzoate
Step 1:5-nitro-3-(N, N-dimethyl) formamyl methyl benzoate
In the 100ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, pack into 5-nitro-3-methoxycarbonyl phenylformic acid (3.15g, 10mmol), DMF (1), anhydrous methylene chloride (70ml) and oxalyl chloride (3.7ml, 42.3mmol).Reaction mixture was stirred under room temperature 2 hours.Vacuum is removed solvent, obtains the acyl chlorides of white solid.Promptly be used for next step with its not purified thirty years of age.
In the round-bottomed flask of the oven drying of being furnished with the magnetic force splash bar, pack into acyl chlorides (14mmol), anhydrous methylene chloride (50ml) and the dimethylamine hydrochloride (70mmol) of above preparation.Drip NEt
3(2ml, 144mmol).After stirring 30-60 minute under the room temperature, add excessive N Et
3(1ml 72mmol) also continues to stir.After 30-60 minute, (2 * 20ml) washings are through dried over sodium sulfate and filtration with saturated sodium carbonate solution for solution.Vacuum is removed solvent, obtains the 3.3g product.It is purified and be used for next step.
Step 2:
According to the method described in intermediate 3 steps 4, prepare title compound by the nitro-compound for preparing in the step 1.Intermediate 135-amino-3-acetylbenzoic acid methyl esters
Step 1:5-nitro-3-acetylbenzoic acid methyl esters
In the 250ml of the oven drying of being furnished with magnetic force splash bar round-bottomed flask, pack into the propanedioic acid di tert butyl carbonate (2.16g, 10mmol), dry toluene (50ml) and NaH (60% suspension at mineral oil, 0.88g, 22mmol).Reaction mixture was stirred 1 hour in 80 ℃.Dry toluene (20ml) solution that adds the 5-nitro-3-chloroformyl methyl benzoate (10mmol) of preparation in intermediate 12 steps 1 continues heating 2 hours.Reaction mixture is cooled to room temperature and add tosic acid (0.21g, 1.2mmol).The mixture of gained is filtered, with toluene wash oiliness residue, until staying white solid.Merging filtrate, vacuum is removed solvent.Be dissolved in the oily matter of gained in the dry toluene (50ml) and add tosic acid (0.3g, 1.74mmol).Be heated to backflow after 18 hours, allow reaction mixture be cooled to room temperature, (2 * 25ml) washings are through dried over sodium sulfate and filtration with saturated sodium carbonate solution.Vacuum is removed solvent.Crude material is through purification by silica gel column chromatography (elutriant: methylene dichloride), obtain product.Output is 1.06g (50%).
Step 2:
According to the method described in intermediate 3 steps 4, prepare title compound by the nitro-compound for preparing in the step 1.Intermediate 145-amino-3-(1-t-butyldimethylsilyloxy base) ethyl benzoate methyl esters
Step 1:5-nitro-3-(1-hydroxyl) ethyl benzoate methyl esters
Compound 5-nitro-3-acetylbenzoic acid methyl esters (0.5g), the BH of preparation in intermediate 13 steps 1 of in the round-bottomed flask of the oven drying of being furnished with the magnetic force splash bar, packing into
3THF (1MTHF solution, 5 molar equivalents) and anhydrous THF.Under room temperature, stirred 24 hours, and added entry (20ml) and solution for vacuum concentration.Residue is absorbed in the water (20ml) also with chloroform (3 * 100ml) extractions.The chloroform extraction liquid that merges is with saturated sodium carbonate solution (20ml) washing, through dried over sodium sulfate and filtration.Vacuum is removed solvent, obtains product.It is purified and be used for next step.
Step 2:5-nitro-3-(1-t-butyldimethylsilyloxy base) ethyl benzoate methyl esters
The alcohol of preparation in the step 1 of in the round-bottomed flask of the oven drying of being furnished with the magnetic force splash bar, packing into (0.5g, 5mmol), tert-BuMe
2SiCl (1.3 molar equivalent), imidazoles (2.15 molar equivalent) and anhydrous THF.Stirred 28 hours under room temperature, vacuum is removed solvent.Chloroform extraction liquid water (50ml) washing that merges is through dried over sodium sulfate and filtration.Vacuum is removed solvent.Crude material is through silica gel purification, and the hexane solution wash-out with the 25-50% methylene dichloride obtains described product (0.69g, 91%).
Step 3:
According to the method described in intermediate 3 steps 4, prepare title compound by the nitro-compound for preparing in the step 2.Intermediate 154-methoxyl group-3-(2-thio-ethyl) Methyl anthranilate
Step 1: two (2-bromotrifluoromethane) disulphide
With dithioglycol (0.79ml, 6.48mmol), carbon tetrabromide (4.3g, 13.0mmol) and 1,3 couples of (diphenylphosphino) propane (5.34g, 13.0mmol) weighing adds in the flask, charges into nitrogen, be absorbed in the methylene dichloride (15ml) then and stirred 16 hours, processing comprises inclines to 1/2 saturated ammonium chloride, with dichloromethane extraction (3 *),, obtain (9.0g) crude product through dried over mgso and concentrated, with its chromatography (hexane: ethyl acetate 9: 1), obtain the 1.49g product.
Step 2: two-(4-methoxyl group-3-(2-dithio ethyl) Methyl anthranilate
Bromide (0.39mg with preparation in the step 1,1.387mmol) and 3-amino-4-methoxyl methyl benzoate (1.00g, 5.51mmol) add in the flask, charge into nitrogen and be absorbed among the DMF (5ml), be heated to then 60 ℃ 24 hours, this moment, reactant diluted with ethyl acetate, with its quencher in water, with ethyl acetate extraction (3 *), the organic layer that merges washes (3 *) with water, dry and concentrate and obtains the 1.27g product, with it through chromatography purification (hexane: ethyl acetate 5: 1-3: 1), obtain the required product of 0.15g.
Step 3:
With in the step 2 preparation disulphide (0.15g, 0.24mmol) and triphenylphosphine (0.14g 0.53mmol) is absorbed among the THF (3ml).Add entry (0.3ml) and 2 concentrated hydrochloric acids, the mixture of gained was stirred 2 hours in 40 ℃, reactant water and ethyl acetate dilution, with ethyl acetate extraction (3 *) and through dried over mgso, obtain the 0.27g crude product, with it through chromatography purification (hexane: ethyl acetate 9: 1-6: 1), obtain the 0.11g title compound.The synthetic method of embodiment 88-135
Can prepare other The compounds of this invention in accordance with the following methods.Specific embodiment according to these method synthetic compounds is below also described.Method A
In the presence of alkali such as salt of wormwood or potassium hydroxide, at solvent system such as water: in ethanol or the ethanol, make aldehyde and heterocycle, the alpha-carbon reaction of 4-thiazolidinedione or rhodanine or 2-thio-hydantoin such as 2.Then in solvent such as DMF or DMSO, with of the product N-alkylation of alkali such as sodium hydride with gained.Then by with hydrogen fluoride solvent such as acetonitrile in the described ester of cracking, obtain final acid.Method B
With the Indoline-2-carboxylic acid alkylation, in mixed solvent (ethanol-benzene-water), under the temperature that improves, use Pd (PPH with suitable alkyl bromide then
3)
4Make it stand Suzuki coupling condition as catalyzer, obtain the indoles that 1-alkyl-5-replaces.Method C
With the starting material 2-ethoxycarbonyl-5-benzyloxy indole I deprotonation of suitable alkali such as sodium hydride with such inhibitor, electrophilic reagent such as alkylogen or benzyl halide alkylation on nitrogen-atoms with selected obtain compound ii.Be used in miscible solvent such as tetrahydrofuran (THF) and the methyl alcohol, with the saponification of ester functionality, the agent III is inhibited with alkali such as aqueous sodium hydroxide solution.Form sour functionality by forming acyl chlorides, and, carry out the further extension on 2 in suitable solvent such as methylene dichloride, reacting in the presence of alkali such as the pyridine with amino ester with suitable reagent such as oxalyl chloride.Saponification provides the acid moieties V of chain extension.Method D
By the nitrile III, prepare sour isostere such as tetrazolium by the carboxylic acid I.By forming acyl chlorides with suitable reagent such as oxalyl chloride and making the acid functionality form primary amide with ammonia react, dewater such as pyridine with suitable reagent such as oxalyl chloride and alkali then, finish conversion to nitrile.By in suitable high boiling solvent such as N-Methyl pyrrolidone with the trinitride source such as reaction of sodium azide, nitrile such as III are converted into tetrazolium, obtain compound such as IV.Method E
By to such as 2 orderings (sequence) of going up unsaturated aldehyde of compound IV, prepare other sour isostere such as thiazolidinedione of having than the long-chain carbon atom bridge.Such as the ester group in the diisobutylaluminium hydride partial reduction I, or is hydroxyl with suitable reagent such as lithium aluminium hydride reduction with suitable reagent, turns to aldehyde with suitable oxidizer oxygen then, obtains the aldehyde II.Carry out Homer-Wittig reaction with trimethoxy phosphino-acetic ester at suitable solvent in such as tetrahydrofuran (THF), obtain the unsaturated ester III, under the condition that II is described, be translated into the aldehyde IV.With alkali such as piperidines described aldehyde is converted into the thiazolidinedione V then, and with acid such as separated from acetic acid.Method F
With highly basic such as sodium hydride (NaH) in THF with the deprotonation of 2-indyl carboxylic acid, ethyl ester I, obtain VI with the reaction of suitable alkyl bromide then.With alkali such as aqueous sodium hydroxide solution hydrolysis VI, and carbodiimide such as dimethylaminopropyl ethyl-carbodiimide hydrochloride (EDCI) in the presence of, change in the methylene dichloride aniline reaction with aniline or replacement at suitable solvent, obtain the acid amides VII.The acid amides VII is hydrolyzed to corresponding sour VIII at alkali in such as aqueous sodium hydroxide solution.Method G
Prepare the aldehyde IX by indyl-2-carboxylic acid, ethyl ester I with two steps: (1) suitable solvent such as THF in 0 ℃ with lithium aluminum hydride or other hydride reaction and (2) solvent such as THF in oxygenant such as the Manganse Dioxide oxidation.In the presence of highly basic such as sodium hydride or KHMDS, in solvent such as DMF with suitable alkyl bromide (or iodine) such as bromotoluene or iodoethane with the alkylation of aldehyde IX, obtain the indoles X.The indoles X can be converted into the unsaturated acid XI with two steps: (1) alkali such as sodium hydride in the presence of, carry out Wittig with suitable reagent such as trimethyl-phosphine yl acetate at solvent in such as THF and react, (2) use the aqueous sodium hydroxide solution hydrolysis.Method H
The indoles I is converted into II with two steps: (1) solvent such as THF in LAH reduction, (2) in solvent such as methylene dichloride or DMF, in the presence of alkali such as imidazoles, the silylanizing of usefulness tert-butyldimethylsilyl chloride (TBDMSCI).Handle such as ethylmagnesium bromide with Grignard reagent in-60 ℃ at solvent such as THF; in ether with the magnesium salts acidylate of suitable chloride of acid such as Acetyl Chloride 98Min. with gained; at last highly basic such as NaH in the presence of in DMF with alkylogen such as monobromoethane alkylation on nitrogen, obtain the ketone III.Remove silyl on the III in such as THF with tetrabutylammonium at solvent, with carbon tetrabromide and pair (diphenylphosphino) ethane the alcohol of gained is converted into bromide in such as methylene dichloride, obtain the bromide IV at solvent.Use mercaptan compound at alkali in the presence of such as cesium carbonate, or, obtain V (being respectively sulfide or ether) at highly basic such as NaH replaces IV with alcohol in DMF bromine.
Method A
Method B
Method F
R=alkoxyl group, benzyloxy, phenoxy group, halogen, CN, NO
2, alkyl or aryl R '=alkyl, benzyl, thiazolinyl, alkynyl, R "=halogen, CN, alkyl, alkoxyl group, carbalkoxy, amido, acyl group, H, OH
Method G
R=alkoxyl group, benzyloxy, phenoxy group, halogen, CN, NO
2, alkyl or aryl R '=alkyl, aryl
Method H
R=alkoxyl group, benzyloxy, phenoxy group, halogen, CN, NO
2, alkyl or aryl R '=alkyl, aryl R "=alkyl, benzyl, alkenyl, alkynyl group R " '=alkyl, aryl X=O, SY=halogen, methanesulfonates embodiment 884-[(5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1, the 3-thiazolane-3-yl) methyl] phenylformic acid
Step 1-is suspended in the aldehyde (5.2g) of embodiment 124 in the ethanol (150ml).In this thick slurry, add 2,4-thiazolidinedione (1.28g) and salt of wormwood (6.1g).Heated mixt in 60 ℃ of baths (reducing to 45 ℃ subsequently).After 1 hour, TLC shows reactionless.Add sodium hydroxide (2.1g) and with mixture in 58 ℃ of heating.After 45 minutes, TLC demonstration reaction is carried out.Add extra 2,4-thiazolidinedione (0.1g).Mixture stirred under room temperature spend the night.Mixture is inclined to water (500ml), be acidified to pH2 with 6N HCl, use ethyl acetate extraction, dry (sal epsom) also filters.From ethanol, grind and obtain orange solids, with its filtration and use washing with alcohol, obtain the required product (5.74g, 94%) of orange solids.
Add sodium hydride (0.08g, 60% dispersion in mineral oil) in DMF (15ml) solution of the material (1.1g) that step 2-prepares in 0 ℃ of step 1.Suspension was stirred 30 minutes.In reaction mixture, add bromotoluene (0.54g) and reactant stirred and spend the night.Add entry, the mixture ethyl acetate extraction.The organic layer that merges is concentrated.Column chromatography (1: 6 ethyl acetate: hexane to 1: 4 ethyl acetate: hexane) obtain the required product (1.18g, 75%) of yellow solid.
Add in acetonitrile (15ml) solution of the material that step 3-prepares in step 2 by syringe (0.34g) HF (48% aqueous solution, 3.7ml).The reactant stirring is spent the night.TLC demonstration reaction is not finished, and therefore adds THF to dissolve starting material and to add extra HF (0.6ml).Reactant was stirred 2 hours, and the reaction of TLC demonstration is after this finished.Add entry, cause forming yellow solid.Yellow solid is dissolved in the ethyl acetate, uses the salt water washing, through dried over mgso and concentrated.The rough solid suspension of gained in ethanol and stirred 30 minutes, is filtered and dry, obtain the title compound (140mg, 48%) of yellow solid.Embodiment 89
5-[(E)-(5-(benzyloxy)-1-{3-[3, two (trifluoromethyl) phenoxy groups of 5-] propyl group }-1H-indoles-2-yl) methylene radical]-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 90
5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 91
5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 92
5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 93
5-{ (E)-[1-(4-benzyl benzyl)-5-(benzyloxy)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 94
5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 95
5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-1,3-thiazolane-2,4-diketone
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles.Embodiment 96
2-(5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) acetate
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles, prepares required intermediate.
Step 2-embodiment 88 steps 2 are described, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.Embodiment 97
4-[(5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) methyl] phenylformic acid
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles, prepares required intermediate.
Step 2-is described according to embodiment 88 steps 2, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.Embodiment 98
2-(5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazo1an-3-yl) acetate
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles, prepares required intermediate.
Step 2-is described according to embodiment 88 steps 2, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.Embodiment 99
4-[(5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) methyl] phenylformic acid
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles, prepares required intermediate.
Step 2-is described according to embodiment 88 steps 2, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.Embodiment 100
2-(5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) acetate
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles, prepares required intermediate.
Step 2-is described according to embodiment 88 steps 2, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.
Described in embodiment 88 steps 1, begin the compound of preparation following examples 101-106 with suitable indoles and rhodanine.Embodiment 101
5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-2-sulfo--1,3-thiazolan-4-ketone embodiment 102
5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone embodiment 103
5-[(E)-(5-(benzyloxy)-1-{3-[3, two (trifluoromethyl) phenoxy groups of 5-] propyl group }-1H-indoles-2-yl) methylene radical]-2-sulfo--1,3-thiazolan-4-ketone embodiment 104
5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone GI1418 embodiment 105
5-{ (E)-[1-(4-benzyl benzyl)-5-(benzyloxy)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone embodiment 106
5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone embodiment 107
4-{[5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-4-oxo-2-sulfo--1, the 3-thiazolan-3-yl] methyl } phenylformic acid
Step 1-is described according to embodiment 88 steps 1, begins with suitable indoles and rhodanine, prepares required intermediate.
Step 2-is described according to embodiment 88 steps 2, with suitable alkylating agent, by the required intermediate of above intermediate preparation.
Step 3-is described according to embodiment 88 steps 3, by above intermediate preparation title compound.Embodiment 108
5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-2-sulfo-tetrahydrochysene-4H-imidazol-4-one
Described according to embodiment 88 steps 1, begin the preparation title compound with suitable indoles and 2-sulfo-rhodanine.Embodiment 109
1-benzyl-5-(2-thienyl)-1H-indole-2-carboxylic acid
To contain 2-[5-bromo-1-benzyl-1H-indole-2-carboxylic acid (100mg, 0.303mmol) and the 2-thienyl boric acid (116mg, 0.909mmol), (C
6H
5)
4Pd (42mg, 0.036mmol), (5/1/2=v/v, 4.5ml) the sealing test tube of mixture was in 100 ℃ of heating 23 hours for the benzene-alcohol-water of yellow soda ash (2.42mmol).Incline mixture to ether and transfer to pH3, use extracted with diethyl ether then.Organic layer washs with SODIUM PHOSPHATE, MONOBASIC, through dried over mgso and evaporation, obtains crude product, and it through silicagel column purifying (hexane solution with 15%EtOAc of 1%HCOOH), is obtained the described product of 65mg.Embodiment 110
5-(1-cumarone-2-yl)-1-benzyl-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use benzo [b] FURAN-2-BORONIC ACID to prepare title compound.Embodiment 111
1-benzyl-5-(4-fluorophenyl)-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use 4-fluorophenyl boric acid to prepare title compound.Embodiment 112
1-benzyl-5-(3-p-methoxy-phenyl)-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use 3-anisole ylboronic acid to prepare title compound.Embodiment 113
1-benzyl-5-phenyl-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use phenyl-boron dihydroxide to prepare title compound.Embodiment 114
1-diphenyl-methyl-5-bromo-1H-indole-2-carboxylic acid
(1.024g in 1-Methyl-2-Pyrrolidone 4.26mmol) (13ml) solution, adds to 5-bromo indole-2-formic acid in 0 ℃
iPr
2NEt (25.6mmol), tetrabutylammonium iodide (157mg, 0.426mmol) and the bromo ditan (1.20g, 4.86mmol).Reaction mixture in 50 ℃ of heating 21 hours, is allocated in it between ether and the frozen water then.After transferring to pH3, the water layer extracted with diethyl ether.Merge organic layer, with the SODIUM PHOSPHATE, MONOBASIC washing, through dried over mgso and be evaporated to dried.Purifying on silicagel column (hexane solution of 15%EtOAc) obtains the described product of 1.51g (87%).Embodiment 115
5-[3-(kharophen) phenyl]-1-diphenyl-methyl-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use 3-kharophen phenylo boric acid and 1-diphenyl-methyl-5-bromo-1H-indole-2-carboxylic acid to prepare title compound.Embodiment 116
1-diphenyl-methyl-5-(2-thienyl)-1H-indole-2-carboxylic acid
According to the method described in the embodiment 109, only be to use 1-diphenyl-methyl-5-bromo-1H-2-formic acid and 2-thienyl boric acid to prepare title compound.Embodiment 117A
5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-the 1H-indole-2-carboxylic acid
Step 1
To ice-cold (0 ℃) 2-ethoxycarbonyl-5-benzyloxy indole (5.0g, add in dimethyl formamide 16.9mmol) (50ml) solution sodium hydride (0.62g, 18.6mmol).Remove ice bath after 10 minutes, with reactant restir 30 minutes under room temperature, drip this moment two (trifluoromethyl) bromotoluenes (3.8ml, 20.3mmol).Green mixture was stirred under room temperature 4 hours, add entry, mixture extracts with EtOAc.The organic layer salt water washing that merges is through dried over mgso and concentrated.With product recrystallization from EtOAc/Hex, obtain the required intermediate of 6.87 (81%) pale powder.
Step 2
(1.3g adds 1NNaOH (5ml) and MeOH (6ml) in THF 2.5mmol) (50ml) solution to above intermediate.Mixture stirred under room temperature spend the night, concentrate then.Residue is suspended in water and use the HOAc acidifying.Product extracts with EtOAc, and the salt water washing of the organic layer of merging through dried over mgso and concentrated, obtains the title compound of the pale solid of quantitative yield.Embodiment 117B
5-[({5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } carbonyl) amino]-2-[(5-chloro-3-pyridyl) the oxygen base] phenylformic acid
Step 1
To above title compound (0.4g, add among (5ml) solution of methylene dichloride 0.8mmol) and the several DMF oxalyl chloride (0.2ml, 2.4mmol).Reactant was stirred 1.5 hours and concentrated.The yellow solid of gained is dissolved in the methylene dichloride (2ml), and add to pyridinylamino benzoic ether ether (0.24g, 0.8mmol) and pyridine (0.1ml is in methylene dichloride 0.9mmol) (8ml) solution.Reactant stirred under room temperature spend the night, add entry, the product dichloromethane extraction.The organic layer that merges is with saturated aqueous ammonium chloride, water, salt water washing and through dried over mgso.Concentrated and flash chromatography (Hex/EtOAc, 3/2) obtains the required intermediate of tawny solid of 0.182g (51%).
Step 2
To above intermediate (0.136g, add in THF 0.2mmol) (3ml) solution LiOH (0.022g, 0.5mmol) and water (5ml).Mixture stirred under room temperature spend the night, concentrate, the residue of gained is suspended in water and use the HOAc acidifying.Described product extracts with EtAOc, the organic layer water of merging, salt water washing and through dried over mgso.Concentrate the title compound (94%) that obtains 0.122g white crystalline solid.Embodiment 117C
5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-the 1H-indole-2-carboxylic acid
According to the method in embodiment 117A step 1 and the step 2, (2.0g 3.2mmol) with suitable alkylating agent, obtains the title compound of 1.7g (yield in two steps are 41%) yellow solid to use 2-ethoxycarbonyl-5-benzyloxy indole.Embodiment 117D
5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-the 1H-indole-2-carboxylic acid
According to the method in embodiment 117A step 1 and the step 2, (2.0g 3.2mmol) with suitable alkylating agent, obtains the title compound of 1.7g (yield in two steps are 41%) yellow solid to use 2-ethoxycarbonyl-5-benzyloxy indole.Embodiment 118
5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-2-(1H-1,2,3,4-tetrazolium-5-yl)-1H-indoles
Step 1
(1.5g, (0.8ml is 9.1mmol) with three DMF to add oxalyl chloride in methylene dichloride 3.0mmol) (20ml) suspension in the acid for preparing in embodiment 117A.Mixture becomes homogeneous phase and it was stirred under room temperature 1 hour.Reactant is concentrated and be dissolved in again in the methylene dichloride (5ml), add ammonium hydroxide (2.0ml).Two phasic property mixtures were stirred 24 hours and concentrated.Remaining water-based residue dichloromethane extraction, the salt water washing of the organic layer of merging, drying also concentrates, and obtains the required intermediate of the yellow powder of 1.4g (95%).
Step 2
To ice-cold DMF (0.23ml, CH 3.0mmol)
3Add in CN (10ml) solution oxalyl chloride (0.24ml, 0.28mmol).Generate white precipitate immediately, with solution restir 5 minutes.Intermediate (1.2g, CH 2.5mmol) above adding
3CN (5ml).With the orange-yellow solution stirring 10 minutes of gained and add pyridine (0.44ml, 5.5mmol).After 5 minutes, mixture is allocated between the 10%HCl aqueous solution and the EtOAc.With organic layer drying and concentrated, obtain the required intermediate of 1.0g (84%) yellow powder.
Step 3
GI1563
5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-the 1H-indole-2-carboxylic acid
To above intermediate (0.94g, add in N-N-methyl-2-2-pyrrolidone N-(10ml) solution 2.0mmol) sodiumazide (0.39g, 5.9mmol).With mixture reflux 2 hours.Allow reactant be cooled to room temperature, and incline to the 50ml frozen water.The solution of gained is transferred to pH=2 with the 10%HCl aqueous solution, form the tawny precipitation.Mixture is filtered and wash with EtOAc.Flash chromatography (methylene dichloride/MeOH, 10: 1) obtains the title compound of 0.78g (78%) white powder.Embodiment 119
According to the similar fashion of embodiment 118, according to step 1-3, begin by the acid for preparing among the embodiment 117C, preparation 1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl }-2-(1H-1,2,3,4-tetrazolium-5-yl)-1H-indoles-5-base ether acid.Embodiment 120
4-{[5-((E)-5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-4-oxo-2-sulfo--1, the 3-thiazolan-3-yl] methyl } phenylformic acid
Step 1
By with sodium hydride (0.006g, 0.22mmol) and DMF (2ml) solution-treated of bromomethyl SEM ester (0.058g0.2mmol), with thiazolidinedione (0.1g, 0.2mmol) alkylation of preparation among the embodiment 101.Flash chromatography (Hex/EtOAc, 4/1) obtains the required intermediate of the thick oily matter of 0.073g (50%).
Step 2
To above intermediate (0.07g, CH 0.1mmol)
3Add 48%HF (2ml) solution in CN (5ml) solution.Add entry after 2 hours, product extracts with EtOAc, the organic layer water of merging, salt water washing and through dried over mgso.Concentrate the title compound (42%) that obtains the 0.025g orange powder.Embodiment 121
5-((Z, 2E)-3-{5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl }-the 2-propenylidene)-1,3-thiazolan-2,4-diketone
Step 1
(4.4g, THF 8.4mmol) (30ml) solution is cooled to 0 ℃, drips THF (1.0M, 8.4ml) solution of lithium aluminum hydride under vigorous stirring with the intermediate of preparation in the embodiment 117A step 1.In 0 ℃ after 1 hour, carefully reactant is used the saturated ammonium chloride solution quencher.Salt is filtered and wash with EtOAc.Concentrated solvent obtains the alcohol of the yellow foam of 3.9g (96%).With alcohol (1.6g, 3.3mmol) be dissolved among the THF (50ml) and add Manganse Dioxide (2.91g, 33.4mmol).Reactant was stirred 12 hours, and pass through diatomite filtration.Concentrated filtrate obtains the required intermediate of the thick transparent oily matter of 1.47g (92%).
Step 2
(0.5ml, (0.14g 3.4mmol), stirs reactant 20 minutes to add sodium hydride in DMF 3.1mmol) (10ml) solution to ice-cold trimethyl-phosphine yl acetate.(1.47g, DMF 3.1mmol) (3ml) solution are removed ice bath, reactant is stirred under room temperature spend the night to add above intermediate.Add entry, water extracts with EtOAc.Organic layer water, salt water washing are through dried over mgso and concentrated.Flash chromatography (Hex/EtOAc, 3/2) obtains the required intermediate of 1.5g (93%) yellow solid.
Step 3
(0.5g 0.9mmol) is dissolved in the methylene dichloride (10ml), solution is cooled to-20 ℃ with above intermediate.(the 1.0M toluene solution 1.9ml), stirs reactant and to spend the night under room temperature to drip diisobutylaluminium hydride.Add entry, mixture filters by Celite pad.Filtrate is diluted with EtOAc, washes with water, and the salt water washing of the organic layer of merging, dry and concentrated.Flash chromatography (Hex/EtOAc, 3/2) obtains 0.49g (75%) orange.Be dissolved in this material among the THF (12ml) and add Manganse Dioxide (1.1g, 12.3mmol).The mixture stirring is spent the night, and filter by Celite pad.Concentrated solvent obtains the required intermediate of the thick tawny oily matter of 0.4g (65%).
Step 4
With above intermediate (0.1g 0.2mmol) is dissolved in the toluene (1ml), add then piperidines (6 μ l, 0.1mmol), acetate (1.2 μ l) and 2, the 4-thiazolidinedione (0.023g, 0.2mmol).With mixture heating up to refluxing 2 hours.Reactant is cooled to room temperature, adds entry, water layer extracts with EtOAc.The organic layer water and the salt water washing that merge, dry and concentrated.Flash chromatography (Hex/EtOAc, 3/2) obtains the title compound of 0.056g (47%) red powder.Embodiment 122
5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-the 1H-indole-2-carboxylic acid
Step 1: under room temperature to 5-phenoxy group-2-indolecarboxylic acid (1g, add in 12mlDMF solution 3.4mmol) sodium hydride (0.163g, 60% oil dispersion, 4.07mmol).Reactant was stirred 30 minutes.(1.54g 3.73mmol), spends the night the reactant stirring to add a-bromo-a '-[3,5-pair of (trifluoromethyl) phenoxy groups]-p-Xylol this moment.When reaction is finished (through the TLC monitoring), with its water quencher, with ethyl acetate extraction (3 *).Organic layer is through dried over mgso, concentrates and is used for next step.
Step 2: with described ester (2.1g, 3.39mmol) be dissolved in the 40ml 1/1 THF/ methyl alcohol, add 1N sodium hydroxide (15ml) then, the mixture of gained was stirred under room temperature 16 hours, processing obtains crude product, with it through chromatography purification (1: 1 hexane with 1% acetate: ethyl acetate) obtain (1.73g, 85%) solid.Embodiment 123
5-({ [1-benzyl-5-(benzyloxy)-1H-indoles-2-yl] carbonyl } amino) m-phthalic acid
Step 1:, use bromotoluene to prepare this intermediate according to method described in the embodiment 122.
Step 2: with the acid (0.27g of preparation in the step 1,0.75mmol), EDCI (0.18g, 0.97mmol), DMAP (3mg, 0.02mmol) and the amino isophthalic acid ester (0.18g of dimethyl-5,0.75mmol) be dissolved among the THF (8.8ml) and refluxed 16 hours, handle back purifying (hexane: ethyl acetate 3: 1) obtain (0.25g, 60%) pure products.
Step 3: according to the method described in embodiment 122 steps 2, the ester that is prepared by above step 2 prepares title compound.Embodiment 124
(E)-3-[-5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl]-2-vinylformic acid
Step 1: (30g 102mmol) is dissolved among the 250mlTHF, is cooled to 0 ℃, adds lithium aluminum hydride (LAH) (255ml 1.0M THF solution) by addition funnel in 40 minutes with 5-benzyloxy-2-indolecarboxylic acid ethyl ester.Reactant again in 0 ℃ of stirring 2 hours, is handled by adding 4N NaOH (190ml).The salt of gained is filtered, with the ethyl acetate washing (3 * 400ml), filtrate merged and through dried over mgso and concentrate, obtain 24.8g (96%).
Step 2: (26.1g 103mmol) is dissolved among the THF (900ml) with the indanol of step 1.Add Manganse Dioxide (106.6g) and mixture was stirred under room temperature 2 hours.After reaction is finished, mixture is washed by diatomite filtration and with ethyl acetate.Filtrate decompression is concentrated, and drying obtains required aldehyde (22.9g, 89%).
Step 3:, prepare intermediate by the indoles and 2-(brooethyl) naphthalene that prepare in the above step 2 according to method described in embodiment 122 steps 1.
Step 4: (0.025g, 60% oil dispersion add trimethyl-phosphine yl acetate (0.1ml, 2.5mlTHF solution 0.62mmol) in 7.5ml THF solution 0.63mmol) to sodium hydride under room temperature.Reactant was stirred 10 minutes, under room temperature, drip aldehyde (0.24g, 2.5ml THF solution 0.62mmol) of preparation in the above step 3.With 30 minutes embodiment 133 of reactant restir
2-([3-ethanoyl-1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(benzyloxy)-1H-indoles-2-yl] and methyl } the sulfane base) acetate]
Step 1 is in 20 minutes, in 0 ℃ of solution that toluoyl base chlorine (0.8M) is added to the triethylamine (2.44eq) that is dissolved in the methylene dichloride and methoxy methyl amine hydrochlorate (1.1eq).With reactant temperature to 25 ℃.After 1 day,, obtain the crude product of about 100% yield in 25 ℃ of stirrings with methylene dichloride and water treatment.
Step 2 is dissolved in benzothiazole among the THF (0.35M) under anhydrous condition.Add BuLi (1.1eq) in-78 ℃.In-78 ℃ after 1 hour, in 15 minutes, be added in the acid amides of the step 1 among the THF.Allow reactant temperature to 25 ℃.After 1 day,, obtain pure tolyl ketone product (52%) in 25 ℃ of stirrings with ethyl acetate and water treatment and chromatographic separation.
Step 3 is dissolved in the tolyl ketone of step 2 in the tetracol phenixin (0.19M), adds NBS (1.2eq) and AIBN (0.11eq).In 60 ℃ after 1 day, there are about 1: 1 starting material and product.Stand identical condition again, filter then and from ethyl acetate recrystallization, obtain pure bromobenzyl ketone product (28%).
Step 4 is dissolved in the intermediate of embodiment 131 steps 3 among the exsiccant DMF (0.1M), adds NaH (1.2eq) then.In 25 ℃ after 1.5 hours, add the bromobenzyl ketone of step 3 and stirred 1 day in 25 ℃.Handle (ethyl acetate/hexane) and grind (ethyl acetate/hexane), obtain described product, yield is 46%.
Step 5 is dissolved in the product of step 4 among methylene dichloride and the 1N HCl (about 0.04M) and in 25 ℃ and stirred 1 hour.Handle (sodium bicarbonate) and obtain product alcohol (89%) with the ether grinding.
Step 6 is dissolved in the alcohol of step 5 in the exsiccant methylene dichloride (0.014M), handles and stirs 1 hour in 25 ℃ with thionyl chloride (1.2eq).Concentrate and grind and obtain product alcohol (100%) with ethyl acetate/hexane.
Table VIII (mensuration of describing among the embodiment 136) and table IX (mensuration of embodiment 137) have been reported the activity data of the compound of embodiment 88-135.Embodiment 136 determinations of activity
(a) vesica is measured
With 1-palmityl-2-[
14C] arachidonic phosphatidyl choline (58mCi/mmol) (final concentration is 6 μ M) and 1,2-two oleoyl glycerine (final concentration is 3 μ M) mix and are incorporated in drying under the nitrogen gas stream.In described lipid, add 50mM Hepes pH7.5 (lipid of 2 * final concentration), with suspension in 4 ℃ of supersound process 3 minutes.In this suspension, add 50mM Hepes pH7.5,300mM NaCl, 2mM DTT, 2mM CaCl
2With 2mg/ml bovine serum albumin (BSA) (Sigma A7511) (lipid of 1.2 * final concentration).Typical mensuration comprises lipid mixt (85 μ l), to wherein adding described inhibitor (the DMSO solution of 5 μ l) and cPLA continuously
2, in 10 μ l BSA damping fluids, add 10ng cPLA for automatic system
2, and add 1ng cPLA for labor measurement
2This mensuration by described below or labor measurement or automatically the mensuration scheme carry out.
(b) soluble substrate is measured (LvsoPC)
Dry 1-[under nitrogen gas stream
14C]-palmityl-2-hydroxyl phosphatidylcholine (57mCi/mmol) (final concentration is 4.4 μ M).By vortex mixed with the lipid resuspending in 80mM Hepes pH7.5,1mM EDTA (1.2 * final concentration).Typical mensuration comprises lipid suspension (85 μ l), to wherein adding described inhibitor (the DMSO solution of 5 μ l) and the 200ng cPLA in 80mMHepes pH7.5,2mM DTT and 1M EDTA continuously
2This mensuration by described below or labor measurement or automatically the mensuration scheme carry out.
(f) RBL measures
At 5%CO
2In the atmosphere, in the MEM that contains non-essential amino acid and 12% foetal calf serum, cultivate the RBL-2H3 cells in 37 ℃ of routines.The experiment the day before yesterday, with cell with 3 * 10
5Cell/ml is inoculated in the turn flask, and adds 100ng/ml DNP specific IgE.After 20 hours, by centrifugal cell harvesting and in the serum-free MEM washing 1 time, resuspending in serum free medium to 2 * 10
6Cell/ml.Then with cell with or the DMSO solution (1%v/v) of inhibitor or DMSO solution (1%v/v) in 37 ℃ of preincubation 15 minutes, use DNP-BSA (300ng/ml) to stimulate then.After 6 minutes, centrifugal removal cell is according to the currently known methods PGD of clear liquid analytically
2Content.
(g) tonka bean camphor (Coumarine) is measured
As previous report (Huang, Z etc., 1994, Analytical Biochemistry 222,10-115), with 6-enanthic acid umbelliferone ester as cPLA
2The monomer substrate.Inhibitor is measured damping fluid (80mMHepes, pH7.5,1mM EDTA) with the 200 μ l that contain 60 μ M 6-enanthic acid umbelliferone esters to be mixed.By adding 4 μ gcPLA in the 50 μ l mensuration damping fluid
2Initial action.In photofluorometer, by excite and monitor the hydrolysis of 6-enanthic acid umbelliferone ester in 360nm in 460nm monitoring emission.The increase of enzymic activity and per minute 460nm emission is proportional.In the presence of the cPLA2 inhibitor, the speed of increase is less.The experiment of embodiment 137 rat carrageenan inductive palmula oedema
Every kind of compound is suspended among the PBS (no calcium or magnesium) of 0.3ml dehydrated alcohol, 0.1ml tween-80 and 2.0mlDulbecco.In this mixture, add 0.1ml 1N NaOH.After dissolving is finished, add the PBS of additional quantity, concentration is transferred to 1mg/ml.All compounds all remain in the solution.Volume with 5ml/kg gives male SpragueDawley rat with the compound intravenously, induces oedema by 0.05ml 1% IV type carrageenan being injected in the palmula of back simultaneously.3 hours measuring claw pads are long-pending before giving described compound and after giving carrageenan.
The table VIII
The table VIII
The table VIII
The table VIII
The table VIII
All patents that this paper quotes and reference are all as being attached to herein that this paper proposes.
Claims (76)
1. have the compound or its pharmacy acceptable salt that are selected from following chemical structural formula:
With
Wherein:
A and any other group are irrelevant, are selected from-CH
2-and-CH
2-CH
2-;
B and any other group are irrelevant, are selected from-(CH
2)
n-,-(CH
2O)
n-,-(CH
2S)
n-,-(OCH
2)
n-,-(SCH
2)
n-,-(CH=CH)
n-,-(C ≡ C)
n-,-CON (R
6)-,-N (R
6) CO-,-O-,-S-and-N (R
6)-;
R
1Irrelevant with any other R group, be selected from-X-R
6,-H ,-OH, halogen ,-CN ,-NO
2, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
2Irrelevant with any other R group, be selected from-H ,-COOH ,-COR
5,-CONR
5R
6,-(CH
2)
n-W-(CH
2)
m-Z-R
5,-(CH
2)
n-W-R
5,-Z-R
5, C
1-C
10The aryl of alkyl, alkenyl and replacement;
R
3Irrelevant with any other R group, be selected from-H ,-COOH ,-COR
5,-CONR
5R
6,-(CH
2)
n-W-(CH
2)
m-Z-R
5,-(CH
2)
n-W-R
5,-Z-R
5, C
1-C
10The aryl of alkyl, alkenyl and replacement;
R
4Irrelevant with any other R group, be selected from-H ,-OH ,-OR
6,-SR
6,-CN ,-COR
6,-NHR
6,-COOH ,-CONR
6R
7,-NO
2,-CONHSO
2R
8, C
1-C
5The aryl of alkyl, alkenyl and replacement;
R
5Irrelevant with any other R group, be selected from-H ,-OH ,-O (CH
2)
nR
6,-SR
6,-CN ,-COR
6,-NHR
6,-COOH ,-NO
2,-COOH ,-CONR
6R
7,-CONHSO
2R
8, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl, replacement ,-CF
3,-CF
2CF
3With
R
6Irrelevant with any other R group, be selected from-H, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
7Irrelevant with any other R group, be selected from-H, C
1-C
5The aryl of alkyl, alkenyl, alkynyl group, aryl and replacement;
R
8Irrelevant with any other R group, be selected from C
1-C
3The aryl of alkyl, aryl and replacement;
R
9Irrelevant with any other R group, be selected from-H ,-OH, halogen ,-CN ,-OR
6,-COOH ,-CONR
6R
7, tetrazolium ,-CONHSO
2R
8,-COR
6,-(CH
2)
nCH (OH) R
6With-(CH
2)
nCHR
6R
5
R
10Irrelevant with any other R group, be selected from-H ,-OH, halogen ,-CN ,-OR
6,-COOH ,-CONR
6R
7, tetrazolium ,-CONHSO
2R
8,-COR
6,-(CH
2)
nCH (OH) R
6With-(CH
2)
nCHR
6R
5
W is each independent use in being included in same compound the time, be selected from-O-,-S-,-CH
2-,-CH=CH-,-C ≡ C-and-N (R
6)-;
X and other any group are irrelevant, each independent use in the time of in being included in same compound, be selected from-O-,-S-and-N (R
6)-;
Z and other any group are irrelevant, and each independent use is selected from-CH in the time of in being included in same compound
2-,-O-,-S-,-N (R
6)-,-CO-,-CON (R
6)-and N (R
6) CO-;
M is the integer of 0-4 when being included in each independent use of time in-compound; And
N and m are irrelevant, and each independent use is the integer of 0-4 in the time of in being included in same compound.
2. have Phospholipid hydrolase and suppress the compound of active claim 1.
3. the compound of claim 1, wherein said compound has following chemical structural formula:
5. the compound of claim 1, wherein said compound has following chemical structural formula:
6. the compound of claim 1, wherein A is-CH
2-, and R
2For-(CH
2)
n-W-(CH
2)
m-ZR
5
7. the compound of claim 6, wherein n is 1, and m is 1, and W is-S-, and Z is-CO-.
8. the compound of claim 7, wherein R
5For-NHR
6
9. the compound of claim 8, wherein R
6Be the aryl that replaces.
10. the compound of claim 9, wherein said aryl independently is selected from following substituting group and replaces with one or more: halogen ,-CF
3,-CF
2CF
3,-(CHO
2)
pCOOH ,-(CH
2)
pCH
3,-O (CH
2)
pCH
3,-(CH
2)
pOH ,-(CH
2)
pS (C
6H
6) ,-(CH
2)
pCONH
2With-CHR
11COOH, wherein R
11Be selected from alkyl, alkenyl, alkynyl group ,-(CH
2)
pOH and-O (CH
2)
pCH
3, and wherein p is the integer of 0-4.
11. the compound of claim 6, wherein R
1Be selected from-H and-OCH
2(C
6H
6).
12. the compound of claim 6, wherein R
3For-COR
5, R
5For-OCH
2R
6, and R
6Be the aryl that replaces.
13. the compound of claim 12, wherein said aryl is selected from following substituting group and replaces with one or more :-CF
3,-CF
2CF
3With-C (CH
3)
2CH
2CH
3
14. the method for the phospholipase activity of inhibitory enzyme comprises giving the compound that mammalian subject is treated the claim 1 of significant quantity.
15. the method for treatment inflammation comprises giving the compound that mammalian subject is treated the claim 1 of significant quantity.
16. medicinal compositions comprises the compound and the pharmaceutically acceptable carrier of claim 1.
17. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1And R
1Independently be selected from C
1-C
6Alkyl ,-Z-C
1-C
6Alkyl, phenyl ,-(CH
2)
n-Z-(CH
2)
n-phenyl, benzyl ,-(CH
2)
n-Z-(CH
2)
n-benzyl, naphthyl ,-(CH
2)
n-Z-(CH
2)
n-naphthyl, pyrimidyl ,-(CH
2)
n-Z-(CH
2)
n-pyrimidyl, described alkyl, phenyl, benzyl, naphthyl and pyrimidyl can randomly be selected from following substituting group by 1-3: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
Z is O or S;
N is the integer of 0-3;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6The part of alkyl or following formula:
N independently is chosen to be the integer that is selected from 0-3 in each case;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
1For-COOH or be selected from following part:
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
3Part or comprise R
3The combination of part comprise the acidic-group that is selected from carboxylic acid or following formula part:
R
5Be selected from:
A) formula L
2-M
2Part;
L
2Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-Z-,-(CH
2)
n-Z-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
2Be selected from-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
R wherein
8And R
9As above definition, and can be substituted any position on described ring or dicyclo; Or
B) part of following formula:
L wherein
3For chemical bond or be selected from following group :-CH
2-,-CH
2-Z-,-C (O)-,-O-,-S-or-(CH
2)
n-Z-(CH
2)
n-;
R
1Be selected from-O-C
1-C
6Alkyl ,-S-C
1-C
6Alkyl ,-the O-phenyl ,-the S-phenyl ,-the O-benzyl ,-the S-benzyl, described alkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6The part of alkyl or following formula:
N independently is chosen to be the integer that is selected from 0-3 in each case;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH-(C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4The combination of part comprise the part of carboxylic acid or following formula:
R
5Be formula-L
2-M
2Structure;
L
2Be selected from chemical bond or be selected from following bridged group :-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (O)-O-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
1Be selected from-O-C
1-C
6Alkyl ,-S-C
1-C
6Alkyl ,-the O-phenyl ,-the O-benzyl ,-the S-benzyl, described alkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
10Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6The part of alkyl or following formula
R wherein
4, R
5, R
8, R
9And R
10Such as claim 19 definition.
21. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 17 of medicinal significant quantity.
22. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 19 of medicinal significant quantity.
23. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1And R
1 'Independently be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; Be connected directly to described indole ring or by-S-,-O-or-(CH
2)
n-bridging is connected to described indole ring following a), b) or loop section c):
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) can randomly contain 1-3 dicyclo part that is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine (napthyridine), described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
Z is O or S;
R
6Be selected from following relevant member: H ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl or-the S-benzyl, the phenyl of these groups or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Independently be selected from following relevant member :-OH ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NH
2,-(CH
2)
n-NH
2,-NH-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,-(CH
2)
n-NH-(C
1-C
6Alkyl) ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, phenyl ,-O-phenyl, benzyl or-the O-benzyl; Or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and can randomly contain the assorted former dicyclo part of giving of ring that 1-3 is selected from N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine, described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3, is preferably 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, phenoxy group-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
6Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N in each case, for independently being selected from the integer of 0-3;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
R
11Be selected from H, C
1-C
6Low alkyl group, C
1-C
6Cycloalkyl ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, preferred 1-3, and more preferably 1-2,
Y is C
3-C
5Cycloalkyl or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium, Evil thiazole, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and can randomly contain the dicyclo part that 1-3 is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or 1,5-naphthyridine, described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
D) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
24. have compound or its pharmacy acceptable salt of the claim 23 of following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; Be connected directly to described indole ring or by-S-,-O-or-(CH
2)
n-bridging is connected to described indole ring following a), b) or loop section c):
A) furans, pyrroles or thiophene, they can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) pyridine, pyrimidine, piperidines or morpholine, they each can randomly be selected from following substituting group and replace by 1-3: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) cumarone, indoles, naphthalene, purine or quinoline, they can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
D) part of following formula:
Z is O or S;
R
6Be selected from following relevant member: H ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl or-the S-benzyl, the phenyl of these groups or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Be selected from following relevant member :-OH ,-CF
3, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NH
2,-(CH
2)
n-NH
2,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2,-(CH
2)
n-NH-(C
1-C
6Alkyl) ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, phenyl ,-O-phenyl, benzyl or-O-benzyl, furans, pyrroles, thiophene, pyridine, pyrimidine, thiazole, pyrazoles or morpholine, the ring of these groups can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3, is preferably 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, phenoxy group-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3Or-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N is chosen to be the integer that is selected from 0-3 in each case independently;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
1For-COOH or be selected from following part:
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2-phenyl-C (O)-benzothiazole or formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
25. have compound or its pharmacy acceptable salt of the claim 24 of following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl ,-S-C
1-C
10Alkyl preferably-S-C
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-the S-benzyl; Or by chemical bond or-S-,-O-or-(CH
2)
n-bridging is connected to furans, pyrroles or the thiophene of described indole ring, and described phenyl, benzyl, furans, pyrroles or thiphene ring can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
N is the integer of 0-3, preferred 1-3, more preferably 1-2;
R
2Be selected from H, halogen ,-CN ,-CHO ,-CF
3,-OH, C
1-C
10Alkyl is C preferably
1-C
6Alkyl, C
1-C
10Alkoxyl group is C preferably
1-C
6Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-C (O) CH
3,-C (O)-(CH
2)
n-CF
3,-CN ,-NO
2,-NH
2,-HN-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl ,-SO
2-C
1-C
6Alkyl, phenyl, phenoxy group, benzyl, phenoxy group-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH, C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3Or-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl), relevant R
3The ring of group can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH; Or the part of following formula:
N is chosen to be the integer that is selected from 0-3 in each case independently;
R
8And R
9Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
4Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CH=CH-COOH, tetrazolium ,-(CH
2)
n-tetrazolium, formula L
1-M
1Part or the part of following formula:
R
12Be selected from H ,-CF
3, C
1-C
6Alkyl ,-(CH
2)
n-C
3-C
6Cycloalkyl, phenyl or benzyl, described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
L
1Be selected from-(CH
2)
n-,-S-,-O-,-C (O)-,-C (O)-O-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-,-C (Z)-NH-SO
2-(CH
2)
n-,-C (O)-(CH
2)
n-O-,-C (O)-N-or-(CH
2)
n-S-(CH
2)
n-C (O)-N-;
M
1For-COOH or be selected from following part:
R
8Independently be selected from each case H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Independently be selected from each case H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-HN (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-CF
3,-OH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl,
Prerequisite is: comprise R
4Part or comprise R
4The combination of part comprise the acidic moiety that is selected from carboxylic acid, tetrazolium or following formula part:
R
5Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
10-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
10Cycloalkyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2-phenyl-C (O)-benzothiazole or formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-CF
3Or-(CH
2)
n-CF
3
B and C independently are selected from phenyl, pyridyl, pyrimidyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CN ,-CHO ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
26. the compound of claim 1, be 4-[(5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
27. the compound of claim 1 is 5-[(E)-(5-(benzyloxy)-1-{3-{[3, two (trifluoromethyl) phenoxy groups of 5-] propyl group }-1H-indoles-2-yl) methylene radical]-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
28. the compound of claim 1 is 5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
29. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
30. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
31. the compound of claim 1 is 5-{ (E)-[1-(4-benzyl benzyl)-5-(benzyloxy)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
32. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
33. the compound of claim 1 is 5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-1,3-thiazolane-2,4-diketone or its pharmacy acceptable salt.
34. the compound of claim 1, be 2-(5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) acetate or its pharmacy acceptable salt.
35. the compound of claim 1 is 4-[(5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) phenylformic acid or its pharmacy acceptable salt.
36. the compound of claim 1 is 2-(5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) acetate or its pharmacy acceptable salt.
37. the compound of claim 1 is 4-[(5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
38. the compound of claim 1 is 2-(5-{ (E)-[5-(benzyloxy)-1-(4-luorobenzyl)-1H-indoles-2-yl] methylene radical }-2,4-dioxo-1,3-thiazolan-3-yl) acetate or its pharmacy acceptable salt.
39. the compound of claim 1 is 5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
40. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
41. the compound of claim 1 is 5-[(E)-(5-(benzyloxy)-1-{3-[3, two (trifluoromethyl) phenoxy groups of 5-] propyl group }-1H-indoles-2-yl) methylene radical]-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
42. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
43. the compound of claim 1 is 5-{ (E)-[1-(4-benzyl benzyl)-5-(benzyloxy)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
44. the compound of claim 1 is 5-{ (E)-[5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] methylene radical }-2-sulfo--1,3-thiazolan-4-ketone or its pharmacy acceptable salt.
45. the compound of claim 1, be 4-{[5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-4-oxo-2-sulfo--1, the 3-thiazolan-3-yl] methyl } phenylformic acid or its pharmacy acceptable salt.
46. the compound of claim 1 is 5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-2-sulfo-tetrahydrochysene-4H-imidazol-4-one or its pharmacy acceptable salt.
47. the compound of claim 1 is 1-benzyl-5-(2-thienyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
48. the compound of claim 1 is 5-(1-cumarone-2-yl)-1-benzyl-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
49. the compound of claim 1 is 1-benzyl-5-(4-fluorophenyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
50. the compound of claim 1 is 1-benzyl-5-(3-p-methoxy-phenyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
51. the compound of claim 1 is 1-benzyl-5-phenyl-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
52. the compound of claim 1 is 1-diphenyl-methyl-5-bromo-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
53. the compound of claim 1 is 5-[3-(kharophen) phenyl]-1-diphenyl-methyl-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
54. the compound of claim 1 is 1-diphenyl-methyl-5-(2-thienyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
55. the compound of claim 1 is 5-[({5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } carbonyl) amino]-2-[(5-chloro-3-pyridyl) the oxygen base] phenylformic acid or its pharmacy acceptable salt.
56. the compound of claim 1 is 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
57. the compound of claim 1 is 5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
58. the compound of claim 1 is 5-[({5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } carbonyl) amino]-2-[(5-chloro-3-pyridyl) the oxygen base] phenylformic acid or its pharmacy acceptable salt.
59. the compound of claim 1 is 5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
60. the compound of claim 1, be 4-{[5-((E)-{ 5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl } methylene radical)-4-oxo-2-sulfo--1, the 3-thiazolan-3-yl] methyl } phenylformic acid or its pharmacy acceptable salt.
61. the compound of claim 1, for 5-((Z, 2E)-3-{5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl-the 2-propenylidene)-1,3-thiazolan-2,4-diketone or its pharmacy acceptable salt.
62. the compound of claim 1 is 5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
63. the compound of claim 1 is 5-({ [1-benzyl-5-(benzyloxy)-1H-indoles-2-yl] carbonyl } amino) m-phthalic acid or its pharmacy acceptable salt.
64. the compound of claim 1 is (E)-3-[5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl]-2-vinylformic acid or its pharmacy acceptable salt.
65. the compound of claim 1 is (E)-3-{5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-1H-indoles-2-yl }-2-vinylformic acid or its pharmacy acceptable salt.
66. the compound of claim 1 is (E)-3-[5-(benzyloxy)-1-(4-benzyl chloride base)-1H-indoles-2-yl]-2-vinylformic acid or its pharmacy acceptable salt.
67. the compound of claim 1 is 1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indole-2-carboxylic acid or its pharmacy acceptable salt.
68. the compound of claim 1, be 5-({ [5-(benzyloxy)-1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] carbonyl } amino)-2-[(5-chloro-3-pyridyl) the oxygen base] phenylformic acid or its pharmacy acceptable salt.
69. the compound of claim 1 is 3-({ [1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] carbonyl } amino) phenylformic acid or its pharmacy acceptable salt.
70. the compound of claim 1 is 2-[4-({ [1-(4-{[3, two (trifluoromethyl) phenoxy groups of 5-] methyl } benzyl)-1H-indoles-2-yl] carbonyl } amino) phenyl] acetate or its pharmacy acceptable salt.
71. the compound of claim 1 is 3-{[3-ethanoyl-5-(benzyloxy)-1-(2-naphthyl methyl)-1H-indoles-2-yl] methoxyl group } phenylformic acid or its pharmacy acceptable salt.
72. the compound of claim 1 is 4-{[5-(benzyloxy)-1-(2-naphthyl methyl)-3-(2,2, the 2-trifluoroacetyl group)-1H-indoles-2-yl] methoxyl group } phenylformic acid or its pharmacy acceptable salt.
73. the compound of claim 1 is 3-{[5-(benzyloxy)-1-[2, two (trifluoromethyl) benzyls of 4-]-3-(2,2, the 2-trifluoroacetyl group)-1H-indoles-2-yl] methoxyl group } phenylformic acid or its pharmacy acceptable salt.
74. the compound of claim 1 is 2-({ [3-ethanoyl-1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(benzyloxy)-1H-indoles-2-yl] methyl } sulfane base) acetate or its pharmacy acceptable salt.
75. the compound of claim 1 is 2-({ [3-ethanoyl-1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(benzyloxy)-1H-indoles-2-yl] methyl } sulfane base) phenylformic acid or its pharmacy acceptable salt.
76. the compound of claim 1 is 4-{[3-ethanoyl-1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(benzyloxy)-1H-indoles-2-yl] methyl the sulfane base) phenylformic acid or its pharmaceutically can the amount of connecing salt.
Applications Claiming Priority (2)
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US3010298A | 1998-02-25 | 1998-02-25 | |
US09/030,102 | 1998-02-25 |
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CN1298404A true CN1298404A (en) | 2001-06-06 |
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ID=21852517
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1999
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- 1999-02-17 EP EP99936073A patent/EP1062216A1/en not_active Withdrawn
- 1999-02-17 AU AU32970/99A patent/AU3297099A/en not_active Abandoned
- 1999-02-17 CN CN99805379A patent/CN1298404A/en active Pending
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- 1999-02-17 WO PCT/US1999/003388 patent/WO1999043672A1/en not_active Application Discontinuation
- 1999-02-17 PL PL99342516A patent/PL342516A1/en unknown
- 1999-02-17 SK SK1278-2000A patent/SK12782000A3/en unknown
- 1999-02-17 EE EEP200000522A patent/EE200000522A/en unknown
- 1999-02-17 KR KR1020007009459A patent/KR20010041346A/en not_active Application Discontinuation
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- 1999-02-17 BR BR9909242-5A patent/BR9909242A/en not_active IP Right Cessation
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BG104781A (en) | 2001-10-31 |
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BR9909242A (en) | 2000-11-14 |
HRP20000513A2 (en) | 2001-12-31 |
EP1062216A1 (en) | 2000-12-27 |
WO1999043672A9 (en) | 2000-05-04 |
SK12782000A3 (en) | 2001-04-09 |
HUP0100156A2 (en) | 2001-07-30 |
EA200000873A1 (en) | 2001-04-23 |
JP2002504551A (en) | 2002-02-12 |
PL342516A1 (en) | 2001-06-18 |
CA2322163A1 (en) | 1999-09-02 |
NO20004217L (en) | 2000-10-23 |
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