CN1426393A - 新化合物 - Google Patents
新化合物 Download PDFInfo
- Publication number
- CN1426393A CN1426393A CN01808412A CN01808412A CN1426393A CN 1426393 A CN1426393 A CN 1426393A CN 01808412 A CN01808412 A CN 01808412A CN 01808412 A CN01808412 A CN 01808412A CN 1426393 A CN1426393 A CN 1426393A
- Authority
- CN
- China
- Prior art keywords
- hydroxyl
- phenyl
- phenoxy group
- propoxy
- ethanamide
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 233
- 238000000034 method Methods 0.000 claims abstract description 60
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 206
- -1 nitro, carboxyl Chemical group 0.000 claims description 197
- 229910052760 oxygen Inorganic materials 0.000 claims description 189
- 239000001301 oxygen Substances 0.000 claims description 187
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 181
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 129
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 110
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 81
- 239000000203 mixture Substances 0.000 claims description 57
- 229940017219 methyl propionate Drugs 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 43
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 31
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 28
- XCJLXFIGEMUOEE-UHFFFAOYSA-N acetamide;2,2,2-trifluoroacetic acid Chemical compound CC(N)=O.OC(=O)C(F)(F)F XCJLXFIGEMUOEE-UHFFFAOYSA-N 0.000 claims description 25
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 23
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 14
- 239000004202 carbamide Substances 0.000 claims description 14
- 235000013877 carbamide Nutrition 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 13
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 229940095102 methyl benzoate Drugs 0.000 claims description 11
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 claims description 10
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- 208000006673 asthma Diseases 0.000 claims description 9
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- VUQZKDREOOPLMD-UHFFFAOYSA-N formamide;2,2,2-trifluoroacetic acid Chemical compound NC=O.OC(=O)C(F)(F)F VUQZKDREOOPLMD-UHFFFAOYSA-N 0.000 claims description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000018569 Respiratory Tract disease Diseases 0.000 claims description 3
- DSFVQIUBODXRLL-UHFFFAOYSA-N acetamide;dihydrochloride Chemical compound Cl.Cl.CC(N)=O DSFVQIUBODXRLL-UHFFFAOYSA-N 0.000 claims description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 102000009410 Chemokine receptor Human genes 0.000 claims description 2
- 108050000299 Chemokine receptor Proteins 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- IMNDHOCGZLYMRO-UHFFFAOYSA-N n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC=C1 IMNDHOCGZLYMRO-UHFFFAOYSA-N 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims 3
- 230000002349 favourable effect Effects 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 281
- 239000002585 base Substances 0.000 description 203
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
- 239000000243 solution Substances 0.000 description 133
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 235000019439 ethyl acetate Nutrition 0.000 description 64
- 238000003756 stirring Methods 0.000 description 64
- 239000011259 mixed solution Substances 0.000 description 63
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- 238000001704 evaporation Methods 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 239000007787 solid Substances 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 38
- 229910002027 silica gel Inorganic materials 0.000 description 38
- 229960001866 silicon dioxide Drugs 0.000 description 38
- 239000002904 solvent Substances 0.000 description 35
- 238000005406 washing Methods 0.000 description 35
- 238000003818 flash chromatography Methods 0.000 description 34
- 239000007864 aqueous solution Substances 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- 230000008020 evaporation Effects 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 238000001035 drying Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 238000013459 approach Methods 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 15
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 15
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 13
- 235000008504 concentrate Nutrition 0.000 description 13
- 229960004756 ethanol Drugs 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 206010039083 rhinitis Diseases 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 150000002924 oxiranes Chemical class 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000007789 sealing Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 230000035605 chemotaxis Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- SCILIBBKSJPQSB-UHFFFAOYSA-N 1-$l^{1}-oxidanylpropan-2-ol Chemical compound CC(O)C[O] SCILIBBKSJPQSB-UHFFFAOYSA-N 0.000 description 4
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 4
- 108010012236 Chemokines Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical class Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 4
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108050006947 CXC Chemokine Proteins 0.000 description 3
- 102000019388 CXC chemokine Human genes 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 125000006252 n-propylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 125000005936 piperidyl group Chemical group 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- BQJBONTVMVGWPV-UHFFFAOYSA-N (2-hydroxyphenyl)urea Chemical group NC(=O)NC1=CC=CC=C1O BQJBONTVMVGWPV-UHFFFAOYSA-N 0.000 description 2
- XNYTZADDSVJMRC-UHFFFAOYSA-N (5-chloro-2-hydroxyphenyl)urea Chemical compound NC(=O)NC1=CC(Cl)=CC=C1O XNYTZADDSVJMRC-UHFFFAOYSA-N 0.000 description 2
- PNDSYXGJCWKNFG-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]piperazine Chemical compound C1=C(Cl)C(Cl)=CC=C1CN1CCNCC1 PNDSYXGJCWKNFG-UHFFFAOYSA-N 0.000 description 2
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 2
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 2
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical class OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 2
- GAWNBKUTBVLIPL-UHFFFAOYSA-N 3-fluoro-2-nitrophenol Chemical compound OC1=CC=CC(F)=C1[N+]([O-])=O GAWNBKUTBVLIPL-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- QQURWFRNETXFTN-UHFFFAOYSA-N 5-fluoro-2-nitrophenol Chemical class OC1=CC(F)=CC=C1[N+]([O-])=O QQURWFRNETXFTN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 description 2
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 2
- 229910013684 LiClO 4 Inorganic materials 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- PQANGXXSEABURG-UHFFFAOYSA-N cyclohex-2-en-1-ol Chemical compound OC1CCCC=C1 PQANGXXSEABURG-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 108010004073 cysteinylcysteine Proteins 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 208000024711 extrinsic asthma Diseases 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- HGDAFIJKXCFHPG-UHFFFAOYSA-N n-(5-chloro-2-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC(Cl)=CC=C1O HGDAFIJKXCFHPG-UHFFFAOYSA-N 0.000 description 2
- 125000006606 n-butoxy group Chemical group 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YZIFVWOCPGPNHB-UHFFFAOYSA-N 1,2-dichloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C(Cl)=C1 YZIFVWOCPGPNHB-UHFFFAOYSA-N 0.000 description 1
- YUAXFSCAJYLTAL-UHFFFAOYSA-N 1-(ethoxymethoxy)-2-nitrobenzene Chemical compound C(C)OCOC1=C(C=CC=C1)[N+](=O)[O-] YUAXFSCAJYLTAL-UHFFFAOYSA-N 0.000 description 1
- GSJXJZOWHSTWOX-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]piperazine Chemical compound C1=CC(Cl)=CC=C1CN1CCNCC1 GSJXJZOWHSTWOX-UHFFFAOYSA-N 0.000 description 1
- HHMICZRJTHFXRX-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]pyrrolidin-2-one Chemical compound C1=CC(Cl)=CC=C1CN1C(=O)CCC1 HHMICZRJTHFXRX-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 1
- LUBVCBITQHEVCJ-UHFFFAOYSA-N 1-trimethylsilylpyrrolidin-2-one Chemical compound C[Si](C)(C)N1CCCC1=O LUBVCBITQHEVCJ-UHFFFAOYSA-N 0.000 description 1
- PIPWSBOFSUJCCO-UHFFFAOYSA-N 2,2-dimethylpiperazine Chemical compound CC1(C)CNCCN1 PIPWSBOFSUJCCO-UHFFFAOYSA-N 0.000 description 1
- OYIDUDAFETVZLJ-UHFFFAOYSA-N 2-(ethoxymethoxy)-4-fluoro-1-nitrobenzene Chemical compound CCOCOC1=CC(F)=CC=C1[N+]([O-])=O OYIDUDAFETVZLJ-UHFFFAOYSA-N 0.000 description 1
- SWFNPENEBHAHEB-UHFFFAOYSA-N 2-amino-4-chlorophenol Chemical compound NC1=CC(Cl)=CC=C1O SWFNPENEBHAHEB-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- HIGRXCJEFUYRNW-UHFFFAOYSA-N 2-fluoro-6-nitrophenol Chemical class OC1=C(F)C=CC=C1[N+]([O-])=O HIGRXCJEFUYRNW-UHFFFAOYSA-N 0.000 description 1
- 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 description 1
- CGPYNUAPVFBCFD-UHFFFAOYSA-N 2-oxabicyclo[3.1.0]hexane Chemical compound C1COC2CC21 CGPYNUAPVFBCFD-UHFFFAOYSA-N 0.000 description 1
- WDNBURPWRNALGP-UHFFFAOYSA-N 3,4-Dichlorophenol Chemical compound OC1=CC=C(Cl)C(Cl)=C1 WDNBURPWRNALGP-UHFFFAOYSA-N 0.000 description 1
- CJWQGCUNKQPNBU-UHFFFAOYSA-N 3-[(4-chlorophenyl)methyl]pyrrolidin-2-one Chemical compound C1=CC(Cl)=CC=C1CC1C(=O)NCC1 CJWQGCUNKQPNBU-UHFFFAOYSA-N 0.000 description 1
- MMNKVWGVSHRIJL-UHFFFAOYSA-N 4'-hydroxy-3'-nitroacetophenone Chemical class CC(=O)C1=CC=C(O)C([N+]([O-])=O)=C1 MMNKVWGVSHRIJL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZYZQSCWSPFLAFM-UHFFFAOYSA-N 4-amino-2-chlorophenol Chemical compound NC1=CC=C(O)C(Cl)=C1 ZYZQSCWSPFLAFM-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-BKLSDQPFSA-N 4-hydroxy-L-proline Chemical compound OC1C[NH2+][C@H](C([O-])=O)C1 PMMYEEVYMWASQN-BKLSDQPFSA-N 0.000 description 1
- NQXUSSVLFOBRSE-UHFFFAOYSA-N 5-methyl-2-nitrophenol Chemical class CC1=CC=C([N+]([O-])=O)C(O)=C1 NQXUSSVLFOBRSE-UHFFFAOYSA-N 0.000 description 1
- 101800001401 Activation peptide Proteins 0.000 description 1
- 102400000069 Activation peptide Human genes 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000035939 Alveolitis allergic Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 201000008283 Atrophic Rhinitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 1
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 description 1
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 102100021984 C-C motif chemokine 4-like Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- 101710155833 C-C motif chemokine 8 Proteins 0.000 description 1
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- ACEDTKJQGPESKT-UHFFFAOYSA-N C1(=CC=CC=C1)O.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O Chemical compound C1(=CC=CC=C1)O.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O ACEDTKJQGPESKT-UHFFFAOYSA-N 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- XIZATRTTYMTECC-UHFFFAOYSA-N CC=1C=CC(=C(OCOCC)C1)[N+](=O)[O-] Chemical compound CC=1C=CC(=C(OCOCC)C1)[N+](=O)[O-] XIZATRTTYMTECC-UHFFFAOYSA-N 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- 108091008928 CXC chemokine receptors Proteins 0.000 description 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010011416 Croup infectious Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 description 1
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 description 1
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 description 1
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 208000009388 Job Syndrome Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 206010024227 Lepromatous leprosy Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000008601 Polycythemia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 206010061926 Purulence Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010039088 Rhinitis atrophic Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010062164 Seronegative arthritis Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007960 acetonitrile Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- CELPHAGZKFMOMR-UHFFFAOYSA-N azanium;dichloromethane;methanol;hydroxide Chemical compound [NH4+].[OH-].OC.ClCCl CELPHAGZKFMOMR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 description 1
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010549 croup Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- PSBABBDEUFNFKJ-UHFFFAOYSA-N cyclopent-2-en-1-ol Chemical compound OC1CCC=C1 PSBABBDEUFNFKJ-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 208000022195 farmer lung disease Diseases 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000003350 kerosene Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- RNFUHDBUTFMERX-UHFFFAOYSA-N methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate Chemical class COC(=O)C(C)(C)NC(=O)C1=CC=CC=C1O RNFUHDBUTFMERX-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- DIERXBUIDJOGAB-UHFFFAOYSA-N n-(3,4-dichlorophenyl)piperidin-4-amine Chemical compound C1=C(Cl)C(Cl)=CC=C1NC1CCNCC1 DIERXBUIDJOGAB-UHFFFAOYSA-N 0.000 description 1
- KCOHNRMFXQLTCW-UHFFFAOYSA-N n-(4-chlorophenyl)piperidin-4-amine Chemical compound C1=CC(Cl)=CC=C1NC1CCNCC1 KCOHNRMFXQLTCW-UHFFFAOYSA-N 0.000 description 1
- ZSYRYBOMHWXRDF-UHFFFAOYSA-N n-(4-fluorophenyl)piperidin-4-amine Chemical compound C1=CC(F)=CC=C1NC1CCNCC1 ZSYRYBOMHWXRDF-UHFFFAOYSA-N 0.000 description 1
- GXAIOAIGWKRNIF-UHFFFAOYSA-N n-(5-acetyl-2-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC(C(C)=O)=CC=C1O GXAIOAIGWKRNIF-UHFFFAOYSA-N 0.000 description 1
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 description 1
- 229960002078 sevoflurane Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- YDJXDYKQMRNUSA-UHFFFAOYSA-N tri(propan-2-yl)silane Chemical compound CC(C)[SiH](C(C)C)C(C)C YDJXDYKQMRNUSA-UHFFFAOYSA-N 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明提供通式(I)的化合物,其中Q、R、R2、R4,R5、R6、R7和R8按本说明书中定义,其制备方法,含有它们的药用组合物及其在治疗中的用途。
Description
本发明涉及新的化合物、其制备方法、含有它们的药用组合物及其在治疗中的用途。
US 5789402描述了某些据称可用于治疗如下疾病的吲哚衍生物,这些疾病由神经系统影响的5-羟色胺的紊乱引起或受此影响,特别是那些与5-羟色胺1A受体有关的疾病以及与5-羟色胺吸收有关的疾病。
在各种疾病和紊乱(包括哮喘和过敏性疾病),以及自身免疫疾病(如类风湿性关节炎和动脉粥样硬化)的免疫和炎症反应中,趋化因子起着重要作用。这些小的分泌性分子是一种特征为保守的四个半胱氨酸基元的8-14kDa蛋白质的生长超家族。可将这种趋化因子超家族分为呈现特征结构基元的主要两组,即Cys-X-Cys(C-X-C)和Cys-Cys(C-C)族。它们区别在于在半胱氨酸残基和类似的序列的NH-近侧对之间插入单个氨基酸。
C-X-C趋化因子包括几种有效的化学引诱物和嗜中性白细胞激活剂,如白细胞介素-8(IL-8)和嗜中性白细胞活化肽2(NAP-2)。
C-C趋化因子包括有效的单核细胞和淋巴细胞(但不包括嗜中性白细胞)的化学引诱物,如人体单核细胞趋化蛋白1-3(MCP-1、MCP-2和MCP-3)、RANTES(调节激活、正常T细胞的表达和分泌)、eotaxin和巨噬细胞炎性蛋白1α和1β(MIP-1α和MIP-1β)。
研究表明:趋化因子的作用由G-蛋白偶联受体的亚族介导,其中将这些受体表示为CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3和CXCR4。由于调节这些受体的药物可用于治疗如前提到的那些紊乱和疾病,所以这些受体代表药物研制的好的靶向。
因此本发明提供一种通式(I)的化合物或其药学上可接受的盐或溶剂化物:其中:
R代表:或者代表:
m是0、1、2或3;
R1各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR9R10、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基(-SO2NH2)、C1-C6烷基磺酰基、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
p是0或1;
X代表氧或硫原子或者CH2、CH(CH3)、OCH2、CH2O、CH2NH、NH或者羰基,Y代表氮原子或者CH或C(OH)基团,条件是当X代表氧或硫原子或者CH2O、CH2NH或NH时,Y代表CH;
Z1代表键或者基团(CH2)q,其中q是1或2;
Z2代表键或者CH2,条件是Z1和Z2不同时代表键;
Q代表氧或硫原子或者CH2或NH;
n是0、1或2;
R3各自独立代表C1-C6烷基、C1-C6烷氧基羰基、-CH2OH或羧基;
R4、R5、R6和R7各自独立代表氢原子或者C1-C6烷基,或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环,或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环;
R8代表氢原子、C1-C6烷基,或者按如上说明与R4相连;
R9和R10各自独立代表氢原子或者C1-C6烷基,或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环;
R11和R12各自独立代表氢原子或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
R13代表氢原子或者C1-C6烷基;
R14代表氢原子或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R15代表羧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷氧基羰基C1-C6烷基或者-NR17R18、-NHSO2CH3、-NHC(O)CH3、-C(O)NR17R18、-NHC(O)NR17R18、-OC(O)NR17R18、-OCH2C(O)NR17R18、-NHC(O)OR17’或者-OR17”;
t是0、1、2或3;
R16各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR19R20、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基(-SO2NH2)、C1-C6烷基磺酰基、-C(O)NR21R22、-NR23C(O)(NH)vR24、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17和R18各自独立代表(i)氢原子,(ii)可含有至少一个选自氮、氧和硫的杂原子的5-至6-元饱和或不饱和环,该环可任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者(iii)C1-C6烷基,其任选被至少一个选自卤素、三氟甲基、羧基、C1-C6烷氧基羰基和5-至6-元饱和或不饱和环的取代基取代,该环可含有至少一个选自氮、氧和硫的杂原子,并任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者
R17和R18与其相连的氮原子一起形成4-至7-元饱和杂环;
R17’代表氢原子,或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17”定义同上述R17,但R17”不代表氢原子;
R19和R20各自独立代表氢原子或者C1-C6烷基,或者R19和R20与其相连的氮原子一起形成4-至7-元饱和杂环;
R21和R22各自独立代表氢原子,或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
v是0或1;
R23代表氢原子或者C1-C6烷基;和
R24代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
条件是当X代表氧原子或者CH2,Y是CH,Z1和Z2各自代表CH2,并且Q是氧原子时,R2不是未取代的吲哚基。
在本说明书的内容中,烷基取代基或取代基中的烷基部分可以是线形或支化的。
另一方面,本发明提供一种通式(I’)的化合物或其药学上可接受的盐或溶剂化物:其中:
m是0、1、2或3;
R1各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR9R10、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基、C1-C6烷基磺酰基、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
p是0或1;
X代表氧或硫原子或者CH2、CH(CH3)、OCH2、CH2O、CH2NH、NH或者羰基,Y代表氮原子或者CH或C(OH)基团,条件是当X代表氧或硫原子或者CH2O、CH2NH或NH时,Y代表CH;
Z1代表键或者基团(CH2)q,其中q是1或2;
Z2代表键或者CH2,条件是Z1和Z2不同时代表键;
Q代表氧或硫原子或者CH2或NH;
R2代表以下基团:
n是0、1或2;
R3各自独立代表C1-C6烷基、C1-C6烷氧基羰基、-CH2OH或羧基;
R4、R5、R6和R7各自独立代表氢原子或者C1-C6烷基,或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环,或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环;
R8代表氢原子、C1-C6烷基,或者按如上说明与R4相连;
R9和R10各自独立代表氢原子或者C1-C6烷基,或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环;
R11和R12各自独立代表氢原子或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
R13代表氢原子或者C1-C6烷基;
R14代表氢原子或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R15代表羧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷氧基羰基C1-C6烷基或者-NR17R18、-NHSO2CH3、-NHC(O)CH3、-C(O)NR17R18、-NHC(O)NR17R18、-OC(O)NR17R18、-OCH2C(O)NR17R18、-NHC(O)OR17’或者-OR17”;
t是0、1、2或3;
R16各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR19R20、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基(-SO2NH2)、C1-C6烷基磺酰基、-C(O)NR21R22、-NR23C(O)(NH)vR24、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17和R18各自独立代表(i)氢原子,(ii)可含有至少一个选自氮、氧和硫杂原子的5-至6-元饱和或不饱和环,该环任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者(iii)C1-C6烷基,其任选被至少一个选自卤素、三氟甲基、羧基、C1-C6烷氧基羰基和5-至6-元饱和或不饱和环的取代基取代,该环可含有至少一个选自氮、氧和硫的杂原子并任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者
R17和R18与其相连的氮原子一起形成4-至7-元饱和杂环;
R17’代表氢原子,或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17”定义同上述R17,但R17”不代表氢原子;
R19和R20各自独立代表氢原子或者C1-C6烷基,或者R19和R20与其相连的氮原子一起形成4-至7-元饱和杂环;
R21和R22各自独立代表氢原子,或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
v是0或1;
R23代表氢原子或者C1-C6烷基;和
R24代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基。
m是0、1、2或3;
R1各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR9R10、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基、C1-C6烷基磺酰基、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
p是0或1;
X代表氧或硫原子或者CH2、CH(CH3)、OCH2、CH2O、CH2NH、NH或者羰基,Y代表氮原子或者CH或C(OH)基团,条件是当X代表氧或硫原子或者CH2O、CH2NH或NH时,Y代表CH;
Z1代表键或者基团(CH2)q,其中q是1或2;
n是0、1或2;
R3各自独立代表C1-C6烷基、C1-C6烷氧基羰基、-CH2OH或羧基;
R4、R5、R6和R7各自独立代表氢原子或者C1-C6烷基,或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环,或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环;
R8代表氢原子、C1-C6烷基,或者按如上说明与R4相连;
R9和R10各自独立代表氢原子或者C1-C6烷基,或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环;
R11和R12各自独立代表氢原子,或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
R13代表氢原子或者C1-C6烷基;和
R14代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
条件是当X是氧原子或者CH2,Y是CH,Z1和Z2各自代表CH2,并且Q是氧原子时,R2不是未取代的吲哚基。
另一方面,本发明提供一种通式(I)的化合物或其药学上可接受的盐或溶剂化物:其中:
m是0、1、2或3;
R1各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR9R10、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基、C1-C6烷基磺酰基、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
p是0或1;
Q代表氧或硫原子或者CH2或NH;
R2代表以下基团: 或
R4、R5、R6和R7各自独立代表氢原子或者C1-C6烷基,或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环,或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环;
R8代表氢原子、C1-C6烷基,或者按如上说明与R4相连;
R9和R10各自独立代表氢原子或者C1-C6烷基,或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环;
R11和R12各自独立代表氢原子,或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
R13代表氢原子或者C1-C6烷基;
R14代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R15代表羧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷氧基羰基C1-C6烷基或者-NR17R18、-NHSO2CH3、-NHC(O)CH3、-C(O)NR17R18、-NHC(O)NR17R18、-OC(O)NR17R18、-OCH2C(O)NR17R18、-NHC(O)OR17’或者-OR17”;
t是0、1、2或3;
R16各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR19R20、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基(-SO2NH2)、C1-C6烷基磺酰基、-C(O)NR21R22、-NR23C(O)(NH)vR24、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17和R18各自独立代表(i)氢原子,(ii)可含有至少一个选自氮、氧和硫杂原子的5-至6-元饱和或不饱和环,该环任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者(iii)C1-C6烷基,其任选被至少一个选自卤素、三氟甲基、羧基、C1-C6烷氧基羰基和5-至6-元饱和或不饱和环的取代基取代,该环可含有至少一个选自氮、氧和硫的杂原子并任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者
R17和R18与其相连的氮原子一起形成4-至7-元饱和杂环;
R17’代表氢原子,或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17”定义同以上R17,但R17”不代表氢原子;
R19和R20各自独立代表氢原子或者C1-C6烷基,或者R19和R20与其相连的氮原子一起形成4-至7-元饱和杂环;
R21和R22各自独立代表氢原子或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
v是0或1;
R23代表氢原子或者C1-C6烷基;和
R24代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基。
整数m优选是0、1或2。
R1各自独立代表卤素(如氯、氟、溴或碘)、氰基、硝基、羧基、羟基、C3-C6环烷基(环丙基、环丁基、环戊基或环己基)、C1-C6,优选C1-C4烷氧基(如甲氧基、乙氧基、正丙氧基或正丁氧基)、C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)、C1-C6,优选C1-C4卤代烷基(如三氟甲基)、C1-C6,优选C1-C4卤代烷氧基(如三氟甲氧基)、-NR9R10、C3-C6环烷基氨基(如环丙基氨基、环丁基氨基、环戊基氨基或环己基氨基)、C1-C6,优选C1-C4烷硫基(如甲硫基或乙硫基)、C1-C6,优选C1-C4烷基羰基(如甲基羰基、乙基羰基、正丙基羰基、异丙基羰基、正丁基羰基、正戊基羰基或正己基羰基)、C1-C6,优选C1-C4烷基羰基氨基(如甲基羰基氨基或乙基羰基氨基)、氨磺酰基、C1-C6,优选C1-C4烷基磺酰基(如甲磺酰基、乙磺酰基、正丙基磺酰基、异丙基磺酰基、正丁基磺酰基、正戊基磺酰基或正己基磺酰基)、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
最优选R1各自独立代表卤素(尤其是氯或氟)、氰基、硝基、C1-C6烷氧基(特别是甲氧基)、C1-C6烷基羰基(特别是甲基羰基)或者C1-C6烷基羰基氨基(尤其是甲基羰基氨基)。
X优选代表氧原子或者CH2、OCH2、CH2O、NH或者羰基。
Y优选代表氮原子或者CH基团。
X-Y的优选组合包括O-CH、OCH2-CH、NH-CH、CH2O-CH、CH2-N、C(O)-N和CH2-CH。
Y、Z1和Z2的优选组合包括:
Y | Z1 | Z2 |
CH | CH2 | 键 |
CH | 键 | CH2 |
CH | CH2 | CH2 |
CH | (CH2)2 | 键 |
N | CH2 | CH2 |
Q优选代表氧原子。
R3各自独立代表C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)、C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)、-CH2OH或羧基。R3优选代表甲基、甲氧基羰基、乙氧基羰基、-CH2OH或羧基。
R4、R5、R6和R7各自独立代表氢原子或者C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基),或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环(如环己基或优选环戊基),或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环(优选环戊基)。
R8代表氢原子、C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基),或者按如上说明与R4相连。
R9和R10各自独立代表氢原子或者C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基),或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环(优选吡咯烷基或哌啶基)。
R11和R12各自独立代表氢原子,或者任选被C1-C6,优选C1-C4烷氧基羰基取代基取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R13代表氢原子或者C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R14代表氢原子,或者任选被羧基、C1-C6,优选C1-C4烷氧基或C1-C6,优选C1-C4烷氧基羰基取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R15代表羧基、C1-C6,优选C1-C4烷基羰基(如甲基羰基、乙基羰基、正丙基羰基、异丙基羰基、正丁基羰基、正戊基羰基或正己基羰基)、C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)、C1-C6烷氧基羰基C1-C6烷基,优选C1-C4烷氧基羰基C1-C4烷基(如甲氧基羰基甲基或甲氧基羰基乙基)或者-NR17R18、-NHSO2CH3、-NHC(O)CH3、-C(O)NR17R18、-NHC(O)NR17R18、-OC(O)NR17R18、-OCH2C(O)NR17R18、-NHC(O)OR17’或者-OR17”。
R15优选代表C1-C4烷氧基(特别是甲氧基)、C1-C4烷基羰基(特别是甲基羰基或乙基羰基)、C1-C4烷氧基羰基C1-C4烷基(特别是甲氧基羰基甲基或甲氧基羰基乙基)、-NHC(O)CH3、-C(O)NR17R18、-NHSO2CH3或-NHC(O)NR17R18。
R16各自独立代表卤素(如氯、氟、溴或碘)、氰基、硝基、羧基、羟基、C3-C6环烷基(环丙基、环丁基、环戊基或环己基)、C1-C6,优选C1-C4烷氧基(如甲氧基、乙氧基、正丙氧基或正丁氧基)、C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)、C1-C6,优选C1-C4卤代烷基(如三氟甲基)、C1-C6,优选C1-C4卤代烷氧基(如三氟甲氧基)、-NR9R10、C3-C6环烷基氨基(如环丙基氨基、环丁基氨基、环戊基氨基或环己基氨基)、C1-C6,优选C1-C4烷硫基(如甲硫基或乙硫基)、C1-C6,优选C1-C4烷基羰基(如甲基羰基、乙基羰基、正丙基羰基、异丙基羰基、正丁基羰基、正戊基羰基或正己基羰基)、C1-C6,优选C1-C4烷基羰基氨基(如甲基羰基氨基或乙基羰基氨基)、氨磺酰基、C1-C6,优选C1-C4烷基磺酰基(如甲磺酰基、乙磺酰基、正丙基磺酰基、异丙基磺酰基、正丁基磺酰基、正戊基磺酰基或正己基磺酰基)、-C(O)NR21R22、-NR23C(O)-(NH)vR24、苯基或者任选被羧基或C1-C6,优选C1-C4烷氧基羰基(如甲氧基羰基或乙氧基羰基)取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
优选R16各自独立代表卤素(尤其是氯或氟)、羟基、氰基、C1-C4烷氧基(特别是甲氧基)、C1-C4烷氧基羰基(特别是甲氧基羰基)、C1-C4卤代烷基(特别是三氟甲基)、C1-C4烷基羰基(尤其是甲基羰基)、苯基或C1-C4烷基(如甲基或叔丁基)。
R17和R18各自独立代表(i)氢原子,(ii)可含有至少一个(如分别为1、2或3个)选自氮、氧和硫的杂原子的5-至6-元饱和或不饱和环(如环戊基、环己基、吡咯基、咪唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、噻吩基或呋喃基),该环任选被至少一个(如分别为1、2或3个)选自卤素(如氯、氟、溴或碘)、甲基和三氟甲基的取代基取代,或者(iii)C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基),其任选被至少一个(如分别为1、2或3个)选自卤素(如氯、氟、溴或碘)、三氟甲基、羧基、C1-C6,优选C1-C4烷氧基羰基(尤其是甲氧基羰基)和5-至6-元饱和或不饱和环(如环戊基、环己基、吡咯基、咪唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、噻吩基或呋喃基)的取代基取代,该环可含有至少一个(如分别为1、2或3个)选自氮、氧和硫的杂原子并任选被至少一个选自卤素(如氟、氯、溴或碘)、甲基和三氟甲基的取代基取代,或者
R17和R18与其相连的氮原子一起形成4-至7-元饱和杂环(如吡咯烷基或哌啶基)。
R17’代表氢原子,或者任选被羧基或更优选C1-C6,优选C1-C4烷氧基羰基(特别是甲氧基羰基)取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R19和R20各自独立代表氢原子或者C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基),或者R19和R20与其相连的氮原子一起形成4-至7-元饱和杂环(如吡咯烷基或哌啶基)。
R21和R22各自独立代表氢原子或者任选被C1-C6,优选C1-C4烷氧基羰基取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R23代表氢原子或者C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
R24代表氢原子或者任选被羧基、C1-C6,优选C1-C4烷氧基或C1-C6,优选C1-C4烷氧基羰基取代的C1-C6,优选C1-C4烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或正己基)。
本发明优选的化合物包括:
N-(2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐,
N-(5-氯代-2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐,
N-(2-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺,
1-(2-氨基苯氧基)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-丙醇二盐酸盐,
N-(2-{3-[3-(3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)-乙酰胺盐酸盐,
2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
2-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
N-[2-({(1R,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(1S,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(2,3-反式)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环己基}氧基)苯基]乙酰胺,
N-(5-氯代-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
1-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-(7-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
1-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-(7-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(5-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
1-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-(7-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(4-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
1-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-(7-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
1-(7-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
1-(7-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮,
N-(4-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-{5-氯代-2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
N-{3-乙酰基-2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺,
N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-甲基-苯基}-乙酰胺,
N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-氟代-苯基}-乙酰胺,
1-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-{7-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-吲哚-1-基}-乙酮,
N-{4-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-联苯-3-基}-乙酰胺,
N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-氟代-苯基}-乙酰胺,
N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺,
N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
N-{5-氯代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
N-{3-乙酰基-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺,
N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-甲基-苯基}-乙酰胺,
N-{5-氟代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
1-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-3-(1H-吲哚-7-基氧基)-丙-2-醇,
1-{7-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-吲哚-1-基}-乙酮,
N-{4-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-联苯-3-基}-乙酰胺,
N-{4-氟代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺,
N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇,
1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
3-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2,6-二甲氧基-苯氧基)-3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-丙-2-醇,
1-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-[2-(3-{[1-(3,4-二氯代苄基)-4-哌啶基]氨基}-2-羟基丙氧基)-4-甲基苯基]乙酰胺,
3-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇,
1-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基)-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基苯甲酰胺,
4-{1-[2-羟基-3-(2-丙酰基-苯氧基)-丙基]-吡咯烷-3-基氧基}-苄腈,
N-(2-{2-羟基-3-[3-(4-甲氧基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基)-乙酰胺,
N-(4-氯代-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(3,4-二氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2,6-二甲氧基-苯氧基)-3-[4-(4-氟代-苯氧基)-哌啶-1-基]-丙-2-醇,
1-[4-(4-氟代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
N-(2-{3-[4-(4-乙酰氨基-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(4-{1-[3-(2-乙酰基-苯氧基)-2-羟基-丙基]-哌啶-4-基氧基}-苯基)-乙酰胺,
N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[4-(4-氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)乙酰胺,
3-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
N-[2-({(1R,2R)-2-[4-(3,4-二氯代苯氧基)-1-哌啶基]-1-羟基环戊基}甲氧基)苯基]乙酰胺,
(2S,4R)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-[(4-氯代苄基)氧基]-2-吡咯烷甲酸甲酯盐酸盐,
N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(4-氯代-2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-氰基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氰基-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-苯基)乙酰胺,
N-(5-氰基-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[3(S)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(R)-羟基-丙氧基}苯基)乙酰胺,
N-(2-{3-[3S-(4-氯代-苯氧基)-吡咯烷-1-基]-2S-羟基-丙氧基}-苯基)乙酰胺盐酸盐,
N-(2-{3-[3(R)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(S)-羟基-丙氧基}-苯基)乙酰胺,
N-[5-氯代-2-({(2S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2R)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2S)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4,5-二氟代-苯基)乙酰胺,
N-{5-氯代-2-[2-羟基-3-(3-苯氧基-吡咯烷-1-基)-丙氧基]-苯基}-乙酰胺,
N-(5-氯代-2-{2-羟基-3-[3-(4-硝基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基}-乙酰胺,
N-(5-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
4-乙酰氨基-3-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
N-(3-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-萘-2-基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氰基-苯基)-乙酰胺,
4-乙酰氨基-3-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
N-(3-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-萘-2-基)-乙酰胺,
N-(5-氰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-三氟甲基-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(5-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-甲磺酰胺,
N-(5-氯代-2-[3-[3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基-丙氧基]-苯基)脲,
1-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
1-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(3,4-二氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
1-(3-{2-[(氨基羰基)氨基]-4-氯代苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-乙基脲盐酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-甲基脲盐酸盐,
(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(4-氯代苯氧基)-2-吡咯烷甲酸;与三氟乙酸的混合物,
(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(3,4-二氯代苯氧基)-2-吡咯烷甲酸乙酯;三氟乙酸盐,
N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐,
N-[2-({(2R)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基-2-甲基丙氧基}苯基)乙酰胺盐酸盐,
N-(2-{(1S*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(1R*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3R*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(1S*,2R*,3S*)-3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3S*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3R*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(1S*,2R*,3S*)-3-[4-(3-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-[5-氯代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[4-氟代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-苯基)乙酰胺二盐酸盐,
N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
1-(5-氯代-2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}苯基)-1-乙酮,
N-(5-氰基-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(4-氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(4-氯代-2-{3-[4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-[5-氯代-2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-{2-[(2S)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N-[2-({(2S)-3-[(3S)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐,
N-(5-氯代-2-{3-[3-(4-氯代苄基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-1-吡咯烷甲酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-羟基苯基)乙酰胺三氟乙酸盐,
N-[2-({(2S)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐,
N-(2-(3-(4-氯代-苯氧基)-吡咯烷-1-基)-2-羟基-丙氧基)-4,6-二氟代苯基)乙酰胺盐酸盐,
N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐,
N-[2-({(2S)-3-[(3R)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐,
N-{2-[(2R)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N-[2-({(2S)-3-[(2R,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺三氟乙酸盐,
N-{2-[(2S)-(3-{(3R)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N’-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-N,N-二甲基脲三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯胺基)-1-吡咯烷基]-2-羟基丙氧基}苯基)乙酰胺,
N-{2-[(3-{3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基-1-甲基丙基)氧基]苯基}乙酰胺盐酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲氧基苯基)乙酰胺盐酸盐,
N-(2-[3-(4-氯代-苄氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-2-甲基-丙氧基}苯基)乙酰胺,
N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-5-氯代-苯基)乙酰胺(非对映体混合物),
N-[2-({(2R,3S)*-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丁基}氧基)-4-甲基苯基]乙酰胺(非对映体混合物),
N-{2-[(3-{4-[(3,4-二氯代苯基)氧基]-1-哌啶基}-2-羟基-2-甲基丙基)氧基]-4-氟代苯基}乙酰胺盐酸盐,
N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-4-氟代-苯基)乙酰胺(非对映体混合物),
N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(4-羟基-2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺(非对映体混合物),
N-(4-羟基-2-{(1S,2R,3S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(4-羟基-2-{(1R,2S,3R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-{5-氯代-2-[((1S,2R,3S)*-3-{[1-(4-氯代苄基)-4-哌啶基]氨基}-2-羟基环戊基)氧基]苯基}乙酰胺(外消旋体混合物),以及
N-[2-({(2S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丙基}氧基)-4-羟基苯基]乙酰胺。
本发明还提供一种制备如上定义的式(I)化合物的方法,该方法包括:(a)使以下通式的化合物
R-H (II)其中R同式(I)中的定义,与以下通式的化合物反应其中Q、R2、R4、R5、R6、R7和R8同式(I)中的定义;或者(b)使以下通式的化合物其中R、R4、R5、R6、R7和R8同式(I)中的定义,与以下通式的化合物反应
L1-Q-R2 (V)其中L1代表氢原子或活性基团(如当Q为CH2时的Li),Q和R2同式(I)中的定义;然后任选将式(I)化合物转化为另一个式(I)化合物;并且如果要求,形成式(I)化合物的药学上可接受的盐或溶剂化物。
一方面中,本发明还提供一种制备如上定义的式(I’)的化合物的方法,该方法包括:(a)使以下通式的化合物
R-H (II’)其中R同式(I’)中的定义,与以下通式化合物反应其中Q、R2、R4、R5、R6、R7和R8同式(I’)中的定义;或者(b)使以下通式化合物其中R、R4、R5、R6、R7和R8同式(I’)中的定义,与以下通式化合物反应
L1-Q-R2 (V’)其中L1代表氢原子或活性基团(如当Q为CH2时的Li),Q和R2同式(I’)中的定义;然后任选将式(I’)化合物转化为另一个式(I’)化合物;并且如果要求,形成式(I’)化合物的药学上可接受的盐或溶剂化物。
另一方面中,本发明还提供一种制备如上定义的式(I”)的化合物的方法,该方法包括:(a)使以下通式化合物
R-H (II”)其中R同式(I”)中的定义,与以下通式化合物反应其中Q、R2、R4、R5、R6、R7和R8同式(I”)中的定义;或者(b)使以下通式化合物其中R、R4、R5、R6、R7和R8同式(I”)中的定义,与以下通式化合物反应
L1-Q-R2 (V”)其中L1代表氢原子或活性基团(如当Q为CH2时的Li),Q和R2同式(I”)中的定义;然后任选将式(I”)的化合物转化为另一个式(I”)的化合物;并且如果要求,形成式(I”)化合物的药学上可接受的盐或溶剂化物。
另一方面中,本发明还提供一种制备如上定义的式(I)化合物的方法,它包括:(a)使以下通式化合物
R-H (I)其中R同式(I)中的定义,与以下通式化合物反应其中Q、R2、R4、R5、R6、R7和R8同式(I)中的定义;或者(b)使以下通式化合物其中R、R4、R5、R6、R7和R8同式(I)中的定义,与以下通式化合物反应
L1-Q-R2 (V)其中L1代表氢原子或活性基团(如当Q为CH2时的Li),Q和R2同式(I)中的定义;然后任选将式(I)化合物转化为另一个式(I)化合物;并且如果要求,可形成式(I)化合物的药学上可接受的盐或溶剂化物。
本发明的方法可方便地在溶剂,例如有机溶剂如醇类(如甲醇或乙醇)、烃类(如甲苯)或乙腈中,在温度如15℃或15℃以上(如在20-120℃的温度)进行。
式(II)、(II’)、(II”)、(II)、(III)、(III’)、(III”)、(III)、(IV)、(IV’)、(IV”)、(IV)、(V)、(V’)、(V”)和(V)的化合物可由市售提供、或者是文献中熟知的化合物或者可采用已知的技术很容易制备出来。
采用标准方法,可将式(I)、(I’)、(I”)或(I)的化合物转化为另一个式(I)、(I’)、(I”)或(I)的化合物。例如在盐酸存在下,通过水解反应,可将其中R15代表-NHC(O)CH3的式(I)化合物转化为其中R15代表-NH2的另一个式(I)化合物。
本领域技术熟练人员会清楚:在本发明的方法中,原料或中间体化合物的某些官能团(如羟基或氨基)需要通过保护基保护。因此,在适当的阶段,式(I)、(I’)、(I”)或(I)化合物的制备可包括除去一或多个保护基。
官能团的保护和脱保护可见P1enum Press(1973)出版,J.W.F.McOmie编辑的“Protective Groups in Organic Chemistry”以及T.W.Greene和P.G.M.Wuts的“Protective Groups in Organic Synthesis”,Wiley-Interscience(1991),第二版。
可将以上式(I)、(I’)、(I”)或(I)化合物转化为其药学上可接受的盐或溶剂化物,优选为酸加成盐,如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。
式(I)、(I’)、(I”)或(I)化合物可存在立体异构体形式。需清楚:本发明包括应用式(I)、(I’)、(I”)或(I)化合物的所有几何和光学异构体及其混合物,包括外消旋混合物。其互变异构体及混合物的应用也形成本发明的一部分。对映体纯的形式特别符合要求。
式(I)、(I’)、(I”)或(I)化合物具有药用活性,尤其可作为趋化因子受体(特别是MIP-1α趋化因子受体)活性的调节剂,并可用于治疗自身免疫、炎性、增生性和增生过高性(hyper proliferative)疾病以及免疫调节的疾病,包括移植器官或组织的排斥和获得性免疫缺陷综合症(AIDS)。
这些症状的实例是:
(1)(呼吸道)呼吸道疾病包括肺慢性阻塞性病疾(COPD),如不可逆性COPD;气喘,如支气管性气喘、变应性哮喘、内因性所喘、外因性气喘和尘埃性哮喘,尤其是慢性或痼疾性哮喘(如晚期哮喘和呼吸道高反应性(hyper-responsiveness));支气管炎;急性鼻炎、变应性鼻炎、萎缩性鼻炎和慢性鼻炎,包括干酪性鼻炎、肥厚性鼻炎、脓炎鼻炎、干性鼻炎和药物性鼻炎;膜性鼻炎,包括格鲁布性、纤维蛋白性、假膜性鼻炎和腺病性鼻炎;季节性鼻炎,包括神经性鼻炎(枯草热)和血管舒缩性鼻炎;结节病、农民肺和相关疾病、纤维化肺和自发的间质性肺病;
(2)(骨和关节)类风湿性关节炎、血清反应阴性的脊椎关节炎(包括关节强硬性脊椎炎、牛皮癣性关节炎和Reiter病)、Behcet病、Sjogren综合征和全身性硬皮病;
(3)(皮肤)牛皮癣、特应性皮炎、接触性皮炎和其它湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱天疱疮、大疱性表皮松解、荨麻疹、angiodermas、脉管炎、红斑、皮肤嗜酸红细胞增多、色素层炎、斑秃和春季结膜炎;
(4)(胃肠道)腹腔疾病、直肠炎、嗜酸性胃肠炎、肥大细胞增多症、Crohn病、溃疡性结肠炎、作用于远离肠处的食物变态反应,如偏头痛、鼻炎和湿疹;
(5)(其它组织和全身性疾病)多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合症(AIDS)、红斑狼疮、系统性狼疮、红斑、桥本氏甲状腺炎、重症肌无力、I型糖尿病、肾变病综合征、嗜酸性筋膜炎(eosinophilia fascitis)、高免疫球蛋白E血症综合征、瘤型麻风、sezary综合征和自发性血小板减少紫癜;
(6)(同种异体移植排斥)如肾、心脏、肝、肺、骨髓、皮肤和角膜移植后的急性和慢性疾病;以及对抗宿主的慢性移植疾病;
(7)癌症,特别是非小细胞肺癌(NSCLC)和鳞状肉瘤;
(8)与CXCR2趋化因子水平升高有关的血管生成疾病(如NSCLC);
(9)胰囊性纤维变性、休克、心脏、脑、外周末端的再灌注损伤、脓毒症;
因此,本发明提供用于治疗作用的式(I)、(I’)、(I”)或(I)的化合物,或其药学上可接受的盐或溶剂化物。
另一方面,本发明提供以上定义的式(I)、(I’)、(I”)或(I)化合物或其药学上可接受的盐或溶剂化物在制备用于治疗作用的药物中的用途。
在本说明书的内容中,除有特别说明,否则术语“治疗”还包括“预防”。术语“治疗的(therapeutic)”和“治疗上(therapeutically)”同样如此。
本发明还提供一种治疗患有炎症或有患有该病危险的患者的方法,该方法包括向该患者给服治疗有效量的以上定义的式(I)、(I’)、(I”)或(I)的化合物或其药学上可接受的盐或溶剂化物。
本发明还提供一种治疗患有呼吸道疾病或有患有该病危险的患者的方法,该方法包括向该患者给服治疗有效量的以上定义的式(I)、(I’)、(I”)或(I)的化合物或其药学上可接受的盐或溶剂化物。
对于以上提到的治疗用途,给药剂量一般随所用的化合物、给药方式、所要求的治疗效果以及治疗的病症而变化。式(I)、(I’)、(I”)或(I)化合物的日剂量可在0.001~30mg/kg的范围。
可使用式(I)、(I’)、(I”)或(I)的化合物及其药学上可接受的盐和溶剂化物它们本身的形式,但一般常以药用组合物的形式给药,在该组合物中式(I)、(I’)、(I”)或(I)的化合物/盐/溶剂化物(活性组分)与药学上可接受的添加剂、稀释剂或载体相结合。根据给药方式的不同,药用组合物中优选含有0.05~99%重量(重量百分数),更优选0.05~80%重量,仍更优选0.10~70%重量,甚至更加优选0.10~50%重量的活性组分,所有重量百分数以总组合物为基础计算。
本发明还提供一种药用组合物,该组合物包含以上定义的式(I)、(I’)、(I”)或(I)化合物或其药学上可接受的盐或溶剂化物,并结合药学上可接受的添加剂、稀释剂或载体。
本发明还提供一种制备本发明药用组合物的方法,该方法包括将以上定义的式(I)、(I’)、(I”)或(I)化合物或其药学上可接受的盐或溶剂化物与药学上可接受的添加剂、稀释剂或载体混合。
本发明药用组合物可以以溶液、混悬液、七氟烷气雾剂和干粉制剂的形式局部给药(如给予肺部和/或呼吸道或者皮肤);或者全身给药,如以片剂、胶囊剂、糖浆剂、粉末剂或颗粒剂形式口服给药,或者以溶液剂或混悬剂形式非肠道给药,或者以栓剂或经皮吸收形式皮下给药或直肠给药。
现在参考下列说明性的实施例,进一步解释本发明,其中1H NMR波谱采用Varian Unity Inova 400记录。采用氘代氯仿的中心溶剂峰(δH7.27ppm)作为内标。低分辨质谱和准确质量的测定采用装备APCI/ESI离子化室的Hewlett-Packard 1100 LC-MS系统测定。所有溶剂和市售试剂都是试验室级,并买来直接使用,不作进一步纯化。化合物所用的命名法采用ACD/IUPAC命名原则。实施例1N-(2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐(i)3-羟基-吡咯烷-1-甲酸叔丁基酯
在通氮气下,将吡咯烷-3-醇(16.25g,186.5mmol)和二碳酸二叔丁酯(40.7g,186.5mmol)的无水THF(50ml)溶液搅拌过夜。减压浓缩,经硅胶快速层析纯化(EtOAc:庚烷,7∶3),得到31.9g(91%)的题述化合物。1H-NMR(400MHz,DMSO-d6):δ4.87(d,1H,J=3.4Hz),4.21(bs,1H),3.31-3.22(m,3H),3.10(d,1H,J=11.5Hz),1.83(m,1H),1.72(m,1H),1.39(s,9H)。APCI-MS:m/z 132[MH+-56](ii)3-(4-氯代-苯氧基)-吡咯烷
在通氮气下,将3-羟基-吡咯烷-1-甲酸叔丁基酯(2.1g,9.9mmol)和三苯膦(2.59g,9.9mmol)溶于无水THF(35ml)中。将该溶液冷却至0℃,加入溶于无水THF(10ml)中的4-氯苯酚(1.28g,9.9mmol),接着加入偶氮二甲酸二乙酯(DEAD)(1.55ml,9.9mmol)。15分钟后,移去冰浴,将反应物搅拌过夜。减压浓缩反应混合液,将所得残留物与乙醚搅拌。滤除固体的三苯基氧化膦。将该溶液用氢氧化钠(1M)洗涤3次,浓缩。将该BOC-保护的产物经硅胶快速层析纯化,用EtOAc/庚烷为洗脱剂。溶于二氯甲烷(35ml)和三氟乙酸(17ml)中。室温下,将反应混合液搅拌过夜,浓缩,经硅胶快速层析纯化(MeOH∶CHCl3∶NH3,100∶100∶1),得到题述化合物(1.72g,88%)。1H-NMR(400MHz,DMSO-d6):δ7.30(d,2H,J=8.9Hz),6.91(d,2H,J=8.9Hz),4.82(m,1H),3.03(dd,1H,J=12.3,5.4Hz),2.82(m,3H),1.99(m,1H),1.72(m,1H)。APCI-MS:m/z 198[MH+](iii)N-(2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐
在75℃下,在密闭管瓶中,将3-(4-氯代-苯氧基)-吡咯烷(0.059g,0.298mmol)和N-乙酰基-2-(2,3-环氧基丙氧基)苯胺(0.062g,0.299mmol)的EtOH(1.5ml,99.5%)溶液搅拌3小时。反应完毕后,蒸发溶剂,所得残留物经硅胶纯化(CH2Cl2∶MeOH,98∶2至97∶3),得到88mg题述化合物的游离胺。将该胺溶于MeOH∶水1∶1(30ml)中,将该溶液用2M盐酸酸化。蒸发甲醇,将残留的水溶液冷冻干燥得到92mg(70%)题述化合物的白色固体。APCI-MS:m/z 405.2,407.2[MH+,同位素方式]实施例2N-(5-氯代-2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐(i)N-(5-氯代-2-羟基-苯基)-乙酰胺
将4-氨基-2-氯苯酚(2.0g,13.9mmol)和乙酸酐(1.77g,17.3mmol)的水(40ml)溶液剧烈搅拌5分钟。然后在搅拌下,将所得反应混合液加热至60℃下30分钟,然后冷却。形成粉色固体,过滤收集所述沉淀,用水洗涤2次,干燥得到1.8g(70%)的题述化合物。1H-NMR(400MHz,DMSO-d6):δ10.09(1H,s);9.25(1H,bs);7.93(1H,s);6.93(1H,dd,J 8.8,2.7Hz);6.84(1H,d,J 8.6Hz);2.09(3H,s)。APCI-MS:m/z 186.0[MH+](ii)N-(5-氯代-2-环氧乙烷基(oxiranyl)甲氧基-苯基)-乙酰胺
在50℃、搅拌下,将N-(5-氯代-2-羟基-苯基)-乙酰胺(0.499g,2.68mmol)、K2CO3(0.60g,4.35mmol)和表溴代醇(0.405g,2.95mmol)的DMF(5ml)溶液加热2小时。然后将混合液在EtOAc和水40+40ml之间分配。将有机相用水洗涤2次,用盐水洗涤1次,最后真空浓缩得到粗产物。该粗产物经硅胶纯化(庚烷∶EtOAc,1∶1),得到0.43g(66%)白色固体。1H-NMR(400MHz,CDCl3):δ8.46(1H,d,J 2.3Hz);7.90(1H,bs);6.98(1H,dd,J 8.7,2.4Hz);6.83(1H,d,J 8.8Hz);4.36(1H,dd,J 11.5,2.4Hz);3.94(1H,dd,J 11.6,6.0Hz);3.41-3.36(1H,m);2.97(1H,dd,J4.7,4.2Hz);2.80(1H,dd,J 4.6,2.6Hz);2.23(3H,s)。(iii)N-(5-氯代-2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐
根据实施例1步骤(iii)中描述的类似方法制备。实施例3N-(2-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺
根据实施例1中描述的方法制备。通过C18-柱层析纯化和分离出游离胺,收率为73%(H2O∶CH3CN,0.1M NH4OAc缓冲液,梯度30%至95% CH3CN)。APCI-MS:m/z 453,455[MH+]1H-NMR(400MHz,CDCl3):δ7.32(d,1H),7.01(d,1H),6.85-8.80(m,2H),6.78-6.69(m,3H),4.31(m,1H),4.15-4.09(m,1H),4.18-3.18(bs,3H),2.91(m,1H),2.71(m,1H),2.62-2.52(m,3H),2.35(m,1H),2.05-1.93(m,2H),1.89-1.77(m,2H)。实施例41-(2-氨基苯氧基)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-丙醇二盐酸盐
将N-(2-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺(1.418g,3.13mmol)溶于50ml HCl(35%水溶液,puriss)中,回流过夜。沉淀出产物并过滤,干燥得到0.835g(65%)的题述化合物。APCI-MS m/z:411,413[MH+]1H-NMR(400MHz,CDCl3):δ8.39-3.31(m,2H),7.31(d,1H),7.01-6.98(m,3H),6.94-6.91(m,1H),6.75(dd,1H),4.31(m,1H),4.12-4.02(m,2H),3.92(dd,1H),2.90(m,1H),2.69(m,1H),2.62-2.51(m,2H),2.46(dd,1H),2.34(m,1H),2.18(s,3H),2.04-1.93(m,2H),1.89-1.77(m,2H)。实施例5N-(2-{3-[3-(3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)-乙酰胺盐酸盐
根据实施例1中描述的方法制备,得到68mg(68%)题述化合物的白色固体。APCI-MS m/z:439,441[MH+]实施例62-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酸甲酯(i)2-环氧乙烷基甲氧基-苯甲酸甲酯
根据实施例2步骤(ii)中描述的方法制备。1H-NMR:(400MHz,CDCl3):δ7.81(1H,dd,J 7.7,1.7Hz);7.46(1H,dt,J 7.7,1.7Hz);7.05-6.98(2H,m);4.33(1H,dd,J 11.3,3.0Hz);4.11(1H,dd,J 11.3,4.8Hz);3.90(3H,s);3.43-3.37(1H,m);2.93-2.90(2H,m)。(ii)2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酸甲酯
根据实施例1步骤(ii)中描述的方法制备。分离出游离的胺。1H-NMR(400MHz,CDCl3):δ7.81(1H,dd,J 8.1,1.8Hz);7.46(1H,dt,J7.8,1.7Hz);7.03-6.91(4H,m);6.86-6.82(2H,m);4.28-4.10(3H,m);4.08-4.00(1H,m);3.88(3H,s);2.92-2.84(1H,m);2.83-2.76(1H,m);2.66-2.53(2H,m);2.46(1H,t,J 10.2Hz);2.36(1H,t,J 10.2Hz);2.02-1.92(2H,m);1.86-1.74(2H,m);1.63(1H,bs)APCI-MS:m/z 404.2[MH+]实施例72-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯(i)2-[(2-羟基苯甲酰基)氨基]-2-甲基丙酸甲酯
向乙酸2-(氯代羰基)苯基酯(20mmol,3.96g)的甲苯(50ml)溶液中,加入N-乙基-N,N-二异丙基胺(22mmol,2.84g)和2-甲基苯胺(22mmol,2.27g)。室温下,将反应混合液搅拌过夜,然后将混合液用250ml甲苯稀释,用1.8%HCl水溶液(250ml)和饱和NaCl水溶液(250ml)洗涤。有机相经Na2SO4干燥,减压浓缩。将所得残留物溶于MeOH(50mL)中并加入3滴浓硫酸。将混合液回流2小时,减压浓缩。将所得残留物溶于250mL EtOAc中,用饱和NaHCO2水溶液(250ml)和饱和NaCl水溶液(250ml)洗涤。有机相经Na2SO4干燥,减压浓缩。得到的粗产物不经进一步纯化直接使用。APCI-MS m/z:238[MH+](ii)2-甲基-2-{[2-(环氧乙烷基甲氧基)苯甲酰基]氨基}丙酸甲酯
在回流温度下,将2-[(2-羟基苯甲酰基)氨基]-2-甲基丙酸甲酯、K2CO3(20mmol,2.68g)和2-(氯甲基)环氧乙烷(20mmol,2.03g)的乙腈(60ml)溶液搅拌过夜。将反应混合液用EtOAc稀释,用1.8%HCl水溶液(250ml)和饱和NaCl水溶液(250ml)洗涤。有机相经Na2SO4干燥,减压浓缩。残留物经C18-柱纯化(H2O∶CH3CN,0.1M NH4OAc缓冲液,梯度10%至95%CH3CN),得到题述化合物(244mg,5%收率,两步)。APCI-MS m/z:294[MH+]1H-NMR(400MHz,CDCl3):δ 8.40(s,1H),8.14(dd,1H),7.41(dt,1H),7.07(t,1H),6.90(d,1H),4.44(dd,1H),4.07(dd,1H),3.74(s,3H),3.45(m,1H),2.94(dd,1H),2.84(dd,1H),1.64(d,6H)。(iii)2-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯
将4-(3,4-二氟代苯氧基)哌啶(0.03ml,0.5M)的甲苯溶液与2-甲基-2-{[2-(2-环氧乙烷基甲氧基)苯甲酰基]氨基}丙酸甲酯(0.03ml,0.5M)混合。将混合液用0.20ml甲苯和0.05ml甲醇稀释。在100℃下,在密闭管瓶中,将该反应混合液搅拌过夜。真空浓缩产物,不经进一步纯化直接使用。APCI-MS m/z:507[MH+]1H-NMR(400MHz,CDCl3):δ8.13(s,1H),7.90(dd,1H),7.33(dt,1H),7.07-6.96(m,2H),6.89(d,1H),6.73-6.68(m,1H),6.58-6.55(m,1H),4.77-4.72(m,1H),4.49(bs,1H),4.20-4.13(m,2H),3.69(s,3H),3.58-3.44(m,2H),3.39-3.26(m,4H),2.54-2.40(m,2H),2.13-2.04(m,2H),1.60(d,6H)。实施例8N-[2-({(1R,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺和N-[2-({(1S,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺(i)N-[2-(2-环戊烯-1-基氧基)苯基]乙酰胺
在0℃下,向氢化钠(煤油中60%.;297mg,7.43mmol,1.1当量)的DMF(3ml)混悬液中,滴加2-乙酰氨基-苯酚(1.02g,6.75mmol,1.0当量)的DMF(12ml)溶液。30分钟后,通过注射器加入氯代环戊-2-烯(R.Moffett,Organic Synthesis,Wiley:New York 1963,Collect.Vol.IV,第238-241页)(762mg,0.76ml,7.43mmol,1.1当量),继续搅拌过夜。水溶液处理,接着经硅胶快速层析纯化(庚烷/乙酸乙酯,2∶1继续至1∶1)得到992mg(68%)题述化合物的深黄色油状物。1H-NMR(400MHz,CDCl3):δ8.35(1H,d,J 8.0Hz),7.73(1H,bs),7.00(1H,td,J 7.9,1.5Hz),6.90-6.95(2H,m),6.17(1H,m),5.95(1H,m),5.36(1H,d,J 5.9Hz),2.59(1H,m),2.38(2H,m),2.17(3H,s),1.97(1H,m)。MS-ESI+:m/z 218.1[MH+](ii)N-{2-(6-氧杂双环[3.1.0]己-2-基氧基)苯基}乙酰胺
向冰浴冷却的N-[2-(2-环戊烯-1-基氧基)苯基]乙酰胺(149mg,686μmol,1.0当量)的二氯甲烷(4ml)溶液中,加入间氯过苯甲酸(85%,146μmol,1.1当量)。再缓慢升至室温下,搅拌过夜,将反应混合液用叔丁基甲醚稀释,顺次用饱和硫酸氢钠溶液、5%氢氧化钠和盐水洗涤,经硫酸钠干燥。蒸发溶剂,经硅胶快速层析(乙酸乙酯/庚烷,2∶3继续至乙酸乙酯),得到93mg(58%)的题述化合物,为反式(少量)和顺式(大量)非对映异构体环氧化物的混合物,浅黄色油状物。通过1H-NMR测得顺/反式比率为2∶1。1H-NMR(400MHz,CDCl3):δ8.39(1H[A],m),8.34(1H[B],d,J 8.2Hz),7.91(1H[A],bs),7.59(1H[B],bs),6.92-7.25(3H[A]+3H[B],m),4.89(1H[B],d,J 5.2Hz),4.77(1H[A],td,J 8.0,1.3Hz),3.66(1H[B],m),3.64(1H[B],m),3.60(1H[A],m),3.54(1H[A],m),2.23(1H[B],d,J 8.4Hz),2.21(3H[A],s),2.19(3H[B],s),2.10(2H[A],m),1.72-1.92(m),1.53-1.63(m),(2H[A]+3H[B])。(A=反式,B=顺式)MS-ESI+:m/z 234.1[MH+](iii)N-[2-({(1R,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺和N-[2-({(1S,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺
将N-{2-(6-氧杂双环[3.1.0]己-2-基氧基)苯基}乙酰胺(反式和顺式非对映体的外消旋混合物)(87mg,373μmol,1.0当量)和4-(3,4-二氯代苯氧基)哌啶(92mg,394μmol,1.06当量)溶于2M高氯酸锂的乙腈(3ml)溶液中,在85℃下,在密封管中加热过夜。水溶液处理,接着将粗产物经硅胶快速层析(庚烷/乙酸乙酯/甲醇/氨=1∶3∶0∶0至0∶90∶10∶1至0∶80∶20∶3),分离出两种非对映体加成产物,得到24mg(14%)的(1S,2S,3R)非对映体(先洗脱出)和75mg(42%)后洗脱的(1R,2S,3R)非对映体。对于(1S,2S,3R)非对映体:1H-NMR(400MHz,CDCl3):δ8.27(1H,dd,J 7.6,1.7Hz),7.91(1H,s),7.29(1H,d,J 8.9Hz),6.88-7.00(4H,m),6.73(1H,dd,J 8.9,2.8Hz),4.45(1H,m),4.28(1H,七重峰,J 3.6Hz),4.18(1H,dd,J 7.1,4.6Hz),2.87(3H,m),2.71(1H,q,J 7.5Hz),2.15(3H,s),2.11(1H,m),1.78-2.02(7H,m)。MS-APCI+:m/z 479.1[MH+]对于(1R,2S,3R)非对映体:1H-NMR(400MHz,CDCl3):δ8.20-8.25(2H,m),7.29(1H,d,J 8.9Hz),6.91-7.00(4H,m),6.74(1H,dd,J 8.9,2.8Hz),4.46(1H,bq,J 4.8Hz),4.29(1H,m),4.13(1H,d,J 7.2Hz),2.95(2H,m),2.84(2H,m),2.50(2H,m),2.15(3H,s),1.93-2.07(5H,m),1.82(2H,m),1.58(1H,m)。MS-APCI+:m/z 479.1[MH+]实施例9N-[2-({(2,3-反式)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环己基}氧基)苯基]乙酰胺(i)N-[2-(2-环己烯-1-基氧基)苯基]乙酰胺
将2-环己烯醇(491mg,0.49ml,5.00mmol,1.0当量)、2-乙酰氨基苯酚(756mg,5.00mmol,1.0当量)和三苯基膦(1.44g,5.50mmol,1.1当量)溶于THF(10ml)中,通过水浴保持在室温下。滴加溶于THF(3ml)中的偶氮二甲酸二乙酯(871mg,0.78ml,5.00mmol,1.0当量),将反应混合液搅拌过夜。萃取处理,再经硅胶快速层析(庚烷/叔丁基甲醚=1∶1),得到224mg(19%)题述化合物的黄色油状物。MS-ESI+:m/z 232.2[MH+](ii)N-[2-(7-氧杂双环[4.1.0]庚-2-基氧基)苯基]乙酰胺
在0℃下,向N-[2-(2-环己烯-1-基氧基)苯基]乙酰胺(76mg,329μmol,1.0当量)的二氯甲烷(5ml)溶液中,加入间氯苯甲酸(85%,121mg,559μmol,1.7当量)。继续搅拌过夜,期间将反应混合液缓慢升至室温。将该非均相混合液用乙酸乙酯稀释,顺次用饱和亚硫酸钠、5%氢氧化钠和盐水洗涤。经硫酸钠干燥,蒸发溶剂,经硅胶快速层析得到59mg(73%)的题述化合物,为非对映异构体混合物(比率A∶B=反式∶顺式=5∶3[1H-NMR])。1H-NMR(400MHz,CDCl3):δ8.35(1H[A]+1H[B],m),8.02(1H[A],bs),7.70(1H[B],bs),6.95-7.04(3H[A]+3H[B],m),4.62(1H [A],dd,J 8.4,5.5,2.1Hz),4.55(1H[B],dd,J 7.5,6.7Hz),3.30-3.36(2H[A]+1H[B],m),3.19(1H[B],t,J 3.6Hz),1.26-2.23(10H[A]+10H[B],m)。LC/MS-ESI+:m/z 248.1[MH+(A)],248.2[MH+(B)](iii)N-[2-({(2,3-反式)-3-[4-(3,4-二氯代-苯氧基)-1-哌啶基]-2-羟基环己基}氧基)苯基]乙酰胺
将N-[2-(7-氧杂双环[4.1.0]庚-2-基氧基)苯基]乙酰胺的非对映体混合物(59mg,239μmol,1.0当量)和4-(3,4-二氯代苯氧基)哌啶(56mg,239μmol,1.0当量)溶于2M高氯酸锂的乙腈(2ml)溶液中,在85℃下,在密封管中加热过夜。水溶液处理,接着经硅胶快速层析(庚烷/乙酸乙酯/甲醇=50∶100∶3),得到86mg(75%)的黄色油状物,为比率69∶31=A∶B(1H-NMR)的非对映体混合物。反相柱上未发现该非对映体的分离。由于混合物光谱复杂,不能分别给出多量和少量非对映体的相对立体化学性质。1H-NMR(400MHz,CDCl3):δ9.48(1H[A],bs),9.25(1H[B],bs),8.46(1H[A]+1H[B],t,J 9.1Hz),7.22-7.32(2H[A]+1H[B],m),6.93-7.08(4H[A]+5H[B],m),6.72-6.76(1H[A]+1H[B],m),4.08-4.30(3H[A]+3H[B],m),3.55-3.64(2H[A]+1H[B],m),2.96-3.07(2H[A]+2H[B],m),2.71(2H[A]+3H[B],m),2.19(3H[A],s),2.16(3H[B],s),1.47-2.37(10H[A]+10H[B],m)。MS-ESI+:m/z 493.1[MH+(A,B)]
下列化合物根据以上实施例中说明的类似路线制备.实施例10N-(5-氯代-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 473.1 475.1[MH+]实施例11N-(3-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 495.1 497.1[MH+]实施例12N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 453.1 455.1[MH+]实施例13N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺APCI-MS:m/z 457.1 459.1[MH+]实施例141-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 421.1 423.1[MH+]实施例151-(7-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 463.1 465.1[MH+]实施例16N-(4-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 515.1 517.1[MH+]实施例17N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺APCI-MS:m/z 457.1 459.1[MH+]实施例18N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 453.1 455.1[MH+]实施例19N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 439.1 441.1[MH+]实施例20N-(5-氯代-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 439.1 441.1[MH+]实施例21N-(3-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 461.1[MH+]实施例22N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 419.1[MH+]实施例23N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺APCI-MS:m/z 423.1[MH+]实施例241-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 387.1[MH+]实施例251-(7-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 429.1[MH+]实施例26N-(4-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 481.1[MH+]实施例27N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺APCI-MS:m/z 423.1[MH+]实施例28N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 419.1[MH+]实施例29N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 405.1[MH+]实施例30N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 423.1[MH+]实施例31N-(3-乙酰基-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 445.3[MH+]实施例32N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 403.3[MH+]实施例33N-(5-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 407.1[MH+]实施例341-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 371.1[MH+]实施例351-(7-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 413.1[MH+]实施例36N-(4-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 465.3[MH+]实施例37N-(4-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 407.1[MH+]实施例38N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 403.1[MH+]实施例39N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 389.1[MH+]实施例40N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 441.1[MH+]实施例41N-(3-乙酰基-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 463.3[MH+]实施例42N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 421.1[MH+]实施例43N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺APCI-MS:m/z 425.1[MH+]实施例441-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 389.1[MH+]实施例451-(7-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 431.1[MH+]实施例46N-(4-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 483.3[MH+]实施例47N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺APCI-MS:m/z 425.1[MH+]实施例48N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 421.1[MH+]实施例49N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 407.1[MH+]实施例50N-(5-氯代-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 487.1 489.1[MH+]实施例51N-(3-乙酰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 509.1 511.1[MH+]实施例52N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 467.1 469.1[MH+]实施例53N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺APCI-MS:m/z 471.1 473.1[MH+]对比实施例541-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 435.1 437.1[MH+]实施例551-(7-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 477.1 479.1[MH+]实施例56N-(4-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 429.1 431.1[MH+]实施例57N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺APCI-MS:m/z 471.1 473.1[MH+]实施例58N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 467.1 469.1[MH+]实施例59N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 453.1 455.1[MH+]实施例60N-(5-氯代-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 453.1 455.1[MH+]实施例61N-(3-乙酰基-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 475.3[MH+]实施例62N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺APCI-MS:m/z 433.1[MH+]实施例63N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺APCI-MS:m/z 437.1[MH+]对比实施例641-[4-(4-氯代-苯氧基)-哌啶-1-基]-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 401.1[MH+]实施例651-(7-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-吲哚-1-基)-乙酮APCI-MS:m/z 443.1[MH+]实施例66N-(4-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺APCI-MS:m/z 495.3[MH+]实施例67N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺APCI-MS:m/z 437.1[MH+]实施例68N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺APCI-MS:m/z 433.1[MH+]实施例69N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 419.1[MH+]实施例70N-{5-氯代-2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 448.1 450.1[MH+]实施例71N-{3-乙酰基-2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺APCI-MS:m/z 470.1[MH+]实施例72N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-甲基-苯基}-乙酰胺APCI-MS:m/z 428.1[MH+]实施例73N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-氟代-苯基}-乙酰胺APCI-MS:m/z 432.1[MH+]实施例741-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 396.1[MH+]实施例751-{7-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-吲哚-1-基}-乙酮APCI-MS:m/z 438.1[MH+]实施例76N-{4-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-联苯-3-基}-乙酰胺APCI-MS:m/z 490.1[MH+]实施例771-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-氟代-苯基}-乙酰胺APCI-MS:m/z 432.1[MH+]实施例78N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺APCI-MS:m/z 428.1[MH+]实施例79N-{2-[3-(8-氯代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 414.1[MH+]实施例80N-{5-氯代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 432.1[MH+]实施例81N-{3-乙酰基-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺APCI-MS:m/z 454.3[MH+]实施例82N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-4-甲基-苯基}-乙酰胺APCI-MS:m/z 412.1[MH+]实施例83N-{5-氟代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 416.1[MH+]实施例841-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-3-(1H-吲哚-7-基氧基)-丙-2-醇APCI-MS:m/z 380.1[MH+]实施例851-{7-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-吲哚-1-基}-乙酮APCI-MS:m/z 422.1[MH+]实施例86N-{4-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-联苯-3-基}-乙酰胺APCI-MS:m/z 474.3[MH+]实施例87N-{4-氟代-2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 416.1[MH+]实施例88N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-5-甲基-苯基}-乙酰胺APCI-MS:m/z 412.1[MH+]实施例89N-{2-[3-(8-氟代-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-羟基-丙氧基]-苯基}-乙酰胺APCI-MS:m/z 398.1[MH+]实施例90N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:453,455[MH+]实施例913-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:482,484[MH+]实施例921-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:456,458[MH+]实施例931-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:426,428[MH+]实施例942-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:467,469[MH+]实施例951-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:452,454[MH+]实施例961-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:438,440[MH+]实施例973-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:418[MH+]实施例981-(2,6-二甲氧基-苯氧基)-3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-丙-2-醇APCI-MS m/z:392[MH+]实施例991-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:362[MH+]实施例100(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:447[MH+]实施例101(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:491[MH+]实施例1022-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯APCI-MS m/z:475[MH+]实施例1032-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:403[MH+]实施例1041-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:404[MH+]实施例1051-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:388[MH+]实施例1061-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:374[MH+]实施例107N-[2-(3-{[1-(3,4-二氯代苄基)-4-哌啶基]氨基}-2-羟基丙氧基)-4-甲基苯基]乙酰胺APCI-MS:m/z 480[MH+]实施例1083-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:436[MH+]实施例1091-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:380[MH+]实施例110(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:465[MH+]实施例1112-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:421[MH+]实施例1121-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:422[MH+]实施例1131-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:406[MH+]实施例1141-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:392[MH+]实施例115N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 452.1[MH+]实施例1163-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:434[MH+]实施例1171-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:408[MH+]实施例1181-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:378[MH+]实施例119(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:463[MH+]实施例1202-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯APCI-MS m/z:491[MH+]实施例1212-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:419[MH+]实施例1221-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:420[MH+]实施例1231-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:404[MH+]实施例1241-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:390[MH+]实施例125N-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:396[MH+]实施例1263-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:425[MH+]实施例127(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:454[MH+]实施例1282-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基苯甲酰胺APCI-MS m/z:410[MH+]实施例1294-{1-[2-羟基-3-(2-丙酰基-苯氧基)-丙基]-吡咯烷-3-基氧基}-苄腈APCI-MS m/z:395[MH+]实施例130N-(2-{2-羟基-3-[3-(4-甲氧基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基)-乙酰胺APCI-MS m/z:401[MH+]实施例131N-(4-氯代-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 486[MH+]实施例1323-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:468,470[MH+]实施例1331-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:412,414[MH+]实施例134(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:497,499[MH+]实施例1352-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯APCI-MS m/z:525,527[MH+]实施例1362-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:453,454[MH+]实施例1371-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:454,456[MH+]实施例1381-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:438,440[MH+]实施例1391-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:424,426[MH+]实施例140N-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:421[MH+]实施例1413-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:450[MH+]实施例1422-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:435[MH+]实施例1431-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:420[MH+]实施例144(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:479[MH+]实施例145N-(2-{3-[3-(3,4-二氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:435[MH+]实施例146N-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:403[MH+]实施例1473-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:432[MH+]实施例1481-(2,6-二甲氧基-苯氧基)-3-[4-(4-氟代-苯氧基)-哌啶-1-基]-丙-2-醇APCI-MS m/z:406[MH+]实施例1491-[4-(4-氟代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:376[MH+]实施例1501-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:388[MH+]实施例1512-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:417[MH+]实施例1521-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:402[MH+]实施例153(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:461[MH+]实施例154N-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:417[MH+]实施例1553-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:446[MN+]实施例1561-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:390[MH+]实施例1571-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:402[MH+]实施例1582-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯APCI-MS m/z:503[MH+]实施例1592-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:431[MH+]实施例1601-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:432[MH+]实施例161N-(2-{3-[4-(4-乙酰氨基-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS m/z:442[MH+]实施例162N-(4-{1-[3-(2-乙酰基-苯氧基)-2-羟基-丙基]-哌啶-4-基氧基}-苯基)-乙酰胺APCI-MS m/z:427[MH+]实施例163N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS m/z:477[MH+]实施例1643-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS:m/z 448[MH+]实施例1651-[4-(4-氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇APCI-MS m/z:392[MH+]实施例1661-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:404[MH+]实施例1672-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯APCI-MS m/z:505[MH+]实施例1682-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:433[MH+]实施例1691-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮APCI-MS m/z:434[MH+]实施例1701-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:418[MH+]实施例171(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯APCI-MS m/z:477[MH+]实施例172N-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)乙酰胺APCI-MS m/z:433[MH+]实施例1733-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯APCI-MS m/z:462[MH+]实施例1741-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮APCI-MS m/z:418[MH+]实施例1752-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺APCI-MS m/z:447[MH+]实施例1761-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮APCI-MS m/z:432[MH+]实施例177N-[2-({(1R,2R)-2-[4-(3,4-二氯代苯氧基)-1-哌啶基]-1-羟基环戊基}甲氧基)苯基]乙酰胺实施例178(2S,4R)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-[(4-氯代苄基)氧基]-2-吡咯烷甲酸甲酯盐酸盐实施例179-189原料:A)(3,4-二氯代-苯基)-哌啶-4-基-胺
在充满氮气的反应容器中,将4-氧代-哌啶-1-甲酸叔丁酯(2.46g,12.3mmol)和3,4-二氯代-苯胺(1.0g,6.17mmol)溶于二氯甲烷(28ml)和乙酸(2.12ml)中。室温下,加入三乙酰氧基硼氢化钠(3.67g,17.3mmol)。将反应物搅拌过夜,然后倒入碳酸氢钠溶液(5%)中。用乙酸乙酯(EtOAc)将水相振摇3次。将合并的有机相用硫酸钠干燥,蒸发,经快速层析纯化(EtOAc∶庚烷3∶7),得到1.7g,81%的纯化合物。将该BOC-保护的题述化合物溶于二氯甲烷(26ml)和三氟乙酸(13ml)中,室温下搅拌3小时,蒸发,溶于乙醚和氢氧化钠(1M)中。分离有机层,将水相用乙醚洗涤2次。将合并的有机层用少量盐水洗涤,经硫酸钠干燥,蒸发得到1.15g(76%)的题述化合物。1H-NMR(400MHz,DMSO-d6):δ7.20(d,1H,J=8.9Hz),6.73(d,1H,J=2.7Hz),6.54(dd,1H,J=8.8,2.7Hz),5.95(d,1H,J=8.1Hz),3.22(m,1H),2.91(bd,2H,J=12.6Hz),2.51(m,2H),2.02(bs,1H),1.81(bd,2H,J=12.4Hz),1.18(m)APCI-MS:m/z 245[MH+]B)(4-氯代-苯基)-哌啶-4-基-胺
按照(A)中相同的方法,用4-氧代-哌啶-1-甲酸叔丁酯(3.59g,18.0mmol)、4-氯代-苯胺(1.15g,9.0mmol)和三乙酰氧基硼氢化钠(5.34g,25.2mmol)的二氯甲烷(40ml)和乙酸(3.1ml)溶液合成。在二氯甲烷(37ml)和三氟乙酸(18ml)中脱保护。收率1.5g,79%。1H-NMR(400MHz,DMSO-d6):δ7.04(d,2H,J=8.9Hz),6.55(d,2H,J=8.9Hz),5.62(d,1H,J=8.1Hz),3.1 8(m,1H),2.92(bd,2H,J=12.6Hz),2.50(m,2H),1.99(bs,1H),1.82(d,2H,J=12.7Hz),1.18(m,2H)。APCI-MS:m/z 211[MH+]C)(4-氟代-苯基)-哌啶-4-基-胺
按照(A)中相同的方法,用4-氧代-哌啶-1-甲酸叔丁酯(3.59g,18.0mmol)、4-氟代-苯胺(1.0g,9.0mmol)和三乙酰氧基硼氢化钠(5.34g,25.2mmol)的二氯甲烷(40ml)和乙酸(3.1ml)溶液合成。在二氯甲烷(37ml)和三氟乙酸(18ml)中脱保护。收率1.1g,63%。1H-NMR(400MHz,DMSO-d6):δ6.85(t,2H,J=9.0Hz),6.51(dd,2H,J=9.1,4.6Hz),5.27(d,1H,J=8.2Hz),3.13(m,1H),2.89(bd,2H,J=12.5Hz),2.48(m,2H),1.80(bd,2H,J=12.3Hz),1.14(m,2H)。APCI-MS:m/z 195[MH+]D)(3,4-二氟代-苯基)-哌啶-4-基-胺
按照(A)中相同的方法,用4-氧代-哌啶-1-甲酸叔丁酯(3.59g,18.0mmol)、3,4-二氟代-苯胺(1.16g,9.0mmol)和三乙酰氧基硼氢化钠(5.34g,25.2mmol)的二氯甲烷(40ml)和乙酸(3.1ml)溶液合成。在二氯甲烷(37ml)和三氟乙酸(18ml)中脱保护。收率1.26g,66%。1H-NMR(400MHz,DMSO-d6):δ7.05(dt,1H,J=10.8,9.2Hz),6.50(ddd,1H,J=14.1,7.0,2.8Hz),6.32(bd,1H,J=9.20Hz),5.64(d,1H,J=8.14Hz),3.17(m,1H),2.90(bd,2H,J=12.6Hz),2.50(m,2H),2.00(bs,1H),1.81(bd,2H,J=12.6Hz),1.16(m,2H)。APCI-MS:m/z 213[MH+]实施例179N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 466[MH+]实施例180N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 418[MH+]实施例181N-(4-氯代-2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺APCI-MS:m/z 452[MH+]实施例182N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-氰基苯基)乙酰胺APCI-MS:m/z 443[MH+]实施例183N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 432[MH+]实施例184N-(5-氯代-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 436[MH+]实施例185N-(5-氯代-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 454[MH+]实施例186N-(5-氰基-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-苯基)乙酰胺APCI-MS:m/z 427[MH+]实施例187N-(5-氰基-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 445[MH+]实施例188N-(2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 416[MH+]实施例189N-(2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 434[MH+]实施例190N-(2-{3-[3(S)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(R)-羟基-丙氧基}苯基)乙酰胺(i)3-(S)-(4-氯代-苯氧基)-吡咯烷CF3COOH
在0℃下,向三苯基膦(4.2g,16.02mmol)的THF(75ml)溶液中,加入偶氮二甲酸二乙酯(2.52ml),15分钟后,加入4-氯苯酚(2.05g,16.02mmol),再过10分钟后,慢慢加入3-羟基-吡咯烷-1-甲酸叔丁酯(3.0g,16.02mmol)的THF(20ml)溶液。加入完毕后,移去冰浴,将反应混合液保持在室温下过夜。真空除去溶剂,将残留物与乙醚搅拌,滤除固体的三苯基氧化膦。残留物经快速层析纯化(0-0.5% MeOH的CHCl3液)得到题述化合物(3.65g,76%),将其溶于二氯甲烷(60ml)中,加入三氟乙酸(15ml)。保持反应混合液在室温下30分钟。真空除去溶剂。将残留物溶于二氯甲烷中,加入乙醚和己烷。过滤固体,得到题除述化合物3.70g,97%。1H-NMR(CDCl3,400MHz):δ10.20(s,1H),9.99(s,1H),7.25(d,J 8.8Hz,2H),6.78(d,J 8.8Hz,2H),4.99(m,1H),3.41(m,4H),2.30(m,1H),2.20(m,1H)。APCI-MS:m/z 198(MH+)(ii)N-(2-{3-[3(S)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(R)-羟基-丙氧基}苯基)乙酰胺
在65℃下,将3-(S)-(4-氯代-苯氧基)-吡咯烷CF3COOH(312mg,1.0mmol)、N-乙酰基-2-(2,3-环氧基丙氧基)苯胺(207mg,1.0mmol)、K2CO3(560mg)的EtOH(10ml)溶液搅拌4小时。真空除去溶剂。将残留物在乙酸乙酯和水之间分配。将有机层顺次用NHCl水溶液和水洗涤。该有机层用Na2SO4干燥,过滤,浓缩。残留物经快速层析纯化(0-3%MeOH的CHCl3溶液),得到非对映体混合物(310mg,77%)。将该非对映体通过HPLC分离,得到N-(2-{3-[3(S)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(R)-羟基-丙氧基}-苯基)乙酰胺(57mg)。1H-NMR(CDCl3,400MHz):δ8.36(m,1H),8.25(s,1H),7.25(m,2H),6.99(m,2H),6.93(m,1H),6.75(m,2H),4.80(m,1H),4.08(m,2H),3.96(m,1H),3.11(dd,J 5.9,10.5Hz,1H),3.01(m,1H),2.82(m,2H),2.59(m,1H),2.51(dd,J 3.2,12.0Hz,1H),2.29(m,1H),2.19(s,3H),2.01(m,1H)。APCI-MS:m/z 405(MH+)实施例191N-(2-{3-[3S-(4-氯代-苯氧基)-吡咯烷-1-基]-2S-羟基-丙氧基}苯基)乙酰胺盐酸盐
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ8.35(m,1H),8.26(s,1H),7.24(m,2H),6.99(m,2H),6.92(m,1H),6.75(m,2H),4.80(m,1H),4.12(m,2H),3.95(m,1H),2.95(m,2H),2.80(m,3H),2.52(dd,3.4,12.2Hz,1H),2.30(m,1H),2.19(s,3H),2.01(m,1H)。APCI-MS:m/z 405(MH+)实施例192N-(2-{3-[3(R)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(S)-羟基-丙氧基}苯基)乙酰胺
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ8.36(m,1H),8.25(s,1H),7.25(m,2H),6.99(m,2H),6.93(m,1H),6.75(m,2H),4.80(m,1H),4.08(m,2H),3.96(m,1H),3.11(dd,J 5.9,10.5Hz,1H),3.01(m,1H),2.82(m,2H),2.59(m,1H),2.51(dd,J 3.2,12.0Hz,1H),2.29(m,1H),2.19(s,3H),2.01(m,1H)。APCI-MS:m/z 405(MH+)实施例193N-[5-氯代-2-({(2S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ8.45(m,1H),8.36(br.s,1H),7.23(m,2H),6.95(m,1H),6.85(m,1H),6.75(m,2H),4.80(m,1H),4.07(m,2H),3.91(m,1H),2.95(m,2H),2.80(m,3H),2.49(dd,J 3.2,12.0Hz,1H),2.30(m,1H),2.19(s,3H),2.03(m,1H)。APCI-MS:m/z 439(MH+)实施例194N-[5-氯代-2-({(2R)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ8.45(m,1H),8.36(br.s,1H),7.23(m,2H),6.95(m,1H),6.85(m,1H),6.75(m,2H),4.80(m,1H),4.07(m,2H),3.91(m,1H),2.95(m,2H),2.80(m,3H),2.49(dd,J 3.2,12.0 Hz,1H),2.30(m,1H),2.19(s,3H),2.03(m,1H)。APCI-MS:m/z 439(MH+)实施例195N-[5-氯代-2-({(2S)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ 8.45(m,1H),8.34(br.s,1H),7.22(m,2H),6.94(m,1H),6.85(m,1H),6.75(m,2H),4.80(m,1 H),4.08(m,2H),3.90(m,1H),3.11(dd,J 5.9,10.5Hz,1H),3.02(m,1H),2.81(m,2H),2.58(m,1H),2.49(dd,J 3.5,12.1Hz,1H),2.30(m,1H),2.18(s,3H),2.01(m,1H)。APCI-MS:m/z 439(MH+)实施例196N-[5-氯代-2-({(2R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺
根据实施例190类似方法实施该反应。1H-NMR(CDCl3,400MHz):δ8.45(m,1H),8.34(br.s,1H),7.22(m,2H),6.94(m,1H),6.85(m,1H),6.75(m,2H),4.80(m,1H),4.08(m,2H),3.90(m,1H),3.11(dd,J 5.9,10.5Hz,1H),3.02(m,1H),2.81(m,2H),2.58(m,1H),2.49(dd,J 3.5,12.1Hz,1H),2.30(m,1H),2.18(s,3H),2.01(m,1H)。APCI-MS:m/z 439(MH+)实施例197N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4,5-二氟代-苯基)乙酰胺i)4,5-二氟代-2-硝基-苯酚
在烧瓶中,将3,4-二氟代苯酚(3.10g,23.7mmol)溶于乙酸(15ml)中。向该搅拌着的溶液中滴加发烟HNO3(1.25g,29.7mmol)的乙酸(6ml)溶液。在整个加料过程中,保持温度在50℃以下。加入完毕后,将混合液再搅拌1小时。然后将反应混合液倒入冰水中,得到浅黄色固体沉淀。过滤收集固体,干燥。该固体经硅胶纯化(己烷∶EtOAc 5∶1),得到题述化合物(2.05g,50%)的黄色油状物,放置结晶。1H-NMR(400MHz,CDCl3):δ10.61(1H,s);8.00(1H,dd,J 9.6,8.2Hz);7.00(1H,dd,J 10.4,6.8Hz)。ii)N-(4,5-二氟代-2-羟基-苯基)-乙酰胺
在烧瓶中,加入i)中得到的产物(0.59g,3.37mmol)和乙酸(10ml)。搅拌下,将溶液加热至90℃,加入锡(粉末,1.60g,13.5mmol)。将烧瓶密封,在搅拌下再加热1小时,通过硅藻土过滤该热溶液。然后将滤器另用10ml热乙酸洗涤。向滤液中加入水(25ml)和乙酸酐(0.5ml,5.29mmol),搅拌下,将得到的混合液在60℃下加热20分钟。将混合液冷却,在EtOAc和水之间分配。收集有机相,用水和盐水洗涤。蒸发有机相得到0.63g(100%)的副标题述化合物固体。1H-NMR(400MHz,DMSO-d6):δ10.25(1H,s);9.31(1H,bs);7.88(1H,dd,J 12.8,7.9Hz);6.83(1H,dd,J 12.1,7.7Hz);2.03(3H,s)。(iii)N-(4,5-二氟代-2-环氧乙烷基甲氧基-苯基)-乙酰胺
在管瓶中加入ii)中得到的化合物(0.4g,2.137mmol)、表溴代醇(0.35g,2.55mmol)、K2CO3(0.6g,4.4mmol)和DMF(2ml)。将该管瓶密封,搅拌下加热(2小时,60℃)。然后将混合液在EtOAc和水之间分配,将有机相用水洗涤2次,用盐水洗涤1次,最后蒸发得到棕色固体。该粗产物环氧化物经硅胶纯化,得到0.27g(52%)题述化合物的浅粉色固体。1H-NMR(400MHz,CDCl3):δ8.37(1H,dd,J 12.2,8.8Hz);7.85(1H,bs);6.78(1H,dd,J 11.2,7.1Hz);4.34(1H,dd,J 11.5,2.2Hz);3.90(1H,dd,11.6,6.3Hz);3.40-3.36(1H,m);2.98(1H,t,J 4.5Hz);2.81(1H,dd,J 4.7,6.3Hz);2.22(3H,s)。iv)N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4,5-二氟代-苯基)乙酰胺
在管瓶中加入iii)中得到的化合物(0.059g,0.24mmol)、3-(4-氯代苯氧基)-吡咯烷(0.048g,0.24mmol)和乙醇(2ml,99.5%)。将管瓶密封,在75℃、搅拌下,将该内容物加热2小时。将该粗溶液蒸发,得到的油状物经硅胶纯化,得到题述化合物的盐酸盐,冷冻干燥。得到的题述化合物为白色固体(0.075g,65%)。该化合物是四种对NMR波谱有影响的立体异构体的混合物。1H-NMR(400MHz,DMSO-d6):δ10.78-10.30(1H,m);9.30(1H,s);8.07(1H,dd,J 12.8,9.3Hz);7.40-7.34(2H,m);7.23(1H,dd,J 12.7,7.5Hz);7.05-6.99(2H,m);6.19(1H,bs);5.23-5.11(1H,m);4.35(1H,bs);4.08-3.97(1.5H,m);3.69-3.90(1H,m);3.84-3.70(1.5H,m);3.63-3.23(4H,m);2.66-2.00(5H,m)。APCI-MS:m/z 411.1[MH+]实施例198N-{5-氯代-2-[2-羟基-3-(3-苯氧基-吡咯烷-1-基)-丙氧基]-苯基}-乙酰胺
根据实施例197类似方法实施该反应。1H-NMR(400MHz,DMSO-d6):δ10.80-10.36(1H,m);9.26(1H,s);8.14(1H,s);7.32(2H,t,J 8.35Hz);7.11-6.95(5H,m);6.31-6.02(1H,m);5.24-5.12(1H,m);4.37(1H,bs);4.10-3.97(1.5H,m);3.95-3.88(1H,m);3.84-3.68(1.5H,m);3.64-3.26(4H,m);2.65-2.52(0.5H,m);2.35-2.02(4.5H,m)。APCI-MS:m/z 405.2[MH+]实施例199N-(5-氯代-2-{2-羟基-3-[3-(4-硝基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基}-乙酰胺
根据实施例197类似方法实施该反应。1H-NMR(400MHz,DMSO-d6):δ10.95-10.48(1H,m);9.26(1H,s);8.24(2H,d,J 9.6Hz);8.13(1H,bs);7.23-7.17(2H,m);7.12-7.02(2H,m);6.20(1H,bs);5.43-5.30(1H,m);4.38(1H,m);4.18-4.06(0.5H,m);4.05-3.97(1H,m);3.95-3.87(1H,m);3.86-3.72(1.5H,m);3.69-3.27(4H,m);2.73-2.60(0.5H,m);2.46-2.08(4.5H,m)。APCI-MS:m/z 450.1[MH+]实施例200N-(5-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺
根据实施例197类似方法制备该化合物。APCI-MS:m/z 481.2,483.2[MH+]实施例2014-乙酰氨基-3-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯
根据实施例197类似方法制备该化合物。APCI-MS:m/z 497.1,499.2[MH+]实施例202N-(3-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-萘-2-基)-乙酰胺
根据实施例197类似方法制备该化合物。APCI-MS:m/z 489.2,491.2[MH+]实施例203N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氰基-苯基)-乙酰胺
根据实施例197的方法制备题述化合物。APCI-MS:m/z 430.2[MH+]实施例2044-乙酰氨基-3-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯
根据实施例197类似方法制备该化合物。APCI-MS:m/z 463.2[MH+]实施例205N-(3-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-萘-2-基)-乙酰胺
根据实施例197的方法制备题述化合物。APCI-MS:m/z 455.2[MH+]实施例206N-(5-氰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺
根据实施例197的方法制备题述化合物。APCI-MS:m/z 478.2,480.1[MH+]实施例207N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-三氟甲基-苯基)-乙酰胺
根据实施例197的方法制备题述化合物。APCI-MS:m/z 521.1,523.2[MH+]实施例208N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐
根据实施例197的方法制备题述化合物。APCI-MS:m/z 423.1,424.9[MH+]实施例209N-(5-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐i)N-(5-乙酰基-2-环氧乙烷基甲氧基-苯基(fenyl))-乙酰胺
向4-乙酰基-2-硝基苯酚(0.50g,2.76mmol)的THF(20ml)溶液中加入10%Pd/C(0.15g)。在1atm(大气压)下,将所得反应混合液用H2氢化5小时,然后通过硅藻土过滤,蒸发得到0.63g红色油状物。加入水(20ml)和乙酸酐(0.35g,3.44mmol),将混合液剧烈搅拌5分钟。然后在60℃、搅拌下,将反应混合液加热30分钟,随后冷却。形成红色固体,过滤收集沉淀,用水洗涤,干燥得到0.27g(1.40mmol)的N-(5-乙酰基-2-羟基-苯基)-乙酰胺。将其溶于DMF(5ml)中。加入K2CO3(0.34g,2.45mmol)和表溴代醇(0.21g,1.54mmol),在50℃、搅拌下,将得到的混合液加热3小时。将该混合液在EtOAc和水40+40ml之间分配。将有机相用水洗涤2次,用盐水洗涤1次,最后真空浓缩得到红色油状物。该粗产物经硅胶纯化(庚烷∶EtOAc,1∶2-1∶4)得到110mg(16%)的题述化合物。1H-NMR(400MHz,CDCl3):δ9.03(1H,d,J 1.9Hz),7.81(1H,bs),7.74(1H,dd,J 8.6,2.3Hz),6.96(1H,d,J 8.6Hz),4.48(1H,dd,J 11.3,2.4Hz),4.00(1H,dd,J 11.4,6.4Hz),3.45-3.40(1H,m),2.99(1H,t,J4.4Hz),2.79(1H,dd,J 4.7,2.6Hz),2.59(3H,s),2.26(3H,s)。ii)N-(5-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐
根据实施例197中说明的方法制备题述化合物。APCI-MS:m/z 447,449[MH+]实施例210N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-甲磺酰胺i)1-(2-氨基苯氧基)-3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-丙醇二盐酸盐
将N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)乙酰胺(0.95g,2.34mmol)和浓盐酸(25ml)加热(100-105℃)3小时,然后在室温下放置过夜。将混合液减压浓缩至其体积的三分之一,用饱和碳酸氢钠碱化。将得到的混悬液用乙酸乙酯萃取2次。将该有机萃取液干燥,减压蒸发溶剂得到浅棕色油状物。将该油状物溶于尽量少量的甲醇中,用乙醚稀释,加入用HCl饱和的乙醚溶液沉淀产物。过滤产物得到该题述化合物(0.93g,91.2%)。APCI-MS:m/z 363[MH+],游离碱ii)N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)-甲磺酰胺
将甲磺酰氯(35mg,0.3mmol)加入到冷却(0℃)、搅拌着的以上得到的胺(110mg,0.25mmol)和吡啶(0.4mL)的无水二氯甲烷(10mL)混合液中。然后在室温下,将所述混合液搅拌1.5小时,接着浓缩。将残留物在乙酸乙酯和水之间分配。将有机相浓缩,残留物经快速层析纯化(硅胶,二氯甲烷-甲醇,25∶1),得到题述化合物(68mg,61.8%)的泡沫状物。1H-NMR(400MHz,CDCl3):δ7.51(dd,1H,J=1.4和8.0Hz),7.22(m,2H),7.10(m,1H),7.68(m,1H),6.92(d,1H,J=9.0Hz),6.76(m,2H),5.78(非常宽的单峰,1H),4.80(m,1H),4.20(m,1H),4.08(m,1H),3.98(m,1H),3.16(m,1H),3.01(m,1H),2.96(s,3H),2.89(m,2H),2.74(m,M),2.68(dd,1H,J=4.O和12.2Hz),2.3(m,1H)和2.02(m,1H)。13C-NMR(400MHz,CDCl3):δ155.9,149.4,129.4,126.9,125.8,125.77,125.75,122.29,122.26,122.17,115.5,113.52,113.50,76.52,76.49,72.15,72.09,67.18,67.08,60.24,60.07,57.96,57.94,53.18,52.98,39.1,31.92,31.90。APCI-MS:m/z 441[MH+]实施例211N-(5-氯代-2-[3-[3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基-丙氧基]-苯基)脲i)N-(5-氯代-2-羟基苯基)脲
将氰酸钾(6.14g,75.6mmol)的水(50mL)溶液滴加至搅拌着的2-氨基-4-氯代苯酚(5.00g,34.8mmol)的乙酸(350mL)和水(250mL)混合液的混悬液中,室温下,将得到的溶液搅拌3小时。将反应混合液用乙醚萃取3次。将乙醚萃取液合并,浓缩得到浓稠油状物。向上述油状物中加入10%碳酸氢钠水溶液(250mL)。过滤固体产物,用水洗涤数次,重结晶(含少量甲醇的甲苯),得到题述化合物(3.27g,50.4%)。1H-NMR(400MHz,DMSO-d6):δ10.1(s,1H),8.07(d,1H,J=2.2Hz),8.04(s,1H),6.75-6.78(m,2H),6.29(bs,2H)。13C-NMR:δ 156.0,144.1,130.0,122.5,120.2,117.5,115.2。ii)N-[5-氯代-2-(2-环氧乙烷基甲氧基)苯基]脲
室温下,将N-(5-氯代-2-羟基苯基)脲(53mg,0.28mmol)、碳酸铯(92mg,0.28mmol)和表溴代醇(49mg,0.36mmol)的无水DMF(0.6mL)混悬液搅拌24小时。然后将混合液在乙酸乙酯和水之间分配。将有机相用水洗涤3次,干燥,浓缩得到固体残留物。将该粗产物重结晶(乙醚和庚烷),得到题述化合物(18mg,26.5%)。1H-NMR(400MHz,DMSO-d6):δ8.20(d,1H,J=2.2Hz),8.00(s,1H),7.00(d,1H,J=8.8Hz),6.88(dd,1H,J=2.4和8.6Hz),6.40(bs,2H),4.40(dd,1H,J=2.2和12.0Hz),3.90(dd,1H,J=6.6和12.0Hz),3.37(m,1H),2.88(t,1H,J=4.8Hz),2.74(m,1H)。iii)N-(5-氯代-2-[3-[3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基-丙氧基]-苯基)脲
将(ii)的题述化合物(16mg,0.07mmol)和3-(3,4-二氯代苯氧基)吡咯烷(17mg,0.07mmol)的无水乙醇(1mL)溶液2小时。减压除去溶剂,残留物经快速层析纯化(二氯甲烷-甲醇,15∶1),得到题述化合物(11mg,33%)。1H-NMR(400MHz,DMSO-d6):δ8.18(d,1H,J=2.6Hz),7.94(s,1H),7.5(d,1H,J=0.0Hz),7.16(d,1H,J=2.1Hz),6.82-6.98(m,3H),6.33(bs,2H),4.98(m,1H),4.90(m,1H),3.85-4.07(m,3H),2.63-2.93(m,5H),2.21-2.30(m,1H),1.74(m,1H)。APCI-MS:m/z 198[MH+]实施例2121-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐ii)N-(2-羟基苯基)脲
在15分钟内,将氰酸钾(3.94g,48.6mmol)的水(30mL)溶液加入到2-氨基苯酚(2.41g,22.1mmol)的50%乙酸水溶液(160mL)的混悬液中。室温下,将得到的溶液放置过夜,然后用乙醚萃取(3次)。将合并的有机萃取液浓缩至少量体积,然后倒入冷的饱和碳酸氢钠水溶液中。过滤固体,用水洗涤,得到题述化合物(1.61g,47.9%)。1H-NMR(400MHz,DMSO-d6):δ9.88(s,1H),7.97(s,1H),7.80(bd,1H),6.77(m,1H),6.68(m,1H),6.17(s,2H)。ii)N-[2-(2-环氧乙烷基甲氧基)苯基]脲
将表溴代醇(0.94g,6.84mmo1)的无水DMF(2mL)溶液滴加到搅拌着的N-(2-羟基苯基)脲(0.65g,4.27mmol)和碳酸铯(2.22g,6.84mmol)的DMF(8mL)混悬液中。2小时后,将混合液在水和乙酸乙酯之间分配。将水相用乙酸乙酯萃取,将合并的有机相用水洗涤(3次),干燥,浓缩。将半固体残留物溶于二氯甲烷/乙醚中,过滤,向该混浊液中加入庚烷。室温放置过夜后,过滤固体,得到题述化合物(0.28g,32%)。1H-NMR(400MHz,DMSO-d6):δ8.07(m,1H),7.82(s,1H),6.97(m,1H),6.85(m,2H),6.24(bs,2H),4.37(dd,1H,J=2.5和11.6Hz),3.89(dd,1H,J=6.4和11.6Hz),3.38(m,1H),2.87(t,1H,J=4.6Hz),2.75(dd,1H,J=2.6和5.2Hz)。APCI-MS:m/z 209[MH+]iii)1-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐
将N-[2-(2-环氧乙烷基甲氧基)苯基]脲(78mg,0.37mmol)和3-(4-氯代苯氧基)吡咯烷(70mg,0.36mmol)的无水乙醇(4mL)溶液加热回流2.5小时。然后浓缩混合液,残留物经HPLC纯化,得到题述化合物(102mg,54.5%)。1H-MR(400MHz,DMSO-d6+D2O):δ7.98(bd,1H,J=7.2Hz),7.36(d,2H,J=8.8Hz),6.95-7.02(m,3H),6.88(m,2H),5.15(bd,1H),4.26(m,1H)。余下的10个脂族质子在δ2.04-4.04之间呈现出复杂的重叠多重峰。APCI-MS:m/z 406[MH+]和408[MH++2],游离碱实施例2131-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(3,4-二氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐
将N-[2-(2-环氧乙烷基甲氧基)苯基]脲(在实施例22步骤ii中描述;69mg,0.33mmol)和3-(3,4-二氯代苯氧基)吡咯烷(77mg,0.33mmol)的无水乙醇(4.5mL)溶液加热至70℃下2小时。蒸发溶剂后,残留物经HPLC纯化,得到题述化合物(133mg,72.3%)。1H-NMR(400MHz,DMSO-d6+D2O):δ7.96(bd,1H,J=7.4Hz),7.54(bd,1H,J=9.0Hz),7.27(bs,1H),6.84-7.00(m,4H),5.20(bd,1H),4.26(m,1H)。余下的10个脂族质子在δ2.05-4.03之间呈现出复杂的重叠多重峰。APCI-MS:m/z 439.9[M]和442[M+2],游离碱实施例2141-(3-{2-[(氨基羰基)氨基]-4-氯代苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐
将N-[2-(2-环氧乙烷基甲氧基)苯基]脲(在实施例212步骤ii中描述;47mg,0.22mmol)和3-(4-氯代苯氧基)吡咯烷(41mg,0.2mmol)的无水乙醇(3mL)溶液加热至70℃下1.5小时。然后蒸发溶剂,残留物经HPLC纯化,得到题述化合物(67mg,60.9%)。1H-NMR(400MHz,CD3OD):δ8.04(s,1H),7.31(d,2H,J=8.6Hz),6.94-6.98(m,4H),5.20(bs,1H),4.40(m,1H)。余下的10个脂族质子在δ2.25-4.13之间呈现出复杂的重叠多重峰。APCI-MS:m/z 440.1[M]和442.1[M+2],游离碱实施例215N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-乙基脲盐酸盐
在室温下,在密封管瓶中,将N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)脲的乙醚溶液[通过将其盐酸盐(110mg,0.25mmol)用1M NaOH处理并用乙醚萃取获得]用异氰酸乙酯(16μl,0.2mmol)处理15小时。蒸发并经硅胶快速层析纯化(EtOAc/MeOH100/5)后,将适当的部分用1M HCl酸化,从乙酸冷冻干燥,得到题述化合物的白色无定形固体(35mg,37%)。该物质是两种成对非对映体的混合物。APCI-MS:m/z 434[MH+]实施例216N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-甲基脲盐酸盐
向N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)脲[通过将其盐酸盐(44mg,0.1mmol)用1M NaOH处理并用乙醚萃取获得]的DCM(3ml)溶液中,加入三碳酸二叔丁基酯(26mg,0.1mmol),将该溶液放置15分钟。加入甲胺(2M的DCM溶液,100μl,0.2mmol),将该溶液放置过夜。蒸发后,粗产物经制备RP-HPLC纯化,用含有0.1%TFA的乙腈和水作为流动相。将适当的部分真空浓缩,用1M NaOH和乙醚萃取。将有机相中的残留物用1M HCl酸化,从乙酸中冷冻干燥,得到题述化合物的白色无定形固体(15mg,30%)。该物质是两种成对非对映体的混合物。APCI-MS:m/z 420[MH+]实施例217(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(4-氯代苯氧基)-2-吡咯烷甲酸;与三氟乙酸的混合物i)(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(4-氯代苯氧基)-2-吡咯烷甲酸甲酯盐酸盐
在100℃下,在密封管瓶中,将溶于叔丁基醇(7ml)中的(2S,4S)-4-(4-氯代苯氧基)-2-吡咯烷甲酸甲酯(370mg,1.0mmol)和N-[2-(2-环氧乙烷基甲氧基)苯基]乙酰胺(207mg,1.0mmol)搅拌过夜。经硅胶快速层析(DCM/MeOH 100/2)处理粗产物,将适当的部分用1M HCl酸化,从乙酸中冷冻干燥,得到题述化合物的白色无定形固体(360mg,72%)。该物质是非对映体混合物。APCI-MS:m/z 463[MH+]ii)(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(4-氯代苯氧基)-2-吡咯烷甲酸;与三氟乙酸的混合物
将化合物(i)(50mg,0.1mmol)溶于乙腈(2ml)和水(3ml)中。加入溶于水(0.5ml)的水和氢氧化锂(8mg,0.2mmol)。通过分析HPLC确定反应在0.5小时后完成。将该混合物用TFA酸化,经制备RP-HPLC纯化,用含有0.1%TFA的乙腈和水为流动相。将适当的部分真空浓缩,残留物在乙酸中冷冻干燥,得到题述化合物的白色无定形固体(27mg,48%)。该物质是非对映体的混合物。APCI-MS:m/z 449[MH+],431[MH+,内酯,微量]实施例218(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(3,4-二氯代苯氧基)-2-吡咯烷甲酸乙酯;三氟乙酸盐i)(2S,4S)-4-(3,4-二氯代苯氧基)-2-吡咯烷甲酸甲酯
根据实施例217 ii)类似的方法,用N-Boc-cis-4-羟基-L-脯氨酸甲酯和3,4-二氯代苯酚制备该化合物。1H-NMR(400MHz,DMSO-d6):δ9.64(bs,2H);7.58(d,1H);7.25(d,1H);6.94(dd,1H);5.24(m,1H);4.66(dd,1H);3.76(s,3H);3.55(dd,1H);3.47(d,1H);2.67-2.58(m,1H);238(d,1H)。APCI-MS:m/z 290,292[MH+,同位素方式]ii)(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(3,4-二氯代苯氧基)-2-吡咯烷甲酸乙酯;三氟乙酸盐
根据实施例217类似的方法,用化合物i)(404mg,1.0mmol)和N-[2-(2-环氧乙烷基甲氧基)苯基]乙酰胺(207mg,1.0mmol)制备该化合物,不同之处在于用乙醇作为溶剂。发生再次酯化,经后处理和纯化后,分离出题述化合物的白色固体(209mg,33%)。该物质是非对映体的混合物。APCI-MS:m/z 511,513[MH+,同位素方式]实施例219N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐和N-[2-({(2R)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐i)[(2S,4S)-4-(4-氯代苯氧基)吡咯烷基]甲醇
在0℃、氩气气氛下,在40分钟内,将(2S,4S)-4-(4-氯代苯氧基)-2-吡咯烷甲酸甲酯(根据实施例217 ii)方法,用cis-4-羟基-L-脯氨酸甲酯制备)(850mg,3.32mmol)的无水THF(20ml)溶液加入到氢化铝锂(505mg,13.3mmol)的无水THF(10ml)混合液中。室温下搅拌过夜后,加入无水硫酸钠(1g),接着滴加水(0.5ml)、氢氧化钠(15%重量/体积,0.5ml)和水(1.5ml)。过滤,蒸发得到浆状物,经硅胶快速层析纯化(二氯甲烷/甲醇/浓氨水100/20/1),得到题述化合物(0.60g,79%)。1H-NMR(400MHz,CDCl3):δ7.22(m,2H),6.78(m,2H),4.79(m,1H),3.62(m,2H),3.39(m,1H),3.23(bd,2H),3.14(dd,1H,J 5.0Hz,12.2Hz),2.28(m,1H),1.72(m,1H)。MS-APCI+:m/z 228[MH+]ii)N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐和N-[2-({(2R)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐
将[(2S,4S)-4-(4-氯代苯氧基)吡咯烷基]甲醇(380mg,1.67mmol)和N-[2-(2-环氧乙烷基甲氧基)苯基]乙酰胺(414mg,2.00mmol)溶于叔丁基醇(5ml)中,并在100℃下,在密封管瓶中搅拌过夜。将该溶液浓缩,残留物经硅胶快速层析纯化(二氯甲烷/甲醇13/1),接着经制备RP-HPLC纯化,用含有0.1%三氟乙酸的乙腈/水为流动相。将适当的部分冷冻干燥,得到题述化合物(差向异构体A:248mg,27%,差向异构体B:115mg,13%;未测出差向异构中心的立体化学)。差向异构体A:1H-NMR(400MHz,MeOD):δ7.82(dd,1H,J 1.3Hz,8.0Hz),7.31(m,2H),7.14(m,1H),7.04(m,1H),6.96(m,3H),5.20(m,1H),4.40(m,1H),4.11(bd,2H),3.79-4.05(m,5H),3.73(dd,1H,J 5.2Hz,12.5Hz),3.43(dd,1H,J 2.6Hz,13.0Hz),2.80(m,1H),2.18(s,3H),2.12(m,1H)。MS-APCI+:m/z 435[MH+]差向异构体B:1H-NMR(400MHz,MeOD):δ7.79(dd,1H,J 1.3Hz,7.9Hz),7.32(m,2H),7.14(m,1H),7.04(m,1H),6.97(m,3H),5.18(m,1H),4.49(m,1H),3.83-4.19(m,7H),3.69(dd,1H,J 4.8Hz,13.2Hz),3.34(m,1H),2.72(m,1H),2.18(s,3H),2.07(m,1H)。MS-APCI+:m/z 435[MH+]实施例220N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基-2-甲基丙氧基}苯基)乙酰胺盐酸盐i)N-{2-[(2-甲基-2-丙烯基)氧基]苯基}乙酰胺
根据实施例8(i)中描述的类似方法,用3-氯代-2-甲基丙烯(1.09g,11.9mmol)和2-乙酰氨基苯酚(1.50g,9.92mmol)制备该化合物(1.74g,85%)。1H-NMR(400MHz,CDCl3):δ8.36(dd,1H,J1.7Hz,7.8Hz),7.80(bs,1H),6.98(m,2H),6.87(dd,1H,J 1.6Hz,7.9Hz),5.08(s,1H),5.04(s,1H),4.51(s,2H),2.21(s,3H),1.85(s,3H)。ii)N-{2-[(2-甲基-2-环氧乙烷基)甲氧基]苯基}乙酰胺
根据实施例8(ii)中描述的类似方法,用N-{2-[(2-甲基-2-丙烯基)氧基]苯基}乙酰胺(800mg,3.90mmol)和间氯代过苯甲酸(80%,1.10g,5.22mmol)制备该化合物(0.56g,65%)。1H-NMR(400MHz,CDCl3):δ8.36(m,1H),8.01(bs,1H),7.01(m,2H),6.91(m,1H),4.07(m,2H),2.96(d,1H,J 4.8Hz),2.79(d,1H,J 4.8Hz),2.22(s,3H),1.49(s,3H)。iii)N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基-2-甲基丙氧基}苯基)乙酰胺盐酸盐
根据实施例1(iii)中描述的类似方法,用N-{2-[(2-甲基-2-环氧乙烷基)甲氧基]苯基}乙酰胺(123mg,0.557mmol)和3-(4-氯代苯氧基)吡咯烷(100mg,0.506mmol)制备题述化合物(255mg,110%)。1H-NMR(400MHz,MeOD):δ7.61(m,1H),7.29(m,2H),7.18(m,1H),7.10(m,1H),6.96(m,3H),5.18(m,1H),3.91-4.22(m,4H),3.37-3.76(m,4H),2.66(m,1/2H),2.37(m,1H),2.25(m,1/2H),2.15(m,3H),1.45(m,3H)。MS-APCI+:m/z 419[MH+]用于实施例221-230的原料的通用制备方法制备环氧化物:A)N-(2-{[(2S*,3S*)-3-甲基环氧乙烷基]甲氧基}苯基)乙酰胺i)N-{2-[(E)-1-丙烯基氧基]苯基}乙酰胺
将市售提供的1-氯代-2-丁烯(Aldrich,主要是反式)(453mg,0.49ml,5.00mmol)、2-乙酰氨基苯酚(756mg,5.00mmol)和碳酸钾(691mg,5.00mmol)的丙酮(10ml)非均相混合液加热回流过夜。蒸发溶剂后,将残留物吸收至乙酸乙酯和水中。将有机相用水、5%氢氧化钠和盐水洗涤,蒸发溶剂,得到粗产物,并将该粗产物经硅胶快速层析纯化(己烷/EtOAc=3∶2)。得到732mg(71%)的棕黄色固体。反式∶顺式=81∶19(根据1H-NMR(400MHz,CDCl3测定比率)。MS-APCI+:m/z 206.1[MH+]ii)将间氯过苯甲酸(70%;270mg,1.92mmol,2.0当量)加入到冰浴冷却的溶于二氯甲烷(3ml)中的化合物i)(112mg,546μmol)的溶液中,不需再冷却下,搅拌过夜。加入乙酸乙酯后,将混合液用饱和亚硫酸钠、5%氢氧化钠和盐水洗涤。经硫酸钠干燥,蒸发溶剂,经硅胶快速层析纯化,得到86mg(71%)的产物,为米色固体,1H-NMR测定的反式:顺式比率为83∶17。1H-NMR(400MHz,CDCl3;仅给出主要异构体的信号):δ8.35(1H,m),7.90(1H,br.s),7.00(2H,m),6.88(1H,m),4.30(1H,dd,J 11.4,2.5Hz),3.96(1H,dd,J 11.4,5.7Hz),3.08(2H,m),2.21(3H,s),1.40(3H,d,J5.2Hz)。MS-APCI+:m/z 222.1[MH+]B)N-(2-{[(2S,3R)-3-甲基环氧乙烷基]甲氧基}苯基)乙酰胺i)N-[2-(2-丁炔基氧基)苯基]乙酰胺
将1-溴代-2-丁炔(1.39g(10.4mmol))、2-乙酰氨基苯酚(1.58mg,10.4mmol)、无水碳酸钾(1.44g,10.4mmol)和碘化钾(30mg)的丁酮(50ml)混合液加热回流过夜。然后将反应混合液过滤,蒸发滤液,将得到的残留物溶于乙酸乙酯中。将得到的溶液用5%氢氧化钠、盐水和水洗涤,经硫酸钠干燥,蒸发。粗产物用庚烷/MTB(1∶1)重结晶,得到1.57g(74%)的浅棕色针状物MS-APCI+:m/z 204.1[MH+]ii)N-{2-[(Z)-2-丁烯基氧基]苯基}乙酰胺
在室温、大气压力下,将炔i)(357mg,1.76mmol)和5%Pd/BaSO4(22mg)的吡啶(2.0ml)混合液氢化2小时30分钟。此时原料已完全消耗掉,LC/MS观测到一些对应烷烃的过度还原产物。将反应混合液通过硅藻土过滤,用乙酸乙酯充分洗涤。然后将该滤液用1N HCl洗至酸性,最后用盐水洗至中性。经硫酸钠干燥,蒸发溶剂,得到318mg(88%)的粗产物,其除含有所要求的Z-烯烃外,还含有一些E-烯烃和作为副产物的对应的烷烃。根据1H-NMR(400MHz,CDCl3)测定的比率是E∶Z∶烷烃=83∶10∶7。粗产物不经进一步纯化直接用于下一步。MS-APCI+:m/z 206.1[MH+]iii)将烯烃ii)(310mg,1.51mmol)溶于二氯甲烷(10ml)中,在0℃下,加入间氯过苯甲酸(80%;587mg,2.72mmol,1.8当量)。室温下搅拌过夜,接着蒸发溶剂,得到的残留物溶于乙酸乙酯,用饱和亚硫酸钠、5%氢氧化钠和盐水洗涤,经硫酸钠干燥。蒸发溶剂,经硅胶快速层析(乙酸乙酯/庚烷=2∶1持续至乙酸乙酯),得到269mg(81%)的环氧化物,E∶Z比率为82∶18(经1H-NMR测定),为白色粉末。1H-NMR(400MHz,CDCl3;仅给出主要异构体的信号):δ8.37(1H,dd,J 7.5,2.1Hz),7.81(1H,br.s),7.02(2H,m),6.91(1H,dd,J 7.4,1.7Hz),4.32(1H,dd,J 11.1,3.6Hz),4.03(1H,dd,J 11.1,6.9Hz),3.33(1H,dt,J 7.0,4.0Hz),3.24(1H,dt,J 9.9,5.5Hz),2.21(3H,s),1.38(3H,d,J 5.7Hz)。MS-APCI+:m/z 222.1[MH+]C)N-{2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺i)(2-环戊烯-1-基氧基)(三异丙基)硅烷
室温下,将2-环戊烯醇(K.Alder,F.H.Flock,Che m.Ber.1956,89,1732.)(2.31g,27.5mmol)、(三异丙基)氯硅烷(5.30g,5.9mL,27.5mmol)、咪唑(2.06g,30.2mmol)的DMF(50ml)溶液搅拌3小时,再在50℃下搅拌1小时。然后将该溶液用乙酸乙酯稀释,用水洗涤4次,经硫酸钠干燥。蒸发溶剂得到6.32g(96%)的甲硅烷基醚513/13,为无色液体。1H-NMR波谱中未见主要杂质。1H-NMR(400MHz,CDCl3):δ5.88(1H,m),5.76(1H,m),4.98(1H,m),2.48(1H,m),2.27-2.17(2H,m),1.70(1H,m),1.12-1.05(21H,m)。ii)三异丙基[(1R,2R,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]硅烷
将间氯过苯甲酸(70%;5.41g,21.9mmol,1.7当量)加入到冰浴冷却的溶于二氯甲烷(25ml)中的化合物i)(3.10g,12.9mmol)的溶液中,不需再冷却下,再搅拌90分钟。过滤反应混合液后,蒸发滤液,将残留物溶于乙酸乙酯中,用饱和亚硫酸钠、5%氢氧化钠和盐水洗涤,经硫酸钠干燥。蒸发溶剂得到粗产物,为反式/顺式比率是78∶22的非对映体环氧化物(1H-NMR)。经硅胶快速层析分离(庚烷/乙酸乙酯=95∶5持续至90∶10),得到1.65g(50%)所要求的反-环氧化物(1R,2R,5R)*,为先洗脱的非对映体。两种非对映体环氧化物的总收率为2.86g(87%)。1H-NMR(400MHz,CDCl3):δ4.39(1H,d,J 3.4Hz),3.54(1H,d,J 2.5Hz),3.37(1H,d,J 2.5Hz),1.94(1H,m),1.84(dtd,J 13.7,9.3,1.1Hz),1.60-1.55(2H,m),1.13-1.04(21H,m)。iii)(1S,2R,5R)*-6-氧杂双环[3.1.0]己-2-醇
向甲硅烷基醚ii)(280mg,1.09mmol)的THF(2.0mL)溶液中,加入氟化四丁基铵(1.0M的THF溶液;1.2mL,1.20mmol)。室温下搅拌3小时后,将混合液用乙酸乙酯稀释,用盐水洗涤,经硫酸钠干燥。经硅胶层析过滤(庚烷/叔丁基甲醚2∶1持续至乙酸乙酯),得到79mg(72%)浅黄色油状物。1H-NMR(400MHz,CDCl3):δ4.36(1H,d,J 5.1Hz),3.55(1H,s),3.42(1H,d,J 1.5Hz),1.99(1H,m),1.84(1H,dddd,J 13.9,10.1,9.0,1.1Hz),1.69-1.53(3H,m)。iv)根据以下通用方法(I)制备题述化合物。1H-NMR(400MHz,CDCl3):δ 8.38(1H,m),7.91(1H,br.s),7.02-6.98(2H,m),6.94(1H,m),4.78(1H,td,J 8.0,1.2Hz),3.61(1H,m),3.54(1H,d,J 2.7Hz),2.21(3H,s),2.21(1H,m),2.10(1H,dt,J 12.8,12.0Hz),1.76(1H,dtd,J 14.3,10.4,1.4Hz),1.58(1H,m)。MS-APCI+:m/z 234.1[MH+]N-{2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺的制备通用方法(I)步骤1-Mitsunobu偶合:
向冰浴冷却的环氧乙醇546/16(1.0当量)、三苯基膦(1.2当量)和2-硝基苯酚(1.0当量)的无水THF(2mL/mmol)溶液中,滴加偶氮二甲酸二乙酯(1.2当量)。不再冷却下,继续搅拌过夜。经水溶液、碱性处理,接着经快速层析纯化(典型洗脱剂∶庚烷/乙酸乙酯=1∶1),得到2-硝基苯酚的酯,其中经常含有等摩尔量的副产物1,2-肼二甲酸二乙酯。步骤2-氢化:
在室温、大气压力下,将步骤1中得到的2-硝基苯酚酯、二异丙基(乙基)胺(2.0当量)、乙酸酐(2.0当量)和5%Pt/C(10mg/mmol)的乙酸乙酯(10mL/mmol)混合液氢化1小时。在有未卤化的芳族Pd/C情况下,可用更短的反应时间,一般约为5分钟。然后用填充硅藻土的过滤漏斗滤除催化剂,用乙醇洗涤。蒸发滤液,剩余的残留物经水溶液、碱性处理。然后经硅胶快速层析纯化(典型洗脱剂∶乙酸乙酯/庚烷=2∶1),得到各自的乙酰胺,一般收率为50-70%(2步)。D)N-{5-氯代-2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺
根据方法(I)制备。1H-NMR(400MHz,CDCl3):δ8.47(1H,d,J 2.5Hz),7.89(1H,br.s),6.97(1H,dd,J 8.8,2.5Hz),6.85(1H,d,J 8.8Hz),4.74(1H,td,J 8.0,1.3Hz),3.58(1H,m),3.56(1H,m),2.21(1H,m),2.21(3H,s),2.09(dt,J 13.0,7.4Hz),1.76(1H,dtd,J 14.3,10.1,1.3Hz),1.56(1H,m)。MS-APCI+:m/z 268.0[MH+]E)N-{4-氟代-2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺
根据方法(I)制备。1H-NMR(400MHz,CDCl3):δ8.23(1H,dd,J 10.7,2.8Hz),7.99(1H,m),6.89(1H,dd,J 9.0,5.5Hz),6.69(1H,ddd,J 11.1,9.0,3.1Hz),4.70(1H,t,J7.8Hz),3.56(2H,s),2.21(1H,dd,J 14.7,8.4Hz),2.21(3H,s),2.08(1H,dt,J13.0,8.2Hz),1.75(1H,dtm,J 14.3,9.5Hz)。MS-APCI+:m/z 252.1[MH+]将氨基环化物加入到取代的2-(芳氧基甲基)环氧乙烷中的通用方法(II)
在密闭管中,将溶解于LiClO4的饱和乙腈溶液(1ml/100μmol)中的等摩尔量的氨基环化物和环氧化物加热至100℃。反应时间一般为从形成开链的环氧化物的3小时至形成氧杂双环[3.1.0]己烷的18小时之间。冷却至室温后,将反应混合液用乙酸乙酯稀释,再进行水溶液处理。通常可定量得到粗产物,经硅胶快速层析纯化(典型洗脱剂∶乙酸乙酯/甲醇=80∶20)。
根据通用方法(I)和(II),制备下列实施例221-230。实施例221N-(2-{(1S*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ8.20(1H,d,J 7.4Hz),8.07(1H,br.s),7.21(2H,m),7.01-6.96(2H,m),6.92(1H,dm,J 7.4Hz),6.77(2H,dm,J8.8Hz),4.77(1H,m),4.54(1H,br.q,J 4.8Hz),4.15(1H,m),3.04-2.91(3H,m),2.81(1H,q,J 6.8Hz),2.62(1H,五重峰,J 7.3Hz),2.29(1H,m),2.16(3H,s),2.13-1.90(5H,m),1.63(1H,m)。MS-APCI+:m/z 431.2[MH+]实施例222N-(2-{(1R*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ8.26(1H,m),7.90(1H,br.d,J 9.5Hz),7.20(2H,m),6.97(2H,m),6.88(1H,br.d,J 7.3Hz),6.76(2H,m),4.76(1H,m),4.50(1H,m),4.21(1H,dt,J 14.1,5.5Hz),3.00-2.89(3H,m),2.67-2.54(2H,m),2.28(1H,m),2.15(3H,s),2.11(1H,m),1.97(2H,m),1.87(2H,m)。MS-APCI+:m/z 431.2[MH+]实施例223N-(2-{(2R*,3R*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ 8.27(1H,dd,J 7.6,1.6Hz),8.07(1H,br.s),7.30(1H,d,J 8.8Hz),7.04-6.92(4H,m),6.74(1H,dd,J 8.8,2.9Hz),4.26(1H,m),4.23(1H,dd,J 9.9,2.7Hz),4.06(1H,m),3.96(1H,dd,J 9.9,8.0Hz),2.86-2.72(3H,m),2.58(1H,m),2.47(1H,m),2.18(3H,s),1.99(2H,m),1.80(2H,m),1.12(3H,d,J 6.9Hz)。MS-APCI+:m/z 469.1[MH+]实施例224N-(2-{(1S*,2R*,3S*)-3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ8.26(1H,m),8.20(1H,br.s),7.19(2H,m),7.02(2H,m),6.95(1H,m),6.84(2H,m),4.49(1H,q,J 5.2Hz),4.31(1H,m),4.15(1H,m),2.95(2H,q,J 7.8Hz),2.87(1H,m),2.51(2H,br.q,J 10.2Hz),2.19(3H,s),2.10-1.95(5H,m),1.86(2H,m),1.60(1H,m)。MS-APCI+:m/z 445.0[MH+]实施例225N-(2-{(2R*,3S*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ 8.47(1H,br.s),8.36(1H,dd,J 7.2,1.3Hz),7.32(1H,d,J 9.0),7.04-6.93(4H,m),6.75(1H,dd,J 9.0,2.9Hz),4.34(1H,m),4.11(1H,m),3.96(1H,dd,J 10.5,5.2Hz),3.66(1H,m),3.00-2.80(2H,m),2.71(2H,m),2.42(1H,m),2.19(3H,s),2.05(1H,m),1.94-1.81(2H,m),1.08(3H,d,J 6.7Hz)。MS-APCI+:m/z 466.9[MH+]实施例226N-(2-{(2R*,3R*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ8.34(1H,t,J 4.5Hz),8.18(1H,br.s),7.22(2H,m),6.99(2H,m),6.93(1H,m),6.76(2H,m),4.78(1H,m),4.20(1H,m),4.07(1H,dt,J 10.1,2.9Hz),3.95(1H,dd,J 10.1,8.2Hz),3.15(0.5H,dd,J 10.7,6.1Hz),2.97-2.94(1.5H,m),2.89(0.5H,q,J 7.6Hz),2.82(0.5H,dd,J 10.5,2.5Hz),2.73(0.5H,qm,J 7.5Hz),2.65(0.5H,m),2.58(1H,m),2.26(1H,m),2.01(1H,m),1.09(3H,显示为dd,J 6.7,1.7Hz)。MS-APCI+:m/z 419.1[MH+]实施例227N-(2-{(2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ 8.48(1H,m),8.37(1H,m),7.22(2H,m),7.04-6.93(3H,m),6.77(2H,m),4.80(1H,m),4.12(1H,m),3.97(1H,dd,J10.5,5.3Hz),3.65(1H,m),3.09(0.5H,dd,J 10.3,6.0Hz),3.09-2.99(1.5H,m),2.94(0.5H,q,J 8.0Hz),2.87-2.67(2.5H,m),2.25(1H,m),2.02(1H,m),1.05(3H,显示为dd,J 6.7,5.2Hz)。MS-APCI+:m/z 418.9[MH+]实施例228N-(2-{(1S*,2R*,3S*)-3-[4-(3-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400MHz,CDCl3):δ8.25(1H,m),8.17(1H,br.s),7.18(1H,t,J8.1Hz),7.01(2H,m),6.97-6.90(3H,m),6.79(1H,dm,J 9.0 Hz),4.48(1H,q,J 5.5Hz),4.34(1H,七重峰,J 3.5Hz),4.15(1H,dd,J 7.2,5.5Hz),2.95(2H,q,J 7.4Hz),2.87(1H,m),2.52(2H,br.q,J 9.6Hz),2.19(3H,s),2.09-1.94(6H,m),1.86(2H,m),1.59(1H,m)。MS-APCI+:m/z 445.1[MH+]实施例229N-[5-氯代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺1H-NMR(400MHz,CDCl3):δ8.38(2H,m),7.31(1H,d,J 8.7Hz),6.99(1H,d,J 8.8Hz),6.95(1H,dd,J 8.8,2.6Hz),6.86(1H,d,J 8.8Hz),6.75(1H,dd,J 8.8,2.9Hz),4.38(1H,q,J 4.0Hz),4.31(1H,七重峰,J3.7Hz),4.10(1H,dd,J≈7.6Hz),3.00(1H,q,J 7.1Hz),2.91-2.82(1H,m),2.53(2H,m),2.17(3H,s),2.08-1.93(5H,m),1.85(2H,m),1.60(1H,m)。MS-APCI+:m/z 513.1[MH+]实施例230N-[4-氟代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺1H-NMR(400MHz,CDCl3):δ8.58(1H,br.s),8.19(1H,dd,J 10.9,3.2Hz),7.3 1(1H,d,J 8.8Hz),7.00(1H,d,J 2.9Hz),6.89(1H,dd,J 9.0,5.2Hz),6.75(1H,dd,J 9.0,2.9Hz),6.67(1H,td,J 8.8,3.1Hz),4.35-4.29(2H,m),4.09(1H,dd,J 7.8,5.0Hz),3.04(1H,q,J 7.8Hz),2.88(2H,m),2.54(2H,m),2.18(3H,s),2.08(5H,m),1.85(2H,m),1.61(1H,m)。MS-APCI+:m/z 497.2[MH+]实施例231-248的原料的制备A)(S*R*)-1-(3,4-二氯代苄基)-2,5-二甲基-哌嗪
将1,2-二氯代-4-氯甲基-苯(1.1ml,7.89mmol)的DMF(5ml)溶液加入到溶于DMF(25ml)中的2,5-二甲基-哌嗪(1.0g,8.77mmol)中。将反应物搅拌过夜,倒入EtOAc和碳酸钠(5%)的混合液中。将水相用EtOAc洗涤2次,将合并的有机相用盐水洗涤一次,经硫酸钠干燥。蒸发后,将粗产物溶于甲醇中。二苄基化的哌嗪不溶解。将滤液通过短硅胶柱过滤,用甲醇作为洗脱剂,蒸发得到纯产物。收率:812mg,38%。1H-NMR(400MHz,DMSO-d6):δ7.56(d,1H,J=8.1Hz),7.52(d,1H,J=1.8Hz),7.20(dd,1H,J=8.2,1.8Hz),3.97(d,1H,J=14.1Hz),3.04(d,1H,J=14.2Hz),2.76(dd,1H,J=11.9,3.0Hz),2.59(m),2.48(dd,1H,J=11.9,2.6Hz),2.37(t,1H,J=10.8Hz),2.12(m),1.89(s),1.57(t,1H,J=10.4Hz),1.00(d,1H,J=6.1Hz),0.82(d,1H,J=6.3Hz)。APCI-MS:m/z 273[MH+]B)(S*R*)-1-(4-二氯代-苄基)-2,5-二甲基-哌嗪
按照A)中相同的方法,由1-氯代-4-氯甲基-苯(1.27g,7.89mmol)和2,5-二甲基哌嗪(1.0g,8.77mmol)在DMF中的溶液合成。收率:701mg.37%。1H-NMR(400MHz,DMSO-d6):δ7.36(d,2H,J=8.4Hz),7.30(d,2H,J=8.4Hz),3.97(d,1H,J=13.9Hz),3.01(d,1H,J=13.8Hz),2.75(dd,1H,J=11.9,3.0Hz),2.57(m,1H,J=10.8,2.6Hz),2.47(dd,1H,J=10.9,2.6Hz),2.36(dd,1H,J=11.6,10.1Hz),2.10(m,1H),1.88(bs,1H),1.53(t,1H,J=10.5Hz),1.01(d,3H,J=6.1Hz),0.80(d,3H,J=6.4Hz)。APCI-MS:m/z 239[MH+]C)1-(3,4-二氯代苄基)哌嗪
室温下,将3,4-二氯代苄基氯(170mg,0.872mmol)加入到哌嗪(150mg,1.74mmol)和三乙胺(1ml)的DMF(10ml)溶液中。2小时后,真空浓缩该溶液。将得到的残留物在乙醚中研磨,将得到的固体用水洗涤,然后溶解于甲醇中,与甲苯共蒸发,得到固体产物89mg。APCI-MS:m/z 245,247[MH+]1H-NMR(400MHz,CD3OD):δ7.41(d,1H,J=2.0Hz),7.37(d,1H,J=8.2Hz),7.13(dd,1H,J=8.2Hz,J=2.0Hz),3.5(s,2H),3.05(m,4H),2.57(m,4H)。D)1-(4-氯代苄基)哌嗪
根据以上C)类似的方法制备。实施例231N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-苯基)乙酰胺二盐酸盐
将N-乙酰基-2-(2,3-环氧丙氧基)苯胺(87.53mg,0.422mmol)和1-(3,4-二氯代苄基)哌嗪的乙醇(10ml,99.5%)溶液回流3小时。减压蒸发去溶剂,得到的残留物经硅胶柱层析纯化(二氯甲烷/甲醇20∶1),得到题述化合物,为胶状物。加入1.0M醚化HCl溶液,得到固体产物78mg(40%)。APCI-MS:m/z 452,454[MH+]1H-NMR(400MHz,CD3OD):δ8.00(1H,dd,J=1.53Hz,J=8.01Hz),7.5(1H,d,J=1.91Hz),7.45(1H,d,J=8.2Hz),7.23(1H,dd,J=6.1Hz,J=2.1Hz),6.89-7.08(4H,m),4.15(1H,m),3.9-4.1(2H,m),3.48(2H,s),2.45-2.60(10H,m),2.17(3H,s)。根据实施例231方法,用以上原料A)-D)合成实施例232-248。实施例232N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺APCI-MS:m/z 470[MH+]实施例233N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基乙酰胺APCI-MS:m/z 480[MH+]实施例234N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 486[MH+]实施例235N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 480[MH+]实施例236N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 494[MH+]实施例237N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺APCI-MS:m/z 498[MH+]实施例238N-(2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 480[MH+]实施例239N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 446[MH+]实施例240N-(5-氯代-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 514[MH+]实施例241N-(5-氯代-2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 480[MH+]实施例2421-(5-氯代-2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}苯基)-1-乙酮APCI-MS:m/z 451[MH+]实施例243N-(5-氰基-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 505[MH+]实施例244N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺APCI-MS:m/z 471[MH+]实施例245N-(5-氯代-2-{3-[4-(4-氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 452[MH+]实施例246N-(4-氯代-2-{3-[4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺APCI-MS:m/z 460[MH+]实施例247N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺APCI-MS:m/z 457[MH+]实施例248N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺APCI-MS:m/z 446[MH+]实施例249N-[5-氯代-2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺MS-APCI+:m/z 464.9[MH+][α]22=-47.6(CH2C2)实施例250N-{2-[(2S)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺APCI-MS:m/z 423.1[M+]实施例251N-[2-({(2S)-3-[(3S)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐i)3-(4-氯代苄基)吡咯烷
在N2下,用两三分钟的时间,向搅拌着的3-(4-氯代苄基)-2-吡咯烷酮(420mg,2mmol)的无水THF(25mL)溶液中,分次加入LAH(190mg,5mmol)。将温度升高至60℃,继续搅拌2.5小时。将混合液用200μL水、200μL 5M NaOH和600μL水猝灭。滤除固体LI-和Al-盐,蒸发滤液得到无色油状物(387mg,99%)。APCI-MS:m/z 196,198[MH+]ii)(2S)-1-[3-(4-氯代苄基)-1-吡咯烷基]-3-(2-硝基苯氧基)-2-丙醇
将化合物(i)(387mg,2mmol)和(2S)-2-[(2-硝基苯氧基)-甲基]环氧乙烷(390mg,2mmol)的乙醇(6mL)溶液回流,直至通过LCMS测得反应完成(2h)。蒸发溶剂得到橙色油状物(650mg,83%),该油状物不经进一步纯化使用。APCI-MS:m/z 391,393[MH+]iii)(2S)-1-(2-氨基苯氧基)-3-[3-(4-氯代苄基)-1-吡咯烷基]-2-丙醇
在60℃下,向化合物(ii)(650mg,1.67mmol)的乙醇(10mL)溶液中,加入二水合氯化锡(II)(2.25g,10mmol)和35%盐酸(2.5mL)。温度快速升至75℃。在60℃下,将混合液再搅拌30分钟。蒸发溶剂后,将残留物用5M NaOH和乙醚萃取。将有机相用水洗涤,干燥和蒸发。残留物经RP-HPLC纯化,用含0.1%TFA的乙腈和水作为流动相。将适当的部分蒸发,将残留物用1M NaOH和乙醚萃取。从有机相中得到题述化合物的无色油状物(400mg,66%)。APCI-MS:m/z 361,363[MH+]iv)向化合物(iii)(400mg,1.1mmol)的DCM(10mL)溶液中,加入乙酸酐(200μL,2.1mmol),将混合液放置过夜。蒸发后,将残留物溶于甲醇中,加入1.5M甲醇钠的甲醇(2mL)溶液。将混合液放置2小时,蒸发,并溶于乙醚和水中。从有机相中得到两种非对映体的混合液。经手性柱HPLC分离该非对映体,用异己烷、2-丙醇和甲醇混合液作为流动相。将分离的对映体溶于甲醇(1mL)中,用1M盐酸(1mL)酸化,用水稀释,冷冻干燥得到题述化合物的白色无定形固体(156mg和173mg)。未测定出绝对立体异构构型。APCI-MS:m/z 403,405[MH+]实施例252N-(5-氯代-2-{3-[3-(4-氯代苄基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐i)3-(4-氯代-苄基)-吡咯烷-2-酮
在烧瓶中加入二异丙胺(3.22g,31.8mmol)和无水THF(60ml)。将所述烧瓶中的内容物保持在氮气下,然后冷却至-76℃。向该冷却的溶液中滴加正丁基锂(n-BuLi,32mmol,20ml,1.6M己烷溶液)。加入完毕后,将溶液搅拌10分钟,再滴加1-三甲基甲硅烷基-吡咯烷-2-酮(5.00g,31.8mmol,根据文献方法制备)的无水THF(5ml)溶液。然后再将该溶液搅拌20分钟,在5分钟内,通过注射器加入4-氯代苄基氯(5.13g,32mmol)的THF(5ml)溶液。在-76℃下,将得到的混合液搅拌1小时,然后使温度达到室温,搅拌过夜。加入水(40ml),将混合液剧烈搅拌60分钟。分离两相,将有机相用盐水洗涤,最后蒸发,得到油状物,放置结晶。将该固体用己烷∶EtOAc 2∶1研磨,过滤,得到部分纯的固体。该固体经硅胶纯化(DCM至DCM∶MeOH 99∶1至98∶2至97∶3梯度),得到1.3g(20%)的题述化合物。1H-NMR(400MHz,CDCl3):δ7.27(2H,d,J 8.4Hz),7.16(2H,d,J 8.4Hz),5.43(1H,bs),3.31-3.13(3H,m),2.74-2.61(2H,m),2.20-2.12(1H,m),1.88-1.77(1H,m)。ii)3-(4-氯代-苄基)吡咯烷
在烧瓶中,将a)中得到的化合物(0.20g,0.95mmol)溶于无水THF(10ml)中。在10分钟内,以少量多次加入LiAlH4(0.17g,4.53mmol)。加入完毕后,在氮气下,将混合液加热至60℃下约3小时,通过LC-MS监测反应,反应完成后,猝灭反应物。在猝灭之前,将反应物冷至室温,小心的滴入水(0.160ml)。滴加NaOH(10%水溶液,0.16ml),最后再加部分水(0.48ml)。将混合液搅拌1小时,然后过滤。真空浓缩滤液,得到副标题的化合物(0.18g,97%),为无色油状物。MS-APCI+:m/z 196.1[M+H]iii)N-(5-氯代-2-{3-[3-(4-氯代苄基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)乙酰胺三氟乙酸盐
根据实施例1 iii)中描述的方法,用ii)中得到的化合物制备题述的化合物。1H-NMR(400MHz,DMSO):δ9.93-9.62(1H,m),9.12(1H,s),8.11(1H,s),7.38(2H,d,J 8.9Hz),7.29-7.23(2H,m),7.13-7.02(2H,m),6.11-6.02(1H,m),4.29-4.16(1H,bs),4.05-3.95(1H,m),3.95-3.87(1H,m),3.75-3.50(2H,m),3.40-3.22(3H,m),2.91-2.65(3H,m),2.62-2.52(1H,m),2.13(3H,s),2.11-1.94(1H,m),1.81-1.55(1H,m)。实施例253N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-1-吡咯烷甲酰胺三氟乙酸盐i)2-[(5-甲基-2-硝基苯氧基)甲基]环氧乙烷
将5-甲基-2-硝基苯酚(7.7g,50mmol)、碳酸钾(13.8g,0.1mmol)和表溴代醇(8.25mL,0.1mmol)溶于DMF(100mL)中,在氮气气氛、100℃下,搅拌2-3小时。将混合液用乙醚(0.5L)稀释,用水萃取至pH=7。将有机相蒸发,残留物经硅胶快速层析纯化(DCM),得到题述的化合物,为黄色固体(8.65g,83%)。1H-NMR(400MHz,CDCl3):δ7.80(d,1H);6.91(s,1H);6.86(d,1H);4.39(dd,1H);4.15(dd,1H);3.43-3.37(m,1H);2.93(dd,1H);2.89(dd,1H);2.42(s,3H)。ii)1-[3-(4-氯代苯氧基)-1-吡咯烷基]-3-(5-甲基-2-硝基苯氧基)-2-丙醇
将化合物i)(1.05g,5.0mmol)和3-(4-氯代苯氧基)吡咯烷(988mg,5.0mmol)的乙醇(12mL)混合液回流2小时。蒸发溶剂得到粗产物,为橙色油状物,不经进一步纯化直接使用。APCI-MS:m/z 407,409[MH+]iii)1-(2-氨基-5-甲基苯氧基)-3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-丙醇
在50℃下,向搅拌着的化合物ii)(2.1g,5.0mmol)的乙醇(10mL)溶液中,加入二水合氯化锡(II)(5.6g,25mmol)的35%盐酸(6mL)溶液。开始放热反应,温度快速升至75℃。将混合液维持在60℃下0.5小时。将冷却的混合液用1M氢氧化钠(180mL)碱化,用乙醚萃取,将有机相用水洗涤,干燥,蒸发得到题述化合物的浅黄色油状物(1.34g,71%)。NMR:由于是两对非对映体的混合物,积分得到的是部分质子。1H-NMR(400MHz,CDCl3):δ7.23(d,2H);6.77(d,2H);6.67-6.65(m,1H);6.64-6.63(m,1H);4.83-4.76(m,1H);4.14-4.06(m,1H);4.01(d,2H);3.71(bs,2H);3.41(bs,1H);3.10(dd,0.5H);3.01-2.90(m,1.75H);2.87-2.70(m,2.7H),2.66-2.57(m,1.5H);2.28(h,1H);2.25(s,3H);2.06-1.95(m,1H)。APCI-MS:m/z 377,379[MH+]iv)N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-1-吡咯烷甲酰胺三氟乙酸盐
室温下,将化合物(iii)(75mg,0.2mmol)和三碳酸二叔丁基酯(53mg,0.2mmol)的DCM(3ml)溶液搅拌1小时。加入吡咯烷(33μl,0.4mmol),继续搅拌1小时。通过LCMS测定反应完成。加入TFA(1mL),将溶液放置1小时。蒸发挥发性部分,粗产物经制备RP-HPLC纯化,用含有0.1%TFA的乙腈和水为流动相。将适当的部分真空浓缩,将残留物冷冻干燥,得到题述化合物,为白色无定形固体(85mg,72%)。NMR:由于是两对非对映体的混合物,积分得到的是部分质子。数据是游离碱的数据。1H-NMR(400MHz,CDCl3):δ8.03(dd,1H);7.24(d,2H);6.94(bs,1H);6.82-6.74(m,2H);6.78(d,2H);6.73-6.68(m,1H);4.85-4.76(m,1H);4.11-3.94(m,3H);3.52-3.42(m,5.6H);3.11(dd,0.5H);3.05-2.92(m,0.45H);2.95(d,1H);2.87-2.72(m,2.5H);2.62-2.52(m,1.4H);2.37-2.21(m,0.7H);2.29(s,3H);2.08-1.90(m,4.6H)。APCI-MS:m/z 474,476[MH+]实施例254N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-羟基苯基)乙酰胺三氟乙酸盐
在室温、N2下,向搅拌着的以下实施例265 iii)化合物的游离碱(128mg,0.29mmol)的DCM(4ml)溶液中,加入1M三溴化硼的DCM(0.58mL,0.58mmol)溶液。将该非均相混合液搅拌过夜,倒入甲醇中。蒸发后,粗产物经制备RP-用HPLC纯化,用含有0.1%TFA的乙腈和水为流动相。将适当的部分冷冻干燥,得到题述化合物的白色无定形固体(113mg,73%)。APCI-MS:m/z 421,423[MH+]实施例255N-[2-({(2S)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐i)(2S)-2-[(5-氟代-2-硝基苯氧基)甲基]环氧乙烷
在烧瓶中加入(R)-缩水甘油(0.994g,13.4mmol)、三苯基膦(3.52g,13.4mmol)、THF(20ml,经分子筛干燥)和5-氟-2-硝基苯酚(2.10g,13.4mmol)。将混合液搅拌至形成均相溶液。将溶液冰浴冷却,用数分钟滴加偶氮二甲酸二乙酯(DEAD,2.11ml,13.4mmol)。加入完毕后,将烧瓶升至室温,再搅拌2小时。真空除去溶剂,向残留物中加入氯仿(5-10mi)。过滤除去沉淀(PPh3O),将固体再用氯仿(5-10ml)洗涤。将滤液加入到快速层析柱(Si2O,庚烷∶乙酸乙酯4∶1),纯化,将纯产物部分浓缩后得到2.02g(71%)题述化合物的结晶物质。1H-NMR(400MHz,CDCl3):δ7.97(1H,dd,J 9.3,6.0Hz);6.86(1H,dd,J10.0,2.5Hz);6.80-6.74(1H,m);4.44(1H,dd,J 11.4,2.6Hz);4.12(1H,dd,J 11.2,5.1Hz);3.44-3.38(1H,m);2.95(1H,t,J 4.5Hz);2.90(1H,dd,J 4.8,2.6Hz)。ii)(2S)-1-[4-(3,4-二氯代苯氧基)-1-哌啶基]-3-(5-氟代-2-硝基苯氧基)-2-丙醇
在管瓶中加入4-(3,4-二氯代苯氧基)-哌啶(0.123g,0.5mmol)和i)中得到的化合物(0.106g,0.5mmol)和乙醇(99.5%,3mL)。将管瓶密封,在65℃、搅拌下,将内容物加热3小时,LC-MS监测反应。将管瓶冷却,蒸发溶剂,得到油状物,经硅胶纯化(DCM至DCM∶MeOH 99∶1至98∶2至97∶3作为分级梯度)。将纯产物部分蒸发,得到0.22g(96%)题述化合物的油状物。APCI-MS(m/z):459.1[M+H]iii)N-[2-({(2S)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐
将ii)中得到的化合物(0.22g,0.48mmol)溶于乙醇(99.5%,7mL)中,搅拌下加热至60℃。加入SnCl2×2H2O(0.56g,5当量)的浓盐酸(0.63ml)溶液,在60℃下搅拌1小时。然后将混合液冷却。通过加入过量的2M NaOH碱化该溶液,将溶液用乙醚萃取(3×50ml)。将合并的乙醚溶液用盐水洗涤,蒸发。将得到的油状物溶于THF(8ml)中,加入水(8ml),接着加入乙酸酐(50ml,0.52mmol)。在40℃下,将混合液搅拌15分钟。真空除去有机溶剂,将残留物用EtOAc(3×30ml)萃取。将合并的有机相用盐水洗涤,然后真空浓缩。残留的油状物经制备HPLC纯化,得到55g(20%,98%纯度)的题述化合物的三氟乙酸盐,冷冻干燥纯产物部分后为白色固体。APCI-MS(m/z):471.0,472.0,473.0和474.0[M+H]实施例256N-(2-(3-(4-氯代-苯氧基)-吡咯烷-1-基)-2-羟基-丙氧基)-4,6-二氟代苯基)乙酰胺盐酸盐i)3,5-二氟代-6-硝基苯酚
向搅拌的2,3,4-三氟硝基苯(5g,28.23mmol)的无水甲醇(70ml)溶液中,加入钠(0.68g,29.46mmol)的无水甲醇(30ml)溶液。将所得溶液搅拌至原料完全消耗(~2h)。浓缩后,加入水,将该溶液用乙醚萃取,经Na2SO2干燥,过滤,浓缩得到黄色残留物(4.65g)。向该黄色残留物的二氯甲烷(140ml)溶液中加入三溴化硼(1M的二氯甲烷溶液,40ml),室温下搅拌过夜。然后加入水,将溶液再搅拌30分钟。分离有机相,将水相用乙醚萃取。合并的有机相经Na2SO2干燥,过滤,真空浓缩得到棕色残留物。将残留物溶于乙醚中,用2M氢氧化钠和水洗涤。合并水和氢氧化钠洗液,用6M HCl中和,用乙醚萃取,经Na2SO2干燥,蒸发得到黄色残留物,经硅胶快速层析纯化,用EtOAc∶庚烷1∶2为洗脱剂,得到所要求的产物2g,11.42mmol。GC-MS:m/z 175(M+)1H-NMR(400MHz,CD3OD):δppm 6.63-6.68(1H,m),6.60-6.67(1H,dt)。ii)2-[(3,5-二氟代-2-硝基苯氧基)甲基]环氧乙烷
向3,5-二氟代-2-硝基苯酚(100mg,0.571mmol)和碳酸钾(394mg)的DMF(5ml)混合液中,加入表溴代醇(80mg,0.582mmol),在70℃下搅拌3小时。加入水和乙酸乙酯,分离出有机相,干燥并浓缩。得到的残留物经层析纯化(乙酸乙酯∶庚烷1∶3),得到所要求的固体产物16 1mg(0.696mmol)。GC-MS:m/z 231(M+)iii)1-[3-(4-氯代苯氧基)-1-吡咯烷基]-3-(3,5-二氟代-2-硝基苯氧基)-2-丙醇
将3-(4-氯代苯氧基)吡咯烷和2-[(3,5-二氟代-2-硝基苯氧基)甲基]环氧乙烷(50mg,0.216mmol)的乙醇溶液回流3小时。减压蒸馏出溶剂,得到的残留物经硅胶柱层析纯化(二氯甲烷/甲醇20∶1),得到45mg(0.105mmol)的固体题述化合物。iv)N-(2-(3-(4-氯代-苯氧基)-吡咯烷-1-基)-2-羟基-丙氧基)-4,6-二氟代苯基)乙酰胺盐酸盐
将装载于碳上的氧化铂加入到1-[3-(4-氯代苯氧基)-1-吡咯烷基]-3-(3,5-二氟代-2-硝基苯氧基)-2-丙醇(40mg,0.0932mmol)的乙醇溶液中,在1atm下将所得的混合液氢化4小时。将混合液通过硅藻土过滤,用热乙醇洗涤数次,将合并的滤液真空浓缩。将得到的黄色残留物溶于二氯甲烷中,再向所得的溶液中加入乙酸酐。室温下将该溶液搅拌2小时,然后浓缩。加入1.0M醚化氯化氢溶液,生成20mg固体题述化合物。APCI-MS:m/z 441[MH+]实施例257N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐
根据以下实施例260中描述的方法,制备题述化合物。1H-NMR(400MHz,DMSO-d6):δ9.89(1H,bs);9.05(1H,s);7.79(1H,dd,J 8.8,6.6Hz);7.37(2H,d,J 9.6Hz);7.00-6.94(3H,m);6.75(1H,dt,J 8.6,2.6Hz);6.00(1H,bs);5.17-5.10(1H,m);4.32-4.20(1H,m);4.05(1H,dd,J 10.1,4.6Hz);3.97(1H,dd,J 9.9,5.7Hz);3.78-3.50(3H,m);3.47(1H,t,J 11.6Hz);3.17(1H,t,J 13.3Hz);2.83(1H,p,J 6.9Hz);2.07(3H,s);1.90-1.80(1H,m);1.42(3H,d,J 6.4Hz)。实施例258N-[2-({(2S)-3-[(3R)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐
根据实施例251中描述的方法制备。实施例259N-{2-[(2R)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺APCI-MS:m/z 423.1[M+]实施例260N-[2-({(2S)-3-[(2R,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺三氟乙酸盐i)(2S,4R)-4-羟基-1,2-吡咯烷二甲酸1-(叔丁基)2-甲酯
在烧瓶中,将(2S,4R)-4-羟基-脯氨酸盐酸盐(5.4g,30mmol)溶于THF(200ml)、水(170ml)和NaOH(30ml,2M水溶液,60mmol)的混合液中。向该乳液中加入二碳酸二叔丁基酯(Boc2O,6.54g,30mmol),将混合液剧烈搅拌1小时。加入乙醚(100ml),相分离。将水相再用100ml乙醚萃取。弃去水相,将合并的有机相用1M HCl(水溶液)、碳酸钾(饱和水溶液)和盐水洗涤。萃取物经Na2SO4干燥,真空浓缩得到残留物,该残留物经硅胶纯化(庚烷∶EtOAc 5∶1至3∶1至1∶1分级梯度,用I2/MeOH可见斑点)。真空浓缩纯产物部分,得到4.2g(57%)的题述化合物,为无色油状物。1H-NMR(400MHz,CDCl3):δ4.50(1H,bs);4.45-4.35(1H,m);3.74(3H,s);3.64(1H,dd,J 11.7,4.3Hz);3.59-3.42(1H,m);2.35-2.20(1H,m);2.14-2.03(1H,m);1.97(1H,dd,J 23.3,3.7Hz);1.44(9H,d,J 18.9Hz)。ii)(2S,4S)-4-(4-氯代苯氧基)-1,2-吡咯烷二甲酸1-叔丁基2-甲酯
在烧瓶中,在磁力搅拌下,将i)中得到的化合物(2.54g,10.3mmol)、三苯基膦(2.71g,10.3mmol)和4-氯苯酚(1.33g,10.3mmol)溶于THF(50ml,经分子筛干燥)中。将烧瓶在冰浴中冷却,在几分钟内,向该搅拌着的溶液中加入偶氮二甲酸二乙酯(DEAD,1.8g,10.3mmol)。将反应物放置过夜,让冰融化,反应物升至室温。蒸发溶剂,将残留物用乙醚(30ml)处理,使氧化磷沉淀。滤除固体,真空浓缩滤液。残留物经硅胶纯化(庚烷∶EtOAc 8∶1至6∶1至3∶1,分级梯度,用Seebach氏试剂在TLC上观测斑点)。浓缩纯产物部分,得到2.51g(68%)题述化合物的无色粘稠油状物。1H-NMR(400MHz,CDCl3):δ7.26-7.20(2H,m);6.77-6.70(2H,m);4.86(1H,bs);4.55(1/2H,dd,J 8.6,2.6Hz);4.43(1/2H,dd,J 7.6,3.9Hz);3.84-3.60(5H,m);2.53-2.36(2H,m);1.47(9H,d,J 18.2Hz)。iii)(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)-1-吡咯烷甲酸叔丁酯
在烧瓶中,将ii)中得到的化合物(0.951g,2.67mmol)溶于THF(10ml,经分子筛干燥)中。将该溶液在冰浴中冷却,加入LiBH4(0.09g,4.07mmol)。将混合液搅拌过夜,让冰融化,使溶液升至室温。然后将该粗混合液在EtOAc(100ml)和水(100ml)之间分配。弃去水相,将有机溶液用0.5M HCl(水溶液)、NaHCO3(饱和水溶液)和盐水洗涤。将该溶液蒸发,得到看似被无机盐污染的油状物。将其溶于DCM中,通过Celite过滤,得到0.82g(94%)题述化合物的无色油状物。1H-NMR(400MHz,DMSO-d6):δ7.33(2H,d,J 9.5Hz);6.95(2H,d,J9.5Hz);4.96(1H,bs);4.71(1H,bs);3.84-3.55(3H,m);3.32(2H,bs);2.29-2.07(2H,m);1.41(9H,s)。iv)(2S,4S)-4-(4-氯代苯氧基)-2-{[(甲磺酰基)氧基]甲基}-1-吡咯烷甲酸叔丁酯
在烧瓶中,将iii)中得到的化合物(0.82g,2.5mmol)溶于二氯甲烷(10ml,经分子筛干燥)中。将烧瓶在冰浴中冷却,用注射器加入三乙胺(0.69ml,5.0mmol)。用几分钟滴加甲磺酰氯(0.30ml,3.86mmol),将得到的混合液搅拌过夜,让冰融化。向该混合液中加入DCM(60ml),将该溶液用1M HCl(水溶液)、NaHCO3(饱和水溶液)和盐水洗涤。将该溶液蒸发,得到0.876g(86%)题述化合物的黄色油状物,该油状物不经进一步纯化直接用于下一步。1H-NMR(400MHz,DMSO-d6):δ7.3 5(2H,d,J 9.4Hz);6.99(2H,d,J9.4Hz);5.07-5.01(1H,m);4.37(1H,dd,J 8.9,4.2Hz);4.20-4.05(2H,m);3.71(1H,dd,J 11.8,5.0Hz);3.32(2H,s);3.15(3H,s);2.07(1H,d,J14.4Hz);1.41(9H,s)。v)(2R,4S)-4-(4-氯代苯氧基)-2-甲基-1-吡咯烷甲酸叔丁酯
在烧瓶中,将iv)中得到的化合物(0.876g,2.16mmol)溶于THF(10ml,经分子筛干燥)中。将反应混合液保持在惰性气体下,然后在冰浴中冷却。在15分钟内,通过注射器加入LiB(Et)3H(1M三乙基硼氢化锂的THF溶液,9ml,9mmol)。移去冰浴,将所得混合液搅拌过夜。将该粗混合液在EtOAc(100ml)和水(100ml)之间分配。弃去水相,将有机相用1M HCl(水溶液)、NaHCO3(饱和水溶液)和盐水洗涤。将该溶液蒸发,残留物经硅胶纯化(庚烷∶EtOAc 10∶1至5∶1至4∶1至2∶1梯度,用Seebach氏试剂观测TLC斑点),得到0.401g(60%)题述化合物的无色油状物。1H-NMR(400MHz,DMSO-d6):δ7.33(2H,d,J 8.7Hz);6.96(2H,d,J8.7Hz);5.00-4.94(1H,m);3.89(1H,bs);3.64(1H,dd,J 12.5,5.2Hz);3.38(1H,d,J 12.2Hz);2.41-2.28(1H,m);1.79(1H,d,J 13.7Hz);1.40(9H,s);1.23(3H,d,J 6.6Hz)。vi)(2R,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷三氟乙酸盐
在烧瓶中,将v)中得到的化合物(0.390g,1.25mmol)溶于二氯甲烷(DCM,15ml)中。向该溶液中加入TFA(三氟乙酸,6ml),将混合液放置3小时,然后真空除去挥发物。将残留物与DCM共蒸发2次,得到题述化合物的油状物。APCI-MSm/z:212[M+H]vii)N-[2-({(2S)-3-[(2R,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺三氟乙酸盐
根据实施例255中指出的方法,用vi)中得到的物质和(2S)-2-[(2-硝基苯氧基)甲基]环氧乙烷制备题述化合物。得到收率为25%的化合物。1H-NMR(400MHz,DMSO-d6):δ9.88(1H,bs);9.02(1H,s);7.89(1H,d,J 7.7Hz);7.37(2H,d,J 7.7Hz);7.09-6.88(5H,m);6.02(1H,bs);5.18-5.11(1H,m);4.34-4.22(1H,m);4.02(1H,dd,J 10.2,4.3Hz);3.94(1H,dd,J 9.8,5.7Hz);3.77-3.30(4H,m);3.19(1H,t,J 10.7Hz);2.84(1H,p,J6.7Hz);2.09(3H,s);1.91-1.81(1H,m);1.43(3H,d,J 6.4Hz)。APCI-MS:m/z 419.2[MH+]实施例261N-{2-[(2S)-(3-{(3R)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺APCI-MSm/z:423.1[M+]实施例262N’-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-N,N-二甲基脲三氟乙酸盐
根据实施例253中描述的类似方法,用iii)的化合物(75mg,0.2mmol)和二甲胺(2M的THF溶液,200μL,0.4mmol)制备题述化合物。得到的物质为白色无定形固体(73mg,65%)。1H-NMR(400MHz,MeOH-d4):δ7.54(dd,1H);7.51(d,2H);7.16和7.15(d,2H);7.05(bs,1H);6.96(bd,1H);5.40-5.35(m,1H);4.54-4.46(m,1H);4.27(d,2H);4.16-3.56(m,6H);3.20(bs,6H);2.84-2.59(m,1H);2.59-2.44(m,1H);2.50(s,3H)。APCI-MSm/z:448,450[MH+]实施例263N-(2-{3-[3-(4-氯代苯胺基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)乙酰胺i)3-羟基-1-吡咯烷甲酸叔丁酯
向3-羟基-1-吡咯烷(871mg,10mmol)的THF(30mL)溶液中加入二碳酸二叔丁酯(2.18g,10mmol)的THF(2mL)溶液,在室温下,将反应混合液搅拌过夜。真空除去溶剂,残留物经快速层析(0-2%MeOH的CHCl3溶液)纯化,得到题述化合物(1.7g)。1H-NMR(CDCl3,400MHz):δ4.45(m,1H);3.55-3.25(m,4H);2.18-1.85(m,3H);1.45(s,9H)。APCI-MS:m/z 166(M-Boc)ii)2-氧代-1-吡咯烷甲酸叔丁酯
将氧化铬(IV)(800mg,8.0mmol)加入到吡啶(1.6mL)的CH2Cl2(10mL)溶液中,在室温下,将得到的溶液搅拌15分钟。加入3-羟基-1-吡咯烷甲酸叔丁酯(374.5mg,2.0mmol)的CH2Cl2(5mL)溶液,随即加入乙酸酐,将反应混合液保持在室温下15分钟。加入乙酸乙酯,倾析,通过短硅胶柱过滤。浓缩滤液,得到题述产物(193mg),直接用于下一步。iii)3-(4-氯代苯胺基)-1-吡咯烷甲酸叔丁基酯
将2-氧代-1-吡咯烷甲酸叔丁酯(190mg,1.02mmol)、4-氯代苯胺(64mg,0.5mmol)和乙酸(184mg)在二氯乙烷(5mL)中混合。加入三乙酰氧基硼氢化钠(326.5mg),在室温下,将反应混合液搅拌过夜。加入NaHCO3水溶液后,往反应混合液中加入乙酸乙酯稀释。分离成两层。有机层经Na2S04干燥,过滤,浓缩。残留物经快速层析纯化(0-15%乙酸乙酯的石油溶剂油(40-60)溶液),得到题述产物(140mg)。1H-NMR(CDCl3,400MHz):δ7.18(m,2H);6.50(m,2H);3.99(m,1H);3.70(m,2H);3.46(m,2H);3.20(m,1H);2.18(m,1H);1.87(m,1H);1.45(s,9H)。APCI-MS:m/z 197(M-Boc)(iv)N-(4-氯代苯基)-3-吡咯烷胺(2×CF3COOH)
向3-(4-氯代苯胺基)-1-吡咯烷甲酸叔丁酯(130mg,0.438mmol)的CH2Cl2(5mL)溶液中,加入CF3COOH(1mL)。30分钟后,真空除去挥发物,得到题述产物(186mg),直接用于下一步。(v)N-(2-{3-[3-(4-氯代苯胺基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)乙酰胺
在65℃下,将N-(4-氯代苯基)-3-吡咯烷胺(2×CF3COOH)(186mg,0.438mmol)、N-[2-(2-环氧乙烷基甲氧基)苯基]乙酰胺(91mg,0.438mmol)和K2CO3(200mg)的乙醇(6ml)混合液搅拌2.5小时。真空除去挥发物。将残留物在乙酸乙酯和NH4Cl水溶液之间分配。将有机层用水洗涤,经Na2SO4干燥,过滤并浓缩。残留物经快速层析纯化(0-3%MeOH的CHCl3液),得到题述化合物(70mg)。1H-NMR(CDCl3,400MHz):δ8.35(m,1H);8.21(br.s,1H);7.12(m,2H);7.01(m,2H);6.92(m,1H);6.48(m,2H);4.13-3.92(m,4H);3.84(br.s,1H);2.99(m,1H);2.87-2.30(m,6H);2.18(s,3H);1.66(m,1H)。APCI-MS:m/z 446(MH+)实施例264N-{2-[(3-{3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基-1-甲基丙基)氧基]苯基}乙酰胺盐酸盐i)N-{2-[(1-甲基-2-丙烯基)氧基]苯基}乙酰胺
根据实施例8i)中描述的类似方法,用3-氯-1-丁烯(747ml,7.42mmol)和2-乙酰氨基苯酚(1.02g,6.75mmol)制备该化合物(557mg,40%)。1H-NMR(400MHz,CDCl3):δ8.37(m,1H);7.80(bs,1H);6.94(m,3H);5.93(m,1H);5.25(m,2H);4.84(m,1H);2.21(s,3H);1.49(d,J 6.3Hz,3H)。ii)N-{2-[1-(2-环氧乙烷基)乙氧基]苯基}乙酰胺
根据实施例8 ii)中描述的类似方法,用N-{2-[(1-甲基-2-丙烯基)氧基]苯基}乙酰胺(549ml,2.67mmol)和间氯过苯甲酸(80%,923mg,4.28mmol)制备该化合物。用石油醚/乙酸乙酯10/15为洗脱剂,经硅胶纯化。分离出两种非对映体对。非对映体1:(53mg,9%),Rf=0.27非对映体2:(406mg,69%),Rf=0.201H-NMR(400MHz,CDCl3):δ8.39(m,1H);8.01(bs,1H);7.00(m,3H);3.98(m,1H);3.24(m,1H);2.94(t,J 4.5Hz,1H);2.71(dd,J 2.6Hz,J4.5Hz,1H);2.23(s,3H);1.47(d,J 6.3Hz,3H)。iii)N-{2-[(3-{3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基-1-甲基丙基)氧基]苯基}乙酰胺盐酸盐
根据实施例1(iii)中描述的类似方法,用N-[2-(1-环氧乙烷基乙氧基)苯基]乙酰胺非对映体2(123mg,0.557mmol)和3-(4-氯代苯氧基)吡咯烷(100mg,0.506mmol)制备题述化合物。1H-NMR(400MHz,MeOD):δ7.86(m,1H),7.30(m,2H),7.09(m,2H),6.97(m,3H),5.21(m,1H),4.51(m,1H),3.82-4.22(m,3H),3.37-3.62(m,4H),2.68(m,1/2H),2.38(m,1H),2.27(m,1/2H),2.19(m,3H),1.32(m,3H)。MS-APCI+:m/z 419[MH+]实施例265N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲氧基苯基)乙酰胺盐酸盐i)1-[3-(4-氯代苯氧基)-1-吡咯烷基]-3-(5-甲氧基-2-硝基苯氧基)-2-丙醇
根据实施例253 ii)的类似方法,用2-[(5-甲氧基-2-硝基苯氧基)甲基]环氧乙烷(320mg,1.6mmol)和3-(4-氯代苯氧基)吡咯烷(365mg,1.6mmol)制备题述化合物。得到黄色油状物的粗产物(580mg),不经进一步纯化直接使用。APCI-MS:m/z 423,425[MH+]ii)1-(2-氨基-5-甲氧基苯氧基)-3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-丙醇
根据实施例253 iii)的类似方法,用化合物i)(290mg,0.7mmol)制备题述化合物。得到无色油状物的粗化合物(233mg,85%),不经进一步纯化直接使用。APCI-MS:m/z 393,395[MH+]iii)N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲氧基苯基)乙酰胺盐酸盐
向化合物(ii)(157mg,0.4mmol)的吡啶(3mL)溶液中,加入乙酸酐(1mL)。室温下,将所得混合液搅拌1小时。蒸发,然后将残留物溶于甲醇(mL)中,加入1.5M甲醇钠的甲醇溶液(1mL)。室温下将混合物放置过夜。蒸发,残留物溶于乙醚和水中。从有机相中得到题述化合物的游离碱,为无色油状物(171mg,98%)。将该游离碱(43mg)溶于甲醇(5mL)中,用1M盐酸酸化至pH<2,用水(50mL)稀释并冷冻干燥。得到题述化合物,为白色无定形物(30mg,64%)APCI-MS:m/z 435,437[MH+]实施例266N-(2-[3-(4-氯代-苄氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐i)3-(4-氯代-苄氧基)-吡咯烷-1-甲酸叔丁酯
将3-羟基-1-吡咯烷甲酸叔丁酯(0.27g,1.44mmol)的无水THF(4mL)溶液滴加到冷(0℃)、搅拌着的氢化钠(0.078g,2.17mmol,约50%油的混悬液)的THF(10mL)混悬液中。30分钟后,加入4-氯苄基溴(0.36g,1.74mmol)的THF(2mL)溶液,室温下,将得到的混悬液搅拌过夜。将反应混合液在水和乙酸乙酯之间分配。将水相用乙酸乙酯萃取,将合并的有机相用饱和氯化钠水溶液洗涤,干燥并浓缩。残留物经快速层析纯化(庚烷-乙酸乙酯,6∶1),得到题述化合物3-(4-氯代-苄氧基)-吡咯烷-1-甲酸叔丁酯的油状物(0.30g,66.8%)。1H-NMR(CDCl3):δ7.30(m,4H),4.49(bs,2H),4.11(m,1H),3.45(m,4H),1.90-2.08(m,2H),1.46(s,9H)。ii)3-(4-氯代-苄氧基)-吡咯烷
在0℃下,将3-(4-氯代-苄氧基)-吡咯烷-1-甲酸叔丁酯(0.28g,0.9mmol)的90%甲酸水溶液(7.5mL)搅拌30分钟,然后在室温下过夜。减压除去溶剂,将残留物用饱和碳酸钾水溶液处理,用正丁醇萃取2次。将合并的有机相浓缩,残留物经快速层析纯化(SiO2,二氯甲烷-甲醇-氢氧化铵,比率为8∶8∶1然后为50∶10∶1),得到题述化合物3-(4-氯代-苄氧基)-吡咯烷(0.13g,70%)。1H-NMR(DMSO-d6):δ7.32-7.41(m,4H),4.42(s,2H),4.02(m,1H),3.18(bs,2H),2.75-2.86(m,3H),2.68(m,1H),1.66-1.81(m,2H)。APCI-MS:m/z 212[MH+]iii)N-(2-[3-(4-氯代-苄氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐
在密闭管瓶中,在70℃下,将3-(4-氯代-苄氧基)-吡咯烷(0.050g,0.24mmol)和N-(2-环氧乙烷基甲氧基-苯基)-乙酰胺(0.049g,0.24mmol)的无水乙醇(3mL)溶液加热2小时。产物经HPLC纯化,得到题述化合物(0.60g,47%)1H-NMR(CD3OD):δ7.85(m,1H),7.35(m,4H),7.12(m,1H),7.02(d,1H,J=8Hz),6.96(m,1H),4.56(m,2H),4.39(m,2H),4.05(d,2H,J=5.9Hz),3.85(m,2H),3.48(m,4H),2.10-2.55(m,5H)。APCI-MS:m/z 419[MH+]和421[MH+2+]实施例267N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-2-甲基-丙氧基}苯基)乙酰胺
根据以下实施例270类似的方法制备该混合物。APCI-MS:m/z 419[MH+]实施例268N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-5-氯代-苯基)乙酰胺(非对映体混合物)
根据实施例271的方法,用N-{5-氯代-2-[(1R,2S,5S)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺(5.3mg,20μmol)和(3S)-3-(3,4-二氟代-苯氧基)-吡咯烷(4.0mg,20μmol)制备。MS-APCI+:m/z 467[M+]实施例269N-[2-({(2R,3S)*-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丁基}氧基)-4-甲基苯基]乙酰胺(非对映体混合物)
根据实施例271的方法,用N-(4-甲基-2-{[(2S,3R)*-3-甲基环氧乙烷基]甲氧基}苯基)乙酰胺(4.7mg,20μmol)和(3S)-3-(4-氯代-苯氧基)-吡咯烷(4.0mg,20μmol)制备。MS-APCI+:m/z 433[M+]实施例270N-{2-[(3-{4-[(3,4-二氯代苯基)氧基]-1-哌啶基}-2-羟基-2-甲基丙基)氧基]-4-氟代苯基}乙酰胺盐酸盐i)N-[4-氟代-2-(2-甲基-烯丙基氧基)-苯基]-乙酰胺
将3-氯代-2-甲基丙烯(1.36g,15mmol)加入到5-氟-2-硝基苯酚(1.57g,10mmol)、碳酸钾(2.76g,20mmol)、四丁基硫酸氢铵(0.068g,0.2mmol)和乙腈(30ml)混合液中,将所述混合液加热回流18小时。将冷却的反应混合液用甲苯稀释,用5%碳酸钾水溶液洗涤,干燥,蒸发。在75℃下,将部分残留物(0.631g,3mmol)、连二亚硫酸钠(1.04g,6mmol)的EtOH-THF-H2O(2∶1∶1,3ml)溶液加热4小时。将混合液在二氯甲烷和15%碳酸钾水溶液之间分配,将有机溶液干燥,浓缩。将得到的残留物用甲醇(1.5ml)稀释,并在50℃下与乙酸酐(1.5ml)反应2分钟,然后用20分钟时间使达到室温,加入吡啶(4ml),再在50℃下将该溶液加热3分钟,冷却并浓缩。得到物质经硅胶层析纯化(轻石油醚-乙酸乙酯2∶1),得到95mg题述化合物。1H-NMR(300Hz,CDCl3):δ8.28(dd,1H),7.62(bs,1H),6.70-6.60(m,2H),5.07(dd,2H),4.49(s,2H),2.20(s,3H),1.84(s,3H)。ii)N-(4-氟代-2-{[(2-甲基-2-环氧乙烷基)甲基]氧基}苯基)乙酰胺
根据实施例8 ii)中描述的类似方法,用N-[4-氟代-2-(2-甲基-烯丙基氧基)-苯基]-乙酰胺制备题述化合物。1H-NMR(300Hz,CDCl3):δ8.31-8.26(dd,1H),7.79(bs,1H),6.75-6.65(m,2H),4.14(d,1H),3.97(d,1H),2.93(d,1H),2.80(d,1H),2.21(s,3H),1.50(s,3H)。APCI-MS:m/z 240[MH+]iii)N-{2-[(3-{4-[(3,4-二氯代苯基)氧基]-1-哌啶基}-2-羟基-2-甲基丙基)氧基]-4-氟代苯基}乙酰胺盐酸盐
在密封管瓶中,在77℃下,将4-(3,4-二氯代-苯氧基)-哌啶(36mg,0.146mmol)、N-(4-氟代-2-{[(2-甲基-2-环氧乙烷基)甲基]氧基}苯基)乙酰胺(35mg,0.146mmol)的乙醇(1ml,95%)溶液搅拌2.5小时。蒸发溶剂,残留物经硅胶纯化(二氯甲烷-甲醇,15∶1,含1%的NH4OH(25%)),得到45mg题述化合物对应的游离胺。该题述化合物对应的游离胺的1H-NMR(400Hz,CDCl3):δ8.26-8.22(dd,1H),7.89(bs,1H),7.31(d,1H),7.01(d,1H),6.77-6.65(m,3H),4.30(m,1H),3.80(dd,2H),2.93-2.81(m,2H),2.67(d,1H),2.63-2.51(m,2H),2.45(d,1H),2.19(s,3H),1.96(m,2H),1.83(m,2H),1.62(bs,1H),1.31(s,3H)。iv)N-{2-[(3-{4-[(3,4-二氯代苯基)氧基]-1-哌啶基}-2-羟基-2-甲基丙基)氧基]-4-氟代苯基}乙酰胺盐酸盐
将上述游离胺的甲醇溶液(10ml)用HCl(浓,0.020ml)酸化至pH3,浓缩。将残留物与甲苯共蒸发3次,得到题述化合物的白色粉末。APCI-MS:m/z 485,487[MH+]实施例271N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-4-氟代-苯基)乙酰胺(非对映体混合物)
将N-{4-氟代-(2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-1-基氧基]苯基)乙酰胺(5.0mg,20μmol)和(3S)-3-(4-氯代-苯氧基)-吡咯烷(3.9mg,20μmol)溶于2M LiClO4的乙腈(0.2ml)溶液中,在密封管中加热至100℃。用乙酸乙酯稀释,中性溶液处理,蒸发溶剂得到粗产物,不经进一步纯化直接使用。MS-APCI+:m/z 449[M+]实施例272N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}苯基)-乙酰胺APCI-MS:m/z 441.1[MH+]实施例273N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺APCI-MS:m/z 423.1[MH+]实施例274N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺APCI-MS:m/z 477[MH+]实施例275N-(4-羟基-2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺(非对映体混合物)
i)将N-{4-甲氧基-2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-1-基氧基]苯基)乙酰胺(32mg,122μmol)和(3 S)-3-(4-氯代-苯氧基)-吡咯烷(24mg,122μmol)溶于2M LiCl04的乙腈(1ml)溶液中,在密封管中加热至100℃。用乙酸乙酯稀释,中性溶液处理,蒸发溶剂,得到62mg(110%)的粗加成产物,室温下使其与三溴化硼(1M的CH2Cl2溶液,0.37mL,371μmol)的二氯甲烷(1mL)反应过夜。将反应物用甲醇(1.0mL)猝灭,蒸发所有挥发性组分。剩余的粗产物经反相HPLC纯化,得到30mg(54%)题述化合物的非对映体混合物。MS-APCI+:m/z 447.1[MH+]
ii)非对映体的分离
将以上i)项下描述的非对映体混合物经手性相HPLC(固定相:Chiralpak AD;流动相:异己烷/异丙醇/甲醇/二乙胺=80∶16∶4∶0.1)分离,先洗脱出的立体异构体为实施例276的化合物,第二个洗脱出的立体异构体为实施例277化合物。各立体异构体下的绝对构型的分配(assignment)可按要求进行设定,这种分配是可以变化的。实施例276N-(4-羟基-2-{(1S,2R,3S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400Hz,CDCl3;OH-质子忽略):δ8.02(1H,s),7.49(1H,d,J8.4Hz),7.17(2H,d,J 8.9Hz),6.71(2H,d,J 8.8Hz),6.43(1H,s),6.34(1H,d,J 7.2Hz),4.76(1H,m),4.39(1H,m),4.09(1H,m),3.10-2.95(3H,m),2.89(1H,m),2.77(1H,m),2.24(1H,m),2.08(3H,s),2.10-1.84(3H,m),1.75(1H,m),1.59(1H,m)。MS-APCI+:m/z 447.1[MH+][α]22=+49.5(CH2C2)实施例277N-(4-羟基-2-{(1R,2S,3R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺1H-NMR(400Hz,CDCl3;OH-质子忽略):δ7.75(1H,s),7.60(1H,d,J8.4Hz),7.19(2H,d,J 8.3Hz),6.73(2H,d,J 8.6Hz),6.57(1H,s),6.38(1H,d,J 8.4Hz),4.77(1H,m),4.43(1H,m),4.21(1H,m),3.09-2.94(3H,m),2.79(1H,m),2.68(1H,m),2.28(1H,m),2.08(3H,s),2.05-1.90(3H,m),1.86(1H,m),1.53(1H,m)。MS-APCI+:m/z 447.1[MH+][α]22=-45.2(CH2C2)
根据用于制备实施例221-230化合物所用的类似的方法,制备实施例278和279的非对映体,并根据以上实施例275中的描述进行分离。各异构体的绝对构型可如以上描述按要求进行分配,因此是可以变化的。实施例278N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺先洗脱的异构体。MS-APCI+:m/z 431.1[MH+][α]22=+72.2(CH2C2)实施例279N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺第二次洗脱的异构体。MS-APCI+:m/z 431.1[MH+][α]22=-51.4(CH2C2)
根据用于制备实施例221-230的化合物所用的类似的方法,制备实施例280和249非对映体,并根据以上实施例275中的描述进行分离。实施例280化合物是先被洗脱出的异构体,实施例249化合物是第二种被洗脱出的异构体。各异构体的绝对构型可如以上描述按要求进行分配,因此是可以变化的。实施例280N-[5-氯代-2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺MS-APCI+:m/z 464.9[MH+][α]22=+53.0(CH2C2)实施例281N-{5-氯代-2-[((1S,2R,3S)*-3-{[1-(4-氯代苄基)-4-哌啶基]氨基}-2-羟基环戊基)氧基]苯基}乙酰胺(外消旋体混合物)
根据实施例271的方法,用N-{5-氯代-2-[(1R,2S,5R)*-6-氧杂双环[3.1.0]己-2-基氧基]苯基}乙酰胺(5.3mg,20μmol)和1-(4-氯代苄基)-4-哌啶胺(4.5mg,20μmol)制备。MS-APCI+:m/z 492[M+]实施例282N-[2-({(2S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丙基}氧基)-4-羟基苯基]乙酰胺i)(2S)-2-[(5-甲氧基-2-硝基苯氧基)甲基]环氧乙烷
在Mitsunobu条件下,采用无水THF作为溶剂,用(R)-(+)-缩水甘油(198mg,1mmol)、5-甲氧基-2-硝基苯酚(169mg,1mmol)、三苯基膦(263mg,1mmol)和DEAD(157μl,1mmol)制备题述化合物。粗产物经硅胶快速层析纯化,用乙酸乙酯和庚烷混合液作为流动相。收集适当的部分,得到不纯产物的白色晶体(175mg)。该产物被已还原的DEAD以摩尔比1∶1污染,这与所要求产物的收率100mg,44%一致。1H-NMR(400Hz,CDCl3):δ8.00(d,1H);6.60(d,1H);6.55(dd,1H);6.4(bs,1H,还原的DEAD);4.41(dd,1H);4.22(q,4H,还原的DEAD);4.13(dd,1H);3.89(s,3H);3.44-3.39(m,1H);2.95(dd,1H);2.92(dd,1H);1.29(t,6H,还原的DEAD)。APCI-MS:m/z 226[MH+]ii)(2S)-1-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-3-(5-甲氧基-2-硝基苯氧基)-2-丙醇
根据实施例1(ii)类似的方法,用(i)(169mg,0.43mmol)和(3S)-3-(4-氯代苯氧基)吡咯烷(85mg,0.43mmol)制备题述化合物。得到的产物为黄色油状物,不用进一步纯化直接使用。APCI-MS:m/z 423,425[MH+]iii)(2S)-1-(2-氨基-5-甲氧基苯氧基)-3-[(3S)-3-(4-氯代苯氧基)]-2-丙醇
根据实施例253 iii)的类似方法,用ii)(0.43mmol)制备题述化合物。得到的产物(无色油状物,163mg)是所要求产物与已还原的DEAD以摩尔比5∶1的混合物。产物不经进一步纯化直接使用。1H-NMR(400Hz,CDCl3):δ7.23(d,2H);6.77(d,2H);6.67(d,1H);6.49(d,1H);6.41(bs,还原的DEAD);6.39(dd,1H);4.83-4.77(m,1H);4.22(q,还原的DEAD);4.14-4.07(m,1H);4.01(d,2H);3.75(s,3H);3.01-2.91(m,2H);2.88-2.72(m,3H);2.62(dd,1H);2.29(六重峰,1H);2.06-1.96(m,1H);1.29(t,还原的DEAD)。APCI-MS:m/z 393,395[MH+]iv)N-[2-({(2S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丙基}氧基)-4-甲氧基苯基]乙酰胺
向化合物iii)(157mg)的乙腈(10mL)和水(2mL)混合液的溶液中,加入乙酸酐(1mL),室温下将混合液搅拌过夜。加入1.5M甲醇钠的甲醇溶液(1mL),继续搅拌1小时。蒸发,然后将残留物溶于乙醚和水中。从有机相中得到题述化合物,为无色油状物(155mg)。1H-NMR(400Hz,CDCl3):δ8.18(d,1H);7.95(bs,1H);7.24(d,2H);6.78(d,2H);6.56-6.52(m,2H);4.85-4.78(m,1H);4.22(q,还原的DEAD);4.10-4.02(m,2H);4.00-3.92(m,1H);3.78(s,3H);3.00-2.91(m,2H);2.87-2.73(m,3H);2.53(dd,1H);2.36-2.25(m,1H);2.17(s,3H);2.07-1.99(m,1H);1.29(t,还原的DEAD)。APCI-MS:m/z 435,437[MH+]V)N-[2-({(2S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丙基}氧基)-4-羟基苯基]乙酰胺
根据实施例254类似的方法,用iv)(150mg)制备题述化合物。冷冻干燥后得到产物,为白色无定形固体(101mg,57%)。1H-NMR(400Hz,CDCl3+1滴DMSO-d6):δ8.7(bs,1H);8.34(s,1H);8.73(d,1H);7.18(d,2H);6.73(d,2H);6.40-6.31(m,2H);4.99-4.93(m,1H);4.4-1.9(bm,6H);4.31-4.23(m,1H);3.88-3.78(m,2H);3.39-3.25(m,2H);2.4-2.2(m,2H);2.07(s,3H)。APCI-MS:m/z 421,423[MH+]THP-1趋化性试验
该试验测定人体单核细胞细胞系THP-1中MIP-1α趋化因子诱发的趋化响应。通过对标准浓度的MIP-1α趋化因子的趋化响应的抑制的能力测定,评估实施例的化合物。方法THP-1细胞的培养
在37℃下,将冷冻等份试样中的细胞快速解冻,然后再混悬于装有5ml培养基的25cm烧瓶中,该培养基为添加有不含抗生素的Glutamax和10%热灭活胎牛血清的RPMI-1640培养基(RPMI+10%HIFCS)。3日后,弃去培养基,加入新鲜培养基。
在添加有不含抗生素的10%热灭活胎牛血清和Glutamax的RPMI-1640培养基中,按常规培养THP-1细胞。细胞最适生长要求每3日将它们传代,并且最小传代培养物的密度为4×10+5细胞/毫升。趋化性试验
将细胞从烧瓶中取出,通过在RPMI+10%HIFCS+glutamax中离心洗涤。然后以2×10+7细胞/毫升的浓度,将细胞再混悬于新鲜培养基(RPMI+10%HIFCS+glutamax)中,向其中加入calcein-AM(将5μl储备液稀释至1m,最终浓度为5×10-6M)。轻轻混合后,在37℃下,在CO2培养箱中,将细胞培养30分钟。然后将细胞用培养基稀释至50ml,以400×g速度,通过离心洗涤2次。然后以1×10+7细胞/毫升的细胞浓度,将标记的细胞再悬浮,在37℃下,在湿度CO2培养箱中,与等体积的MIP-1α拮抗剂(10-10M至10-6M终浓度)将细胞培养30分钟。
采用装备有8μm滤器的Neuroprobe 96孔趋化性培养板(目录号101-8)进行趋化性试验。向培养板的较低孔中,加入30μl添加不同浓度拮抗剂或媒介物的化学引诱物,一式三份。然后在顶部小心放置滤器,向该滤器的表面加入25μ1与对应浓度拮抗剂或媒介物预培养的细胞。然后在37℃下,在湿度CO2培养箱中,将培养板温育2小时。通过吸附除去遗留在表面上的细胞,以200rpm的速度,将整个培养板离心10分钟。然后移出滤器,通过测定与calcein-AM有关细胞的荧光性,对迁移至较低孔中的细胞定量。用减去试剂空白后的荧光单位表达细胞迁移,通过将该荧光值与已知数目的标记细胞的荧光值比较,将该值统一为迁移百分率。当将迁移细胞的数量与媒介物进行比较时,以抑制百分率计算拮抗作用。
Claims (19)
1.一种通式(I’)的化合物或其药学上可接受的盐或溶剂化物:其中:
m是0、1、2或3;
R1各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR9R10、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基、C1-C6烷基磺酰基、-C(O)NR11R12、-NR13C(O)-(NH)PR14、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
p是0或1;
X代表氧或硫原子或者CH2、CH(CH3)、OCH2、CH2O、CH2NH、NH或者羰基,Y代表氮原子或者CH或C(OH)基团,条件是当X代表氧或硫原子或者CH2O、CH2NH或NH时,Y代表CH;
Z1代表键或者基团(CH2)q,其中q是1或2;
Z2代表键或者基团CH2,条件是Z1和Z2不同时代表键;
Q代表氧或硫原子或者基团CH2或NH;
R2代表以下基团:
n是0、1或2;
R3各自独立代表C1-C6烷基、C1-C6烷氧基羰基、-CH2OH或羧基;
R4、R5、R6和R7各自独立代表氢原子或者C1-C6烷基,或者R4、R5、R6和R7一起代表C1-C4亚烷基链,并与其相连的两个碳原子形成4-至7-元饱和碳环,或者R5、R6和R7各自代表氢原子而R4和R8与其相连的碳原子一起形成5-至6-元饱和碳环;
R8代表氢原子、C1-C6烷基,或者按如上说明与R4相连;
R9和R10各自独立代表氢原子或者C1-C6烷基,或者R9和R10与其相连的氮原子一起形成4-至7-元饱和杂环;
R11和R12各自独立代表氢原子或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
R13代表氢原子或者C1-C6烷基;
R14代表氢原子或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R15代表羧基、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷氧基羰基C1-C6烷基或者-NR17R18、-NHSO2CH3、-NHC(O)CH3、-C(O)NR17R18、-NHC(O)NR17R18、-OC(O)NR17R18、-OCH2C(O)NR17R18、-NHC(O)OR17’或者-OR17’;
t是0、1、2或3;
R16各自独立代表卤素、氰基、硝基、羧基、羟基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR19R20、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷基羰基、C1-C6烷基羰基氨基、氨磺酰基(-SO2NH2)、C1-C6烷基磺酰基、-C(O)NR21R22、-NR23C(O)(NH)vR24、苯基或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17和R18各自独立代表(i)氢原子,(ii)可含有至少一个选自氮、氧和硫杂原子的5-至6-元饱和或不饱和环,该环任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者(iii)C1-C6烷基,其任选被至少一个选自卤素、三氟甲基、羧基、C1-C6烷氧基羰基和5-至6-元饱和或不饱和环的取代基取代,该环可含有至少一个选自氮、氧和硫的杂原子并任选被至少一个选自卤素、甲基和三氟甲基的取代基取代,或者
R17和R18与其相连的氮原子一起形成4-至7-元饱和杂环;
R17’代表氢原子,或者任选被羧基或C1-C6烷氧基羰基取代的C1-C6烷基;
R17”定义同上述R17,但R17”不代表氢原子;
R19和R20各自独立代表氢原子或者C1-C6烷基,或者R19和R20与其相连的氮原子一起形成4-至7-元饱和杂环;
R21和R22各自独立代表氢原子,或者任选被C1-C6烷氧基羰基取代的C1-C6烷基;
v是0或1;
R23代表氢原子或者C1-C6烷基;和
R24代表氢原子,或者任选被羧基、C1-C6烷氧基或C1-C6烷氧基羰基取代的C1-C6烷基。
2.权利要求1的化合物,其中X代表氧原子或者CH2、OCH2、CH2O、NH或者羰基。
3.权利要求1或2的化合物,其中Y代表氮原子或者CH基团。
4.权利要求1-3中任一项的化合物,其中Q代表氧原子。
5.权利要求1-4中任一项的化合物,其中R15代表C1-C4烷氧基、C1-C4烷基羰基、C1-C6烷氧基羰基C1-C4烷基、-NHC(O)CH3、-C(O)NR17R18、-NHSO2CH3或者-NHC(O)NR17R18。
6.权利要求1-5中任一项的化合物,其中R16各自独立代表卤素、氰基、羟基、C1-C4烷氧基、C1-C4烷基羰基、C1-C4卤代烷基、C1-C4烷基羰基、苯基或者C1-C4烷基。
7.权利要求1定义的式(I’)的化合物或其药学上可接受的盐或其溶剂化物,所述化合物选自:
N-(2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐,
N-(5-氯代-2-{3-[3R,S-(4-氯代-苯氧基)-吡咯烷-1-基]-2R,S-羟基-丙氧基}-苯基)-乙酰胺盐酸盐,
N-(2-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺,
1-(2-氨基苯氧基)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-丙醇二盐酸盐,
N-(2-{3-[3-(3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}苯基)-乙酰胺盐酸盐,
2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
2-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
N-[2-({(1R,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(1S,2S,3R)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(2,3-反式)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环己基}氧基)苯基]乙酰胺,
N-(5-氯代-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
N-(4-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
N-(4-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(5-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(4-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(4-氟代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
N-(4-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
N-(4-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(5-氯代-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(3-乙酰基-2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-氟代-苯基)-乙酰胺,
N-(4-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-联苯-3-基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-4-氟代-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-甲基-苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇,
1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
3-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2,6-二甲氧基-苯氧基)-3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-丙-2-醇,
1-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-[2-(3-{1-(3,4-二氯代苄基)-4-哌啶基]氨基}-2-羟基丙氧基)-4-甲基苯基]乙酰胺,
3-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2,6-二甲氧基-苯氧基)-丙-2-醇,
1-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
(2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-{3-[3-(4-氰基-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基苯甲酰胺,
4-{1-[2-羟基-3-(2-丙酰基-苯氧基)-丙基]-吡咯烷-3-基氧基}-苄腈,
N-(2-{2-羟基-3-[3-(4-甲氧基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基)-乙酰胺,
N-(4-氯代-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
2-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
1-(2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
N-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(3,4-二氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(3,4-二氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2,6-二甲氧基-苯氧基)-3-[4-(4-氟代-苯氧基)-哌啶-1-基]-丙-2-醇,
1-[4-(4-氟代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(4-氟代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
3-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氟代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
N-(2-{3-[4-(4-乙酰氨基-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(4-{1-[3-(2-乙酰基-苯氧基)-2-羟基-丙基]-哌啶-4-基氧基}-苯基)-乙酰胺,
N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
3-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-[4-(4-氯代-苯氧基)-哌啶-1-基]-3-(2-甲氧基-苯氧基)-丙-2-醇,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-2-甲基-丙酸甲酯,
2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-6-甲氧基-苯基)-乙酮,
1-(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
(2-{3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯甲酰氨基)-乙酸甲酯,
N-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)乙酰胺,
3-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙酸甲酯,
1-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酮,
2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-N,N-二甲基-苯甲酰胺,
1-(2-{3-[3-(4-氯代-苯氧基甲基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-丙-1-酮,
N-[2-({(1R,2R)-2-[4-(3,4-二氯代苯氧基)-1-哌啶基]-1-羟基环戊基}甲氧基)苯基]乙酰胺,
(2S,4R)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-[(4-氯代苄基)氧基]-2-吡咯烷甲酸甲酯盐酸盐,
N-(2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(4-氯代-2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)-乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-氰基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氰基-2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氰基-2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(4-氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氟代苯胺基)-1-哌啶基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[3(S)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(R)-羟基-丙氧基}苯基)乙酰胺,
N-(2-{3-[3S-(4-氯代-苯氧基)-吡咯烷-1-基]-2S-羟基-丙氧基}-苯基)乙酰胺盐酸盐,
N-(2-{3-[3(R)-(4-氯代-苯氧基)-吡咯烷-1-基]-2-(S)-羟基-丙氧基}-苯基)乙酰胺,
N-[5-氯代-2-({(2S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2R)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2S)-3-[(3R)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(2R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-4,5-二氟代-苯基)乙酰胺,
N-{5-氯代-2-[2-羟基-3-(3-苯氧基-吡咯烷-1-基)-丙氧基]-苯基}-乙酰胺,
N-(5-氯代-2-{2-羟基-3-[3-(4-硝基-苯氧基)-吡咯烷-1-基]-丙氧基}-苯基}-乙酰胺,
N-(5-乙酰基-2-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
4-乙酰氨基-3-{3-[3-(3,4-二氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-5-氰基-苯基)-乙酰胺,
4-乙酰氨基-3-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯甲酸甲酯,
N-(5-氰基-2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺,
N-(2-{3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丙氧基}-5-三氟甲基-苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(5-乙酰基-2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-甲磺酰胺,
N-(5-氯代-2-[3-[3,4-二氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基]-苯基)脲,
1-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
1-(3-{2-[(氨基羰基)氨基]苯氧基}-2-羟基丙基)-3-(3,4-二氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
1-(3-{2-[(氨基羰基)氨基]-4-氯代苯氧基}-2-羟基丙基)-3-(4-氯代苯氧基)吡咯烷鎓2,2,2-三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-乙基脲盐酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-苯基)-N’-甲基脲盐酸盐,
(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(4-氯代苯氧基)-2-吡咯烷甲酸;与三氟乙酸的混合物,
(2S,4S)-1-{3-[2-(乙酰氨基)苯氧基]-2-羟基丙基}-4-(3,4-二氯代苯氧基)-2-吡咯烷甲酸乙酯;三氟乙酸盐,
N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐,
N-[2-({(2R)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-(羟甲基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺;三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基-2-甲基丙氧基}苯基)乙酰胺盐酸盐,
N-(2-{(1S*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(1R*,2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3R*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(1S*,2R*,3S*)-3-[4-(4-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3S*)-3-[4-(3,4-二氯代-苯氧基)-哌啶-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3R*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(2R*,3S*)-3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-丁氧基}-苯基)-乙酰胺,
N-(2-{(1S*,2R*,3S*)-3-[4-(3-氯代-苯氧基)-哌啶-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-[5-氯代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[4-氟代-2-({(1S,2R,3S)*-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-苯基)乙酰胺二盐酸盐,
N-(2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-(2-{3-[4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}-4-氟代苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(5-氯代-2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
1-(5-氯代-2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}苯基)-1-乙酮,
N-(5-氰基-2-{3-[(S*R*)-4-(3,4-二氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[(S*R*)-4-(4-氯代苄基)-2,5-二甲基哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺,
N-(5-氯代-2-{3-[4-(4-氯代苄基)-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(4-氯代-2-{3-[4-(4-氯代苄基)-2,5-二甲基-1-哌嗪基]-2-羟基丙氧基}苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-5-氰基苯基)乙酰胺,
N-(2-{3-[4-(4-氯代苯甲酰基)-1-哌嗪基]-2-羟基丙氧基}-4-甲基苯基)乙酰胺,
N-[5-氯代-2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-{2-[(2S)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N-[2-({(2S)-3-[(3S)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐,
N-(5-氯代-2-{3-[3-(4-氯代苄基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-1-吡咯烷甲酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-羟基苯基)乙酰胺三氟乙酸盐,
N-[2-({(2S)-3-[4-(3,4-二氯代苯氧基)-1-哌啶基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐,
N-(2-(3-(4-氯代-苯氧基)-吡咯烷-1-基)-2-羟基-丙氧基)-4,6-二氟代苯基)乙酰胺盐酸盐,
N-[2-({(2S)-3-[(2S,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)-4-氟代苯基]乙酰胺三氟乙酸盐,
N-[2-({(2S)-3-[(3R)-3-(4-氯代苄基)吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺盐酸盐,
N-{2-[(2R)-(3-{(3S)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N-[2-({(2S)-3-[(2R,4S)-4-(4-氯代苯氧基)-2-甲基吡咯烷基]-2-羟基丙基}氧基)苯基]乙酰胺三氟乙酸盐,
N-{2-[(2S)-(3-{(3R)-3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基丙基)氧基]-4-氟代苯基}乙酰胺,
N’-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲基苯基)-N,N-二甲基脲三氟乙酸盐,
N-(2-{3-[3-(4-氯代苯胺基)-1-吡咯烷基]-2-羟基丙氧基}苯基)乙酰胺,
N-{2-[(3-{3-[(4-氯代苯基)氧基]-1-吡咯烷基}-2-羟基-1-甲基丙基)氧基]苯基}乙酰胺盐酸盐,
N-(2-{3-[3-(4-氯代苯氧基)-1-吡咯烷基]-2-羟基丙氧基}-4-甲氧基苯基)乙酰胺盐酸盐,
N-(2-[3-(4-氯代-苄氧基)-吡咯烷-1-基]-2-羟基-丙氧基}-苯基)-乙酰胺三氟乙酸盐,
N-(2-{3-[3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-2-甲基-丙氧基}苯基)乙酰胺,
N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-5-氯代-苯基)乙酰胺(非对映体混合物),
N-[2-({(2R,3S)*-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丁基}氧基)-1-甲基苯基]乙酰胺(非对映体混合物),
N-{2-[(3-{4-[(3,4-二氯代苯基)氧基]-1-哌啶基}-2-羟基-2-甲基丙基)氧基]-4-氟代苯基}乙酰胺盐酸盐,
N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-4-氟代-苯基)乙酰胺(非对映体混合物),
N-(5-氯代-2-{3-[3-(3,4-二氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(5-氯代-2-{3-[3-(4-氟代-苯氧基)-吡咯烷-1-基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(4-氰基-2-{3-[4-(3,4-二氯代苯胺基)-1-哌啶基]-2-羟基-丙氧基}苯基)-乙酰胺,
N-(4-羟基-2-{(1S,2R,3S)*-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺(非对映体混合物),
N-(4-羟基-2-{(1S,2R,3S)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-(4-羟基-2-{(1R,2S,3R)-3-[(3S)-3-(4-氯代-苯氧基)-吡咯烷-1-基]-2-羟基-环戊基氧基}-苯基)-乙酰胺,
N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-氯代苯氧基)-吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-[5-氯代-2-({(1S,2R,3S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基环戊基}氧基)苯基]乙酰胺,
N-{5-氯代-2-[((1S,2R,3S)*-3-{[1-(4-氯代苄基)-4-哌啶基]氨基}-2-羟基环戊基)氧基]苯基}乙酰胺(外消旋体混合物),以及
N-[2-({(2S)-3-[(3S)-3-(4-氯代苯氧基)吡咯烷基]-2-羟基丙基}氧基)-4-羟基苯基]乙酰胺。
8.一种制备权利要求1定义的式(I’)的化合物的方法,所述方法包括:(a)使以下通式的化合物
R-H (II’)其中R同式(I’)中的定义,与以下通式的化合物反应其中Q、R2、R4、R5、R6、R7和R8同式(I’)的定义;或者(b)使以下通式的化合物其中R、R4、R5、R6、R7和R8同式(I’)的定义,与以下通式的化合物反应
L1-Q-R2 (V’)其中L1代表氢原子或活性基团,Q和R2同式(I’)中的定义;然后任选将式(I’)的化合物转化为另一个式(I’)的化合物;并且如果要求,形成式(I’)的化合物的药学上可接受的盐或溶剂化物。
9.一种药用组合物,所述药用组合物包含权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物,结合药学上可接受的添加剂、稀释剂或载体。
10.一种制备权利要求9所要求保护的药用组合物的方法,所述方法包括将权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物与药学上可接受的添加剂、稀释剂或载体混合。
11.一种用于治疗的权利要求1-7中任一项的式(I’)的化合物或其药学上可接受的盐或溶剂化物。
12.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗的药物中的应用。
13.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗其中趋化因子受体活性的调节是有利的人体疾病或症状的药物中的应用。
14.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗类风湿性关节炎的药物中的应用。
15.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗肺慢性阻塞性疾病的药物中的应用。
16.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗哮喘的药物中的应用。
17.权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物在制备用于治疗多发性硬化病的药物中的应用。
18.一种治疗患有炎症或有患有该疾病危险的患者的方法,所述方法包括向该患者给服治疗有效量的权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物。
19.一种治疗患有呼吸道疾病或有患有该疾病危险的患者的方法,该方法包括向该患者给服治疗有效量的权利要求1-7中任一项所要求保护的式(I’)的化合物或其药学上可接受的盐或溶剂化物。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE00006205 | 2000-02-25 | ||
SE0000620A SE0000620D0 (sv) | 2000-02-25 | 2000-02-25 | Novel compounds |
SE00022343 | 2000-06-14 | ||
SE0002234A SE0002234D0 (sv) | 2000-06-14 | 2000-06-14 | Novel compounds |
SE00039792 | 2000-10-31 | ||
SE0003979A SE0003979D0 (sv) | 2000-10-31 | 2000-10-31 | Novel Compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1426393A true CN1426393A (zh) | 2003-06-25 |
CN1229343C CN1229343C (zh) | 2005-11-30 |
Family
ID=27354503
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018084125A Expired - Fee Related CN1229343C (zh) | 2000-02-25 | 2001-02-23 | 趋化因子受体活性调节剂 |
CN01808426A Pending CN1426412A (zh) | 2000-02-25 | 2001-02-23 | 新化合物 |
CNB018084842A Expired - Fee Related CN1187326C (zh) | 2000-02-25 | 2001-02-23 | 新化合物 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN01808426A Pending CN1426412A (zh) | 2000-02-25 | 2001-02-23 | 新化合物 |
CNB018084842A Expired - Fee Related CN1187326C (zh) | 2000-02-25 | 2001-02-23 | 新化合物 |
Country Status (29)
Country | Link |
---|---|
US (3) | US6927222B2 (zh) |
EP (3) | EP1263725B1 (zh) |
JP (3) | JP2003523999A (zh) |
KR (3) | KR20020075450A (zh) |
CN (3) | CN1229343C (zh) |
AR (1) | AR029806A1 (zh) |
AT (2) | ATE295833T1 (zh) |
AU (3) | AU783475B2 (zh) |
BR (3) | BR0108677A (zh) |
CA (3) | CA2400435A1 (zh) |
CO (1) | CO5300399A1 (zh) |
CZ (1) | CZ20022870A3 (zh) |
DE (2) | DE60106581T2 (zh) |
DK (2) | DK1263724T3 (zh) |
EE (1) | EE05001B1 (zh) |
ES (2) | ES2241796T3 (zh) |
HK (1) | HK1048990A1 (zh) |
HU (1) | HUP0300922A2 (zh) |
IL (2) | IL151202A0 (zh) |
IS (1) | IS6520A (zh) |
MX (3) | MXPA02008243A (zh) |
NO (3) | NO20023932L (zh) |
NZ (2) | NZ520718A (zh) |
PL (1) | PL358281A1 (zh) |
PT (2) | PT1263725E (zh) |
RU (1) | RU2265011C2 (zh) |
SI (2) | SI1263725T1 (zh) |
SK (1) | SK12132002A3 (zh) |
WO (3) | WO2001062729A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710419A (zh) * | 2015-03-18 | 2015-06-17 | 中国药科大学 | 四氢吡啶[4,3-b]骈吲哚类化合物、其制备方法及医药用途 |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CO5300399A1 (es) | 2000-02-25 | 2003-07-31 | Astrazeneca Ab | Heterocicliocs que contienen nitrogeno, proceso para su preparacion y composiciones farmaceuticas que los contienen |
AR028948A1 (es) * | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | Compuestos novedosos |
US7005439B2 (en) * | 2000-06-20 | 2006-02-28 | Astrazeneca Ab | Compounds |
AR035230A1 (es) * | 2001-03-19 | 2004-05-05 | Astrazeneca Ab | Compuestos de bencimidazol, proceso para su preparacion, composicion farmaceutica, proceso para la preparacion de dicha composicion farmaceutica, y usos de estos compuestos para la elaboracion de medicamentos |
SE0101038D0 (sv) * | 2001-03-23 | 2001-03-23 | Astrazeneca Ab | Novel compounds |
AU2002323570A1 (en) * | 2001-08-30 | 2003-03-10 | Chemocentryx, Inc. | Bicyclic compounds as inhibitors of chemokine binding to us28 |
SE0104251D0 (sv) * | 2001-12-14 | 2001-12-14 | Astrazeneca Ab | Novel compounds |
TW200303304A (en) * | 2002-02-18 | 2003-09-01 | Astrazeneca Ab | Chemical compounds |
CA2485681C (en) * | 2002-05-24 | 2012-10-16 | Millennium Pharmaceuticals, Inc. | Ccr9 inhibitors and methods of use thereof |
US7659305B2 (en) | 2002-10-31 | 2010-02-09 | Pfizer Inc. | Therapeutic proline derivatives |
GB0225379D0 (en) * | 2002-10-31 | 2002-12-11 | Pfizer Ltd | Therapeutic proline derivatives |
GB0402101D0 (en) * | 2004-01-30 | 2004-03-03 | Novartis Ag | Organic compounds |
SE0400208D0 (sv) * | 2004-02-02 | 2004-02-02 | Astrazeneca Ab | Chemical compounds |
WO2006101434A1 (en) * | 2005-03-22 | 2006-09-28 | Astrazeneca Ab | NOVEL TETRAHYDRO-1H-PYRIDO [4,3-b] INDOLE DERIVATIVES AS CB1’ RECEPTOR LIGANDS |
KR20080032135A (ko) * | 2005-08-01 | 2008-04-14 | 아스트라제네카 아베 | 호흡기 질환의 치료에 유용한 케모카인 수용체조절인자로서의 신규 피페리딘 유도체 |
TW200738635A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
TW200734305A (en) * | 2005-08-02 | 2007-09-16 | Astrazeneca Ab | New salt III |
TW200738634A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
US20100041905A1 (en) * | 2006-07-18 | 2010-02-18 | Astrazeneca Ab | Process for the Preparation of Substituted 2-Acetylamino-Alkoxyphenyl |
GB0702456D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | New combination |
WO2008136754A1 (en) * | 2007-05-07 | 2008-11-13 | Astrazeneca Ab | Novel benzyl - 2 -oxo-piperazinyl/ 7-oxo/5-oxa- [1,4] diazepanyl/ 2 -oxo- tetrahydropyrimidinyl derivatives |
WO2008150231A1 (en) * | 2007-06-08 | 2008-12-11 | Astrazeneca Ab | New heterocyclic compounds for treatment of respiratory, airway or inflammatory disorders |
AU2009204048B2 (en) * | 2008-01-11 | 2013-08-01 | Albany Molecular Research, Inc. | (1-azinone) -substituted pyridoindoles as MCH antagonists |
US9625475B2 (en) | 2008-09-29 | 2017-04-18 | Abbvie Inc. | Indole and indoline derivatives and methods of use thereof |
EP2344505A2 (en) | 2008-09-29 | 2011-07-20 | Abbott Laboratories | Indole and indoline derivatives and methods of use thereof |
US9073925B2 (en) * | 2009-07-01 | 2015-07-07 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
WO2011003012A1 (en) * | 2009-07-01 | 2011-01-06 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof |
US8629158B2 (en) * | 2009-07-01 | 2014-01-14 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
US8637501B2 (en) | 2009-07-01 | 2014-01-28 | Albany Molecular Research, Inc. | Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof |
GB0913345D0 (en) | 2009-07-31 | 2009-09-16 | Astrazeneca Ab | New combination 802 |
WO2011061527A1 (en) | 2009-11-17 | 2011-05-26 | Astrazeneca Ab | Combinations comprising a glucocorticoid receptor modulator for the treatment of respiratory diseases |
WO2011073662A1 (en) | 2009-12-17 | 2011-06-23 | Astrazeneca Ab | Combination of a benzoxazinone and a further agent for treating respiratory diseases |
WO2012088124A2 (en) | 2010-12-21 | 2012-06-28 | Albany Molecular Research, Inc. | Tetrahydro-azacarboline mch-1 antagonists, methods of making, and uses thereof |
WO2012088038A2 (en) | 2010-12-21 | 2012-06-28 | Albany Molecular Research, Inc. | Piperazinone-substituted tetrahydro-carboline mch-1 antagonists, methods of making, and uses thereof |
GB201021979D0 (en) | 2010-12-23 | 2011-02-02 | Astrazeneca Ab | New compound |
GB201021992D0 (en) | 2010-12-23 | 2011-02-02 | Astrazeneca Ab | Compound |
WO2012163848A1 (en) | 2011-05-27 | 2012-12-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of crohn's disease |
GB201209587D0 (en) | 2012-05-30 | 2012-07-11 | Takeda Pharmaceutical | Therapeutic compounds |
WO2018026371A1 (en) * | 2016-08-04 | 2018-02-08 | Sunovion Pharmaceuticals Inc. | Dual nav1.2/5ht2a inhibitors for treating cns disorders |
EP4115885A1 (en) | 2021-07-05 | 2023-01-11 | Charité - Universitätsmedizin Berlin | A pharmaceutical composition comprising bay 86-5277 and salts thereof for use in the treatment of viral infections and hyperinflammation |
Family Cites Families (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1220440B (de) * | 1962-02-14 | 1966-07-07 | Sanol Arznei Schwarz Gmbh | Verfahren zur Herstellung von Derivaten des 1-(o-Bromphenoxy)-2-hydroxy-3-amino-propans und deren Saeureadditionssalzen |
US3577432A (en) * | 1968-12-23 | 1971-05-04 | Robins Co Inc A H | 1-substituted-3-phenoxypyrrolidines |
US4029801A (en) * | 1970-09-03 | 1977-06-14 | John Wyeth & Brother Limited | Pharmaceutical compositions and methods of treating hypertension |
JPS5511670B1 (zh) | 1971-07-13 | 1980-03-26 | ||
US3755584A (en) * | 1972-04-03 | 1973-08-28 | Abbott Lab | Tranquilizers |
FR2190430A1 (en) | 1972-06-29 | 1974-02-01 | Ferlux | N-aminomethylhydroxamic acids - with antiinflammatory activity pre-pared by Mannich reaction |
US3775584A (en) | 1972-11-30 | 1973-11-27 | D Moerke | Welding gun |
US3818017A (en) | 1973-01-04 | 1974-06-18 | Janssen Pharmaceutica Nv | 1-{8 1-(2-hydroxy-3-aryloxypropyl)-4-piperidyl{9 -2-benzimidazolinones and related compounds |
US3894030A (en) | 1973-01-04 | 1975-07-08 | Janssen Pharmaceutica Nv | 1-{8 1-(2-Hydroxy-3-aryloxypropyl)-4-piperidyl{9 -2-benzimidazolinones and related compounds |
US4166119A (en) | 1978-04-14 | 1979-08-28 | American Hoechst Corporation | Analgesic and tranquilizing spiro[dihydrobenzofuran]piperidines and pyrrolidines |
US4264613A (en) * | 1979-08-01 | 1981-04-28 | Science Union Et Cie, Societe Francaise De Recherche Medicale | Piperidylbenzimidazolinone compounds |
FR2469411A1 (fr) * | 1979-11-15 | 1981-05-22 | Science Union & Cie | Nouveaux derives de la piperidylbenzimidazolinone, leurs procedes de preparation et les compositions pharmaceutiques les renfermant |
EP0095454A3 (de) | 1982-05-13 | 1985-04-03 | Gerot-Pharmazeutika Gesellschaft m.b.H. | Neue kernsubstituierte Pyrogallol-Derivate |
JPS59222484A (ja) | 1983-06-02 | 1984-12-14 | Kowa Co | テトラヒドロナフチルカルボン酸フエニルエステル誘導体 |
US5614533A (en) * | 1987-03-13 | 1997-03-25 | Bio-Mega/Boehringer Ingelheim Research, Inc. | Substituted pipecolinic acid derivatives as HIV protease inhibitors |
DE3723568C2 (de) | 1987-07-16 | 1994-01-27 | Siemens Ag | Differenzstromschutzschalter |
DE3723648A1 (de) * | 1987-07-17 | 1989-01-26 | Sandoz Ag | Indol-derivate, ihre herstellung und sie enthaltende arzneimittel |
ES2027897A6 (es) | 1991-01-24 | 1992-06-16 | Espanola Prod Quimicos | Procedimiento de preparacion de nuevos derivados de la difenilmetilpiperacina. |
IL105716A0 (en) | 1992-06-08 | 1993-09-22 | Richter Gedeon Vegyeszet | Aminopropanol derivatives,their preparation and pharmaceutical compositions containing them |
NZ248332A (en) | 1992-08-07 | 1995-01-27 | Sankyo Co | Hiv protease inhibitor and its use |
US5627196A (en) * | 1995-01-17 | 1997-05-06 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5741789A (en) | 1995-01-17 | 1998-04-21 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5614523A (en) * | 1995-01-17 | 1997-03-25 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5789402A (en) | 1995-01-17 | 1998-08-04 | Eli Lilly Company | Compounds having effects on serotonin-related systems |
US5576321A (en) | 1995-01-17 | 1996-11-19 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
ZA9610738B (en) * | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
DE19703131A1 (de) | 1997-01-29 | 1998-07-30 | Bayer Ag | Verwendung von Chinoxalin in Dreier-Kombination mit Protease-Inhibitoren und Reverse Transkriptaseinhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen |
IL125658A0 (en) | 1997-08-18 | 1999-04-11 | Hoffmann La Roche | Ccr-3 receptor antagonists |
KR100622613B1 (ko) | 1997-11-18 | 2006-09-11 | 데이진 화-마 가부시키가이샤 | 시클릭 아민 유도체 및 그 약제로서의 용도 |
DE19755268A1 (de) | 1997-12-12 | 1999-06-17 | Merck Patent Gmbh | Benzamidinderivate |
FR2780057B1 (fr) | 1998-06-18 | 2002-09-13 | Sanofi Sa | Phenoxypropanolamines, procede pour leur preparation et compositions pharmaceutiques les contenant |
EP1140086A4 (en) | 1998-12-18 | 2002-04-03 | Du Pont Pharm Co | N-UREIDOALKYL-PIPERIDINES FOR USE AS MODULATORS OF THE ACTIVITY OF CHIMIOKIN RECEPTORS |
CA2346933A1 (en) | 1998-12-18 | 2000-06-22 | Dupont Pharmaceuticals Company | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
WO2000053600A1 (fr) | 1999-03-11 | 2000-09-14 | Banyu Pharmaceutical Co., Ltd. | Derives piperidiniques |
BR0009338A (pt) | 1999-03-26 | 2001-12-26 | Astrazeneca Ab | Composto, processo para a preparação do mesmo,composição farmacêutica, processo para apreparação da mesma, uso de um composto, e,método de tratamento de uma doençainflamatória em um paciente sofrendo ou em riscode dita doença |
DE19922316A1 (de) | 1999-05-14 | 2000-11-16 | Goedecke Ag | Verfahren zur Herstellung von (R)-N-[(Benzo[b]furan-2-yl)-alkoxycarbonyl]-tryptophanalkylestern |
AU5011300A (en) | 1999-05-14 | 2000-12-05 | Combichem, Inc. | Cyclic amine derivatives and their uses |
SE9902987D0 (sv) | 1999-08-24 | 1999-08-24 | Astra Pharma Prod | Novel compounds |
FR2802533B1 (fr) | 1999-12-17 | 2002-02-15 | Sanofi Synthelabo | Phenoxypropanolamines, leur preparation et leur application en therapeutique |
JP4782342B2 (ja) | 1999-12-17 | 2011-09-28 | サノフィ−アベンティス | フェノキシプロパノールアミン類、それらの製造方法およびそれらを含む医薬組成物 |
CO5300399A1 (es) | 2000-02-25 | 2003-07-31 | Astrazeneca Ab | Heterocicliocs que contienen nitrogeno, proceso para su preparacion y composiciones farmaceuticas que los contienen |
GB0011838D0 (en) | 2000-05-17 | 2000-07-05 | Astrazeneca Ab | Chemical compounds |
AR028947A1 (es) * | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | Compuestos novedosos |
US7005439B2 (en) | 2000-06-20 | 2006-02-28 | Astrazeneca Ab | Compounds |
AR028948A1 (es) | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | Compuestos novedosos |
SE0100903D0 (sv) | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
SE0101038D0 (sv) | 2001-03-23 | 2001-03-23 | Astrazeneca Ab | Novel compounds |
-
2001
- 2001-02-22 CO CO01014299A patent/CO5300399A1/es not_active Application Discontinuation
- 2001-02-23 CN CNB018084125A patent/CN1229343C/zh not_active Expired - Fee Related
- 2001-02-23 BR BR0108677-4A patent/BR0108677A/pt not_active IP Right Cessation
- 2001-02-23 JP JP2001561737A patent/JP2003523999A/ja not_active Withdrawn
- 2001-02-23 CN CN01808426A patent/CN1426412A/zh active Pending
- 2001-02-23 EP EP01908558A patent/EP1263725B1/en not_active Expired - Lifetime
- 2001-02-23 CN CNB018084842A patent/CN1187326C/zh not_active Expired - Fee Related
- 2001-02-23 SI SI200130239T patent/SI1263725T1/xx unknown
- 2001-02-23 AT AT01908557T patent/ATE295833T1/de not_active IP Right Cessation
- 2001-02-23 RU RU2002122100/04A patent/RU2265011C2/ru not_active IP Right Cessation
- 2001-02-23 WO PCT/SE2001/000404 patent/WO2001062729A1/en active IP Right Grant
- 2001-02-23 MX MXPA02008243A patent/MXPA02008243A/es unknown
- 2001-02-23 MX MXPA02008241A patent/MXPA02008241A/es active IP Right Grant
- 2001-02-23 MX MXPA02008244A patent/MXPA02008244A/es active IP Right Grant
- 2001-02-23 NZ NZ520718A patent/NZ520718A/en unknown
- 2001-02-23 SK SK1213-2002A patent/SK12132002A3/sk unknown
- 2001-02-23 AU AU36300/01A patent/AU783475B2/en not_active Ceased
- 2001-02-23 CA CA002400435A patent/CA2400435A1/en not_active Abandoned
- 2001-02-23 SI SI200130366T patent/SI1263724T1/xx unknown
- 2001-02-23 DE DE60106581T patent/DE60106581T2/de not_active Expired - Fee Related
- 2001-02-23 KR KR1020027011129A patent/KR20020075450A/ko not_active Application Discontinuation
- 2001-02-23 PT PT01908558T patent/PT1263725E/pt unknown
- 2001-02-23 US US10/204,789 patent/US6927222B2/en not_active Expired - Fee Related
- 2001-02-23 ES ES01908557T patent/ES2241796T3/es not_active Expired - Lifetime
- 2001-02-23 DK DK01908557T patent/DK1263724T3/da active
- 2001-02-23 EP EP01908559A patent/EP1263760A1/en not_active Withdrawn
- 2001-02-23 IL IL15120201A patent/IL151202A0/xx unknown
- 2001-02-23 CA CA002400434A patent/CA2400434A1/en not_active Abandoned
- 2001-02-23 BR BR0108679-0A patent/BR0108679A/pt not_active IP Right Cessation
- 2001-02-23 CA CA002400293A patent/CA2400293A1/en not_active Abandoned
- 2001-02-23 AT AT01908558T patent/ATE280153T1/de not_active IP Right Cessation
- 2001-02-23 US US10/204,754 patent/US6951874B2/en not_active Expired - Fee Related
- 2001-02-23 DE DE60110900T patent/DE60110900T2/de not_active Expired - Fee Related
- 2001-02-23 JP JP2001561736A patent/JP2003523998A/ja not_active Withdrawn
- 2001-02-23 HU HU0300922A patent/HUP0300922A2/hu unknown
- 2001-02-23 CZ CZ20022870A patent/CZ20022870A3/cs unknown
- 2001-02-23 KR KR1020027011128A patent/KR20020076338A/ko not_active Application Discontinuation
- 2001-02-23 WO PCT/SE2001/000403 patent/WO2001062728A1/en active IP Right Grant
- 2001-02-23 BR BR0108678-2A patent/BR0108678A/pt not_active IP Right Cessation
- 2001-02-23 KR KR1020027011127A patent/KR100752033B1/ko not_active IP Right Cessation
- 2001-02-23 EE EEP200200470A patent/EE05001B1/xx not_active IP Right Cessation
- 2001-02-23 PT PT01908557T patent/PT1263724E/pt unknown
- 2001-02-23 ES ES01908558T patent/ES2227140T3/es not_active Expired - Lifetime
- 2001-02-23 NZ NZ520719A patent/NZ520719A/en unknown
- 2001-02-23 DK DK01908558T patent/DK1263725T3/da active
- 2001-02-23 AU AU36299/01A patent/AU783496B2/en not_active Ceased
- 2001-02-23 PL PL01358281A patent/PL358281A1/xx not_active Application Discontinuation
- 2001-02-23 AU AU36301/01A patent/AU3630101A/en not_active Abandoned
- 2001-02-23 WO PCT/SE2001/000405 patent/WO2001062757A1/en not_active Application Discontinuation
- 2001-02-23 US US10/204,790 patent/US6943188B2/en not_active Expired - Fee Related
- 2001-02-23 AR ARP010100842A patent/AR029806A1/es not_active Application Discontinuation
- 2001-02-23 IL IL15120801A patent/IL151208A0/xx unknown
- 2001-02-23 JP JP2001562539A patent/JP2003524011A/ja active Pending
- 2001-02-23 EP EP01908557A patent/EP1263724B1/en not_active Expired - Lifetime
-
2002
- 2002-08-19 NO NO20023932A patent/NO20023932L/no not_active Application Discontinuation
- 2002-08-19 NO NO20023933A patent/NO20023933L/no not_active Application Discontinuation
- 2002-08-19 NO NO20023934A patent/NO323584B1/no unknown
- 2002-08-22 IS IS6520A patent/IS6520A/is unknown
-
2003
- 2003-02-17 HK HK03101130A patent/HK1048990A1/xx not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710419A (zh) * | 2015-03-18 | 2015-06-17 | 中国药科大学 | 四氢吡啶[4,3-b]骈吲哚类化合物、其制备方法及医药用途 |
CN104710419B (zh) * | 2015-03-18 | 2017-05-24 | 中国药科大学 | 四氢吡啶[4,3‑b]骈吲哚类化合物、其制备方法及医药用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1229343C (zh) | 趋化因子受体活性调节剂 | |
CN1207289C (zh) | 金属蛋白酶抑制剂,含有它们的药物组合物和其药物用途,其制备方法和中间体 | |
CN1034934C (zh) | 血管紧张素ii拮抗性吡啶衍生物的制备方法 | |
CN1062865C (zh) | 脒基苯并呋喃衍生物和脒基苯并噻吩衍生物以及它们的盐的制备方法 | |
CN1174978C (zh) | 用作旋转异构酶抑制剂的杂环化合物 | |
CN1700918A (zh) | 关于hiv整合酶的n-取代的羟基嘧啶酮甲酰胺抑制剂 | |
CN1675218A (zh) | 新的三环螺哌啶或螺吡咯烷 | |
CN1476434A (zh) | 新化合物 | |
CN1173132A (zh) | 二氢嘧啶类化合物及其用途 | |
CN1444573A (zh) | 甲酰胺化合物及其作为人11cby受体拮抗剂的用途 | |
CN1902171A (zh) | 用作ccr-5拮抗剂的苄醚胺化合物 | |
CN1662527A (zh) | 作为m3毒蕈碱性受体拮抗剂的吡咯烷鎓衍生物 | |
CN1610666A (zh) | 苄脒衍生物 | |
CN1471536A (zh) | 趋化因子受体拮抗剂及其使用方法 | |
CN101080226A (zh) | 酰氨基化合物及它们作为药物的用途 | |
CN1365281A (zh) | 金属蛋白酶抑制剂 | |
CN101048393A (zh) | 作为γ-分泌酶抑制剂的取代的N-芳基磺酰基杂环胺 | |
CN1545509A (zh) | 用作趋化因子受体活性调节剂的哌啶衍生物 | |
CN1791568A (zh) | Hsp90家族蛋白质阻断剂 | |
CN1930158A (zh) | 新季铵化的奎宁环酯 | |
CN1918160A (zh) | 用作趋化因子受体活性调节剂的新颖三环螺环衍生物 | |
CN1520402A (zh) | 非对称环二胺化合物 | |
CN1617718A (zh) | 用于治疗肥胖症的作为mch拮抗剂的n-芳基-n′-芳基环烷基脲衍生物 | |
CN1500082A (zh) | 氰基取代的二氢嘧啶化合物及其治疗疾病的用途 | |
CN1507435A (zh) | 新型氰基取代的二氢嘧啶化合物及其治疗疾病的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20051130 Termination date: 20100223 |