CN1219753C - 4-碘苯氨基苯氧肟酸的氧合酯 - Google Patents
4-碘苯氨基苯氧肟酸的氧合酯 Download PDFInfo
- Publication number
- CN1219753C CN1219753C CNB018140599A CN01814059A CN1219753C CN 1219753 C CN1219753 C CN 1219753C CN B018140599 A CNB018140599 A CN B018140599A CN 01814059 A CN01814059 A CN 01814059A CN 1219753 C CN1219753 C CN 1219753C
- Authority
- CN
- China
- Prior art keywords
- fluoro
- benzamide
- iodo
- phenylamino
- hydroxyl
- 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.)
- Expired - Lifetime
Links
- 150000002148 esters Chemical class 0.000 title abstract description 8
- QAMBBWKIAJFFRF-UHFFFAOYSA-N n-hydroxy-2-(4-iodoanilino)benzamide Chemical class ONC(=O)C1=CC=CC=C1NC1=CC=C(I)C=C1 QAMBBWKIAJFFRF-UHFFFAOYSA-N 0.000 title abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 326
- -1 4Be hydrogen Chemical class 0.000 claims description 278
- 150000001875 compounds Chemical class 0.000 claims description 140
- 238000002360 preparation method Methods 0.000 claims description 120
- KWBXUOMYWXLJHA-UHFFFAOYSA-N 3-fluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound FC=1C(=C(C(=O)N)C=CC=1)NC1=C(C=C(C=C1)I)F KWBXUOMYWXLJHA-UHFFFAOYSA-N 0.000 claims description 94
- 229910052760 oxygen Inorganic materials 0.000 claims description 60
- 239000001301 oxygen Substances 0.000 claims description 55
- 239000000460 chlorine Substances 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 53
- KGGHWIKBOIQEAJ-UHFFFAOYSA-N 2-fluorobenzamide Chemical compound NC(=O)C1=CC=CC=C1F KGGHWIKBOIQEAJ-UHFFFAOYSA-N 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 239000013078 crystal Substances 0.000 claims description 45
- 238000002425 crystallisation Methods 0.000 claims description 45
- 230000008025 crystallization Effects 0.000 claims description 44
- 230000005855 radiation Effects 0.000 claims description 44
- 229910052731 fluorine Inorganic materials 0.000 claims description 35
- 239000011737 fluorine Substances 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 30
- BIEMUTFZIIFCHB-UHFFFAOYSA-N 3-fluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C=CC=C1C(N)=O BIEMUTFZIIFCHB-UHFFFAOYSA-N 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 23
- 208000002193 Pain Diseases 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- HBICGWPNJHCNEX-UHFFFAOYSA-N C1CC1(CO)CONC(=O)C2=CC=CC=C2F Chemical compound C1CC1(CO)CONC(=O)C2=CC=CC=C2F HBICGWPNJHCNEX-UHFFFAOYSA-N 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- MNJLCPSZNULUTG-UHFFFAOYSA-N C1CC1(CO)CONC(=O)C2=C(C(=CC=C2)F)NC3=C(C=C(C=C3)I)F Chemical compound C1CC1(CO)CONC(=O)C2=C(C(=CC=C2)F)NC3=C(C=C(C=C3)I)F MNJLCPSZNULUTG-UHFFFAOYSA-N 0.000 claims description 12
- 230000036407 pain Effects 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- UJYVDNHYFCJMLL-UHFFFAOYSA-N C1C(C1CONC(=O)C2=CC=CC=C2F)CO Chemical compound C1C(C1CONC(=O)C2=CC=CC=C2F)CO UJYVDNHYFCJMLL-UHFFFAOYSA-N 0.000 claims description 10
- 208000000094 Chronic Pain Diseases 0.000 claims description 10
- AVQJFUIBKNBLBV-UHFFFAOYSA-N C1C(C1CONC(=O)C2=C(C(=CC=C2)F)NC3=C(C=C(C=C3)I)F)CO Chemical compound C1C(C1CONC(=O)C2=C(C(=CC=C2)F)NC3=C(C=C(C=C3)I)F)CO AVQJFUIBKNBLBV-UHFFFAOYSA-N 0.000 claims description 9
- ICCPHCKSXXVZFT-UHFFFAOYSA-N CC(CO)ONC(=O)C1=CC=CC=C1F Chemical compound CC(CO)ONC(=O)C1=CC=CC=C1F ICCPHCKSXXVZFT-UHFFFAOYSA-N 0.000 claims description 9
- RIJLKOXIMDTQMW-UHFFFAOYSA-N CCC(CONC(=O)C1=CC=CC=C1F)O Chemical compound CCC(CONC(=O)C1=CC=CC=C1F)O RIJLKOXIMDTQMW-UHFFFAOYSA-N 0.000 claims description 9
- SCOMFSWLCWYDMW-UHFFFAOYSA-N COCC(CONC(=O)C1=CC=CC=C1F)O Chemical compound COCC(CONC(=O)C1=CC=CC=C1F)O SCOMFSWLCWYDMW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 208000004296 neuralgia Diseases 0.000 claims description 8
- 208000021722 neuropathic pain Diseases 0.000 claims description 8
- 230000002062 proliferating effect Effects 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- DQWLGBUPYAVESD-UHFFFAOYSA-N 2-fluoro-N-(2-methoxyethoxy)benzamide Chemical compound COCCONC(=O)C1=CC=CC=C1F DQWLGBUPYAVESD-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- KTUXEMULTCCCJS-UHFFFAOYSA-N C1=CC=C(C(=C1)NC2=C(C=CC=C2F)C(=O)N)F Chemical compound C1=CC=C(C(=C1)NC2=C(C=CC=C2F)C(=O)N)F KTUXEMULTCCCJS-UHFFFAOYSA-N 0.000 claims description 6
- UFSTYMQSZLCTSS-UHFFFAOYSA-N CC(CO)ONC(=O)C1=C(C(=CC=C1)F)NC2=C(C=C(C=C2)I)F Chemical compound CC(CO)ONC(=O)C1=C(C(=CC=C1)F)NC2=C(C=C(C=C2)I)F UFSTYMQSZLCTSS-UHFFFAOYSA-N 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 208000004550 Postoperative Pain Diseases 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- POGGXJKAOIPUPA-UHFFFAOYSA-N 3-fluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxybutoxy)benzamide Chemical compound FC=1C(=C(C(=O)NOCC(CC)O)C=CC=1)NC1=C(C=C(C=C1)I)F POGGXJKAOIPUPA-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- QVVQTKBJIAUDER-UHFFFAOYSA-N CC1=C(C=CC(=C1)I)NC2=C(C=CC=C2F)C(=O)NOCC3(CC3)CO Chemical compound CC1=C(C=CC(=C1)I)NC2=C(C=CC=C2F)C(=O)NOCC3(CC3)CO QVVQTKBJIAUDER-UHFFFAOYSA-N 0.000 claims description 4
- 229940121849 Mitotic inhibitor Drugs 0.000 claims description 4
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000002352 blister Diseases 0.000 claims description 4
- 238000001959 radiotherapy Methods 0.000 claims description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- 206010039361 Sacroiliitis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 230000008602 contraction Effects 0.000 claims description 3
- 229960003668 docetaxel Drugs 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 claims description 3
- 229960000922 vinflunine Drugs 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 2
- 208000000412 Avitaminosis Diseases 0.000 claims description 2
- 208000037157 Azotemia Diseases 0.000 claims description 2
- UVPRFSYKDRQDLH-UHFFFAOYSA-N C1=CC(=C(C(=C1)F)NC2=C(C=C(C=C2)I)F)C(=O)NOCCCCO Chemical compound C1=CC(=C(C(=C1)F)NC2=C(C=C(C=C2)I)F)C(=O)NOCCCCO UVPRFSYKDRQDLH-UHFFFAOYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000025962 Crush injury Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 206010021135 Hypovitaminosis Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000028389 Nerve injury Diseases 0.000 claims description 2
- 208000005890 Neuroma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 208000004983 Phantom Limb Diseases 0.000 claims description 2
- 206010056238 Phantom pain Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 206010052428 Wound Diseases 0.000 claims description 2
- 208000027418 Wounds and injury Diseases 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 230000008764 nerve damage Effects 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 230000002269 spontaneous effect Effects 0.000 claims description 2
- 208000037816 tissue injury Diseases 0.000 claims description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 2
- 208000009852 uremia Diseases 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 2
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- 208000030401 vitamin deficiency disease Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- WONPVVXVFAABIZ-UHFFFAOYSA-N N-(2-hydroxybutoxy)benzamide Chemical compound OC(CONC(C1=CC=CC=C1)=O)CC WONPVVXVFAABIZ-UHFFFAOYSA-N 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000037976 chronic inflammation Diseases 0.000 claims 1
- 201000005296 lung carcinoma Diseases 0.000 claims 1
- 210000005075 mammary gland Anatomy 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 201000001514 prostate carcinoma Diseases 0.000 claims 1
- 201000010174 renal carcinoma Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- 238000005160 1H NMR spectroscopy Methods 0.000 description 145
- 239000000243 solution Substances 0.000 description 144
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- 239000007787 solid Substances 0.000 description 107
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 88
- 238000004364 calculation method Methods 0.000 description 87
- 238000002474 experimental method Methods 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 85
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 239000002585 base Substances 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 239000011541 reaction mixture Substances 0.000 description 61
- 238000003756 stirring Methods 0.000 description 57
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 57
- 238000004293 19F NMR spectroscopy Methods 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 235000008504 concentrate Nutrition 0.000 description 43
- 239000012141 concentrate Substances 0.000 description 43
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 41
- 239000000706 filtrate Substances 0.000 description 37
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 36
- 238000005406 washing Methods 0.000 description 34
- 239000003921 oil Substances 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 27
- 230000008569 process Effects 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 22
- 238000001035 drying Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 108091000080 Phosphotransferase Proteins 0.000 description 18
- 238000002441 X-ray diffraction Methods 0.000 description 18
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 18
- 238000002050 diffraction method Methods 0.000 description 18
- 102000020233 phosphotransferase Human genes 0.000 description 18
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 18
- 238000010790 dilution Methods 0.000 description 17
- 239000012895 dilution Substances 0.000 description 17
- 238000001556 precipitation Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 230000026731 phosphorylation Effects 0.000 description 16
- 238000006366 phosphorylation reaction Methods 0.000 description 16
- 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 16
- 238000001953 recrystallisation Methods 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 229960004756 ethanol Drugs 0.000 description 14
- 229940124647 MEK inhibitor Drugs 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 235000010418 carrageenan Nutrition 0.000 description 12
- 229920001525 carrageenan Polymers 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000005711 Benzoic acid Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- WTUCZTLXWVYFGC-UHFFFAOYSA-N 3-fluoro-2-(2-fluoro-4-iodoanilino)benzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1NC1=CC=C(I)C=C1F WTUCZTLXWVYFGC-UHFFFAOYSA-N 0.000 description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 9
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical class CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012266 salt solution Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 238000001994 activation Methods 0.000 description 8
- 235000010233 benzoic acid Nutrition 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- YLFIGGHWWPSIEG-UHFFFAOYSA-N aminoxyl Chemical compound [O]N YLFIGGHWWPSIEG-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 235000010290 biphenyl Nutrition 0.000 description 7
- 239000004305 biphenyl Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007822 coupling agent Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 5
- GFGPPOWEMLVELP-UHFFFAOYSA-N CC(C)CC(CONC(=O)C1=CC=CC=C1F)O Chemical compound CC(C)CC(CONC(=O)C1=CC=CC=C1F)O GFGPPOWEMLVELP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 5
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 5
- 125000003368 amide group Chemical group 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 125000006267 biphenyl group Chemical group 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000005897 peptide coupling reaction Methods 0.000 description 5
- 125000005499 phosphonyl group Chemical group 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 4
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 description 4
- 208000004454 Hyperalgesia Diseases 0.000 description 4
- 206010065952 Hyperpathia Diseases 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- DCIKEGMDLASJHI-UHFFFAOYSA-N o-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine Chemical compound CC1(C)OCC(CON)O1 DCIKEGMDLASJHI-UHFFFAOYSA-N 0.000 description 4
- DCIKEGMDLASJHI-RXMQYKEDSA-N o-[[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]hydroxylamine Chemical compound CC1(C)OC[C@H](CON)O1 DCIKEGMDLASJHI-RXMQYKEDSA-N 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 3
- 102000002734 Collagen Type VI Human genes 0.000 description 3
- 108010043741 Collagen Type VI Proteins 0.000 description 3
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 3
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- 238000010306 acid treatment Methods 0.000 description 3
- 125000005262 alkoxyamine group Chemical group 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 125000005027 hydroxyaryl group Chemical group 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- DCIKEGMDLASJHI-YFKPBYRVSA-N o-[[(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]hydroxylamine Chemical compound CC1(C)OC[C@@H](CON)O1 DCIKEGMDLASJHI-YFKPBYRVSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- DMBKPDOAQVGTST-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-LBPRGKRZSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- HKDQXFITKMWGCA-UHFFFAOYSA-N 3-fluoro-2-(4-iodo-2-methylanilino)benzoic acid Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C=CC=C1C(O)=O HKDQXFITKMWGCA-UHFFFAOYSA-N 0.000 description 2
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- GFOCZFXQUADASE-UHFFFAOYSA-N C(N)(OC(C(C)CCO)(C)C)=O Chemical compound C(N)(OC(C(C)CCO)(C)C)=O GFOCZFXQUADASE-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- 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 2
- SXZYCXMUPBBULW-SKNVOMKLSA-N L-gulono-1,4-lactone Chemical compound OC[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O SXZYCXMUPBBULW-SKNVOMKLSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- XEKSPVOVAOAEAT-UHFFFAOYSA-N N-[3-chloro-2-(4-morpholinyl)phenyl]-2,3,5,6-tetrafluoro-4-methoxybenzamide Chemical compound FC1=C(F)C(OC)=C(F)C(F)=C1C(=O)NC1=CC=CC(Cl)=C1N1CCOCC1 XEKSPVOVAOAEAT-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- SUDAHWBOROXANE-SECBINFHSA-N PD 0325901 Chemical compound OC[C@@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-SECBINFHSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000863480 Vinca Species 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- QQEXMHVHLWKOQT-UHFFFAOYSA-N benzene;formamide Chemical compound NC=O.C1=CC=CC=C1 QQEXMHVHLWKOQT-UHFFFAOYSA-N 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 description 2
- VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical class OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002270 ergogenic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 235000014666 liquid concentrate Nutrition 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- HGRVXMYTWATGPH-UHFFFAOYSA-N o-(2-anilinoethyl)hydroxylamine Chemical compound NOCCNC1=CC=CC=C1 HGRVXMYTWATGPH-UHFFFAOYSA-N 0.000 description 2
- OHMDETQKZNUOTA-UHFFFAOYSA-N o-[(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine Chemical compound CC1(C)OC(CON)C(C)(C)O1 OHMDETQKZNUOTA-UHFFFAOYSA-N 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 102220007331 rs111033633 Human genes 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 230000008054 signal transmission Effects 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 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
- 238000012546 transfer Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- GEKRSZPFMBQNCM-ZDUSSCGKSA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@H](C(O)=O)COCC1=CC=CC=C1 GEKRSZPFMBQNCM-ZDUSSCGKSA-N 0.000 description 1
- JNTPPVKRHGNFKM-BNHYGAARSA-N (3s,4r,5s)-5-[(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]-3,4-dihydroxyoxolan-2-one Chemical compound O1C(C)(C)OC[C@H]1[C@@H]1[C@H](O)[C@H](O)C(=O)O1 JNTPPVKRHGNFKM-BNHYGAARSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- COKKIDKKSICZHR-UHFFFAOYSA-N 1,1'-biphenyl;silicon Chemical compound [Si].C1=CC=CC=C1C1=CC=CC=C1 COKKIDKKSICZHR-UHFFFAOYSA-N 0.000 description 1
- YJZDTHNWQIMGBF-UHFFFAOYSA-N 1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol Chemical compound CC(O)C1COC(C)(C)O1 YJZDTHNWQIMGBF-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- XZKFBZOAIGFZSU-UHFFFAOYSA-N 1-bromo-4-methylpentane Chemical compound CC(C)CCCBr XZKFBZOAIGFZSU-UHFFFAOYSA-N 0.000 description 1
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- WBKWWYPEWPHALD-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl WBKWWYPEWPHALD-UHFFFAOYSA-N 0.000 description 1
- WHTMHARNYVWYIS-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl WHTMHARNYVWYIS-UHFFFAOYSA-N 0.000 description 1
- BWWXYDPBLQAIMO-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxybutoxy)benzamide Chemical compound CCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl BWWXYDPBLQAIMO-UHFFFAOYSA-N 0.000 description 1
- DVFFQPCSVDNFLB-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxypentoxy)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl DVFFQPCSVDNFLB-UHFFFAOYSA-N 0.000 description 1
- OQANMZOXPWWLSW-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl OQANMZOXPWWLSW-UHFFFAOYSA-N 0.000 description 1
- MERZHTPZMRTRJF-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl MERZHTPZMRTRJF-UHFFFAOYSA-N 0.000 description 1
- LGXORWWOMRIGGW-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl LGXORWWOMRIGGW-UHFFFAOYSA-N 0.000 description 1
- ADKMKKAXWZSEGH-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(O)CC1 ADKMKKAXWZSEGH-UHFFFAOYSA-N 0.000 description 1
- QMWPDJDSNAFMGV-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(CO)CC1 QMWPDJDSNAFMGV-UHFFFAOYSA-N 0.000 description 1
- PWNCTVHKNUTMQB-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl PWNCTVHKNUTMQB-UHFFFAOYSA-N 0.000 description 1
- DCPWQIJZWVSUFP-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-(3,4-dihydroxybutoxy)-4-fluorobenzamide Chemical compound OCC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1Cl DCPWQIJZWVSUFP-UHFFFAOYSA-N 0.000 description 1
- BMGMINKVTPDDRZ-UHFFFAOYSA-N 2-acetamido-n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide;n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methyl-2-(propanoylamino)pentanamide Chemical compound CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N.CCC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N BMGMINKVTPDDRZ-UHFFFAOYSA-N 0.000 description 1
- ZHPJDHNKDVBXAV-UHFFFAOYSA-N 2-acetyl-4-methoxybenzoic acid Chemical class COC1=CC=C(C(O)=O)C(C(C)=O)=C1 ZHPJDHNKDVBXAV-UHFFFAOYSA-N 0.000 description 1
- MWGATWIBSKHFMR-UHFFFAOYSA-N 2-anilinoethanol Chemical compound OCCNC1=CC=CC=C1 MWGATWIBSKHFMR-UHFFFAOYSA-N 0.000 description 1
- VUIWJRYTWUGOOF-UHFFFAOYSA-N 2-ethenoxyethanol Chemical compound OCCOC=C VUIWJRYTWUGOOF-UHFFFAOYSA-N 0.000 description 1
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-hydroxybutyric acid Chemical class CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- HMGCGUWFPZVPEK-UHFFFAOYSA-N 2-naphthalen-2-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=C1 HMGCGUWFPZVPEK-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- LYIDAFTZPRFBDK-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F LYIDAFTZPRFBDK-UHFFFAOYSA-N 0.000 description 1
- NGHMYNTYUWKZKJ-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F NGHMYNTYUWKZKJ-UHFFFAOYSA-N 0.000 description 1
- PTPNZWBYDGDGGO-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxybutoxy)benzamide Chemical compound CCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F PTPNZWBYDGDGGO-UHFFFAOYSA-N 0.000 description 1
- UQGPYVLXPDVPGU-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxypentoxy)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F UQGPYVLXPDVPGU-UHFFFAOYSA-N 0.000 description 1
- UKGWOWHVPXNWBI-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F UKGWOWHVPXNWBI-UHFFFAOYSA-N 0.000 description 1
- LCDRZNIKRCUYMJ-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F LCDRZNIKRCUYMJ-UHFFFAOYSA-N 0.000 description 1
- LLSITLHETIOLGL-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(O)CC1 LLSITLHETIOLGL-UHFFFAOYSA-N 0.000 description 1
- UNYOURYKWYVKOZ-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(CO)CC1 UNYOURYKWYVKOZ-UHFFFAOYSA-N 0.000 description 1
- SMBBHMWCZMJKOG-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F SMBBHMWCZMJKOG-UHFFFAOYSA-N 0.000 description 1
- COEXMYRMIABFRK-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(N)=O COEXMYRMIABFRK-UHFFFAOYSA-N 0.000 description 1
- IIJDQEBBOFOXKL-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)benzoic acid Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(O)=O IIJDQEBBOFOXKL-UHFFFAOYSA-N 0.000 description 1
- FEQLQZICMOBGRS-UHFFFAOYSA-N 4-fluoro-n-(2-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C FEQLQZICMOBGRS-UHFFFAOYSA-N 0.000 description 1
- MTIKIZZACLCGJG-UHFFFAOYSA-N 4-fluoro-n-(2-hydroxy-4-methylpentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C MTIKIZZACLCGJG-UHFFFAOYSA-N 0.000 description 1
- QBJWJVIWYFPPGV-UHFFFAOYSA-N 4-fluoro-n-(2-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C QBJWJVIWYFPPGV-UHFFFAOYSA-N 0.000 description 1
- IOMVSFTYHJOGQY-UHFFFAOYSA-N 4-fluoro-n-(2-hydroxypentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C IOMVSFTYHJOGQY-UHFFFAOYSA-N 0.000 description 1
- VYFQIGLVLIZTIG-UHFFFAOYSA-N 4-fluoro-n-(3-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCCC(C)(C)O VYFQIGLVLIZTIG-UHFFFAOYSA-N 0.000 description 1
- JBBGNWBHMNUFRU-UHFFFAOYSA-N 4-fluoro-n-(3-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C JBBGNWBHMNUFRU-UHFFFAOYSA-N 0.000 description 1
- OGRRNRJIYSKZQD-UHFFFAOYSA-N 4-fluoro-n-(3-hydroxypentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C OGRRNRJIYSKZQD-UHFFFAOYSA-N 0.000 description 1
- QGRLMTIYRAVMHG-UHFFFAOYSA-N 4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC1(O)CC1 QGRLMTIYRAVMHG-UHFFFAOYSA-N 0.000 description 1
- MKSSPKXNXNFXTA-UHFFFAOYSA-N 4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC1(CO)CC1 MKSSPKXNXNFXTA-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical class OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- BAILDHSVSVQRGM-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl BAILDHSVSVQRGM-UHFFFAOYSA-N 0.000 description 1
- VFVXCMCAEAIQGI-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl VFVXCMCAEAIQGI-UHFFFAOYSA-N 0.000 description 1
- OVUSTCYZPWBWBC-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxypentoxy)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl OVUSTCYZPWBWBC-UHFFFAOYSA-N 0.000 description 1
- MKPUXODZQHCIMH-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl MKPUXODZQHCIMH-UHFFFAOYSA-N 0.000 description 1
- HUBCXORWAAAMLR-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl HUBCXORWAAAMLR-UHFFFAOYSA-N 0.000 description 1
- HWEWVZDFNWGOMO-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl HWEWVZDFNWGOMO-UHFFFAOYSA-N 0.000 description 1
- VZWMNECLDGYCFA-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C(Br)=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(O)CC1 VZWMNECLDGYCFA-UHFFFAOYSA-N 0.000 description 1
- DTACSTASXQLHHW-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C(Br)=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(CO)CC1 DTACSTASXQLHHW-UHFFFAOYSA-N 0.000 description 1
- IJPMVHOFFMNYJQ-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl IJPMVHOFFMNYJQ-UHFFFAOYSA-N 0.000 description 1
- NTXFKHFYNDPCBF-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-(3,4-dihydroxybutoxy)-4-fluorobenzamide Chemical compound OCC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1Cl NTXFKHFYNDPCBF-UHFFFAOYSA-N 0.000 description 1
- JDNMKLHTJMROIH-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F JDNMKLHTJMROIH-UHFFFAOYSA-N 0.000 description 1
- QUTQKXKAPLXSOV-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F QUTQKXKAPLXSOV-UHFFFAOYSA-N 0.000 description 1
- YWVGEFQWABZZDC-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxybutoxy)benzamide Chemical compound CCC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F YWVGEFQWABZZDC-UHFFFAOYSA-N 0.000 description 1
- LEPQNSCDMQATQH-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F LEPQNSCDMQATQH-UHFFFAOYSA-N 0.000 description 1
- XOEBHTMTOGWROY-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F XOEBHTMTOGWROY-UHFFFAOYSA-N 0.000 description 1
- KPDGSFQTMVVJLH-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F KPDGSFQTMVVJLH-UHFFFAOYSA-N 0.000 description 1
- AUGKPDCZUNRTBS-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C(Br)=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(O)CC1 AUGKPDCZUNRTBS-UHFFFAOYSA-N 0.000 description 1
- OQZGXGZEJKXFBQ-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C(Br)=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(CO)CC1 OQZGXGZEJKXFBQ-UHFFFAOYSA-N 0.000 description 1
- QOUVBDFDIWWEQE-UHFFFAOYSA-N 5-bromo-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F QOUVBDFDIWWEQE-UHFFFAOYSA-N 0.000 description 1
- RIFFBBNSIDSYJT-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(2-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C RIFFBBNSIDSYJT-UHFFFAOYSA-N 0.000 description 1
- AVGJMEHQVUIXKQ-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(2-hydroxy-4-methylpentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C AVGJMEHQVUIXKQ-UHFFFAOYSA-N 0.000 description 1
- YXSCJSQZELLLTI-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(2-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C YXSCJSQZELLLTI-UHFFFAOYSA-N 0.000 description 1
- OECVIUXHAQAAPD-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(2-hydroxypentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C OECVIUXHAQAAPD-UHFFFAOYSA-N 0.000 description 1
- MHTFFFYKALMEMW-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(3-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Br)C=C1C(=O)NOCCC(C)(C)O MHTFFFYKALMEMW-UHFFFAOYSA-N 0.000 description 1
- FWKMFXRLIZHFDB-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(3-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C FWKMFXRLIZHFDB-UHFFFAOYSA-N 0.000 description 1
- VKURWXJXXYFNOI-UHFFFAOYSA-N 5-bromo-4-fluoro-n-(3-hydroxypentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1C VKURWXJXXYFNOI-UHFFFAOYSA-N 0.000 description 1
- YDSYVNIUPLOBRS-UHFFFAOYSA-N 5-bromo-4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Br)C=C1C(=O)NOCC1(O)CC1 YDSYVNIUPLOBRS-UHFFFAOYSA-N 0.000 description 1
- VWHMIPFWWHPYAH-UHFFFAOYSA-N 5-bromo-4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Br)C=C1C(=O)NOCC1(CO)CC1 VWHMIPFWWHPYAH-UHFFFAOYSA-N 0.000 description 1
- XPWLWFYYEVAKLL-UHFFFAOYSA-N 5-bromo-4-fluoro-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Br)C=C1C(=O)NOCC1C(CO)C1 XPWLWFYYEVAKLL-UHFFFAOYSA-N 0.000 description 1
- CRYWQMLPWHZGMV-UHFFFAOYSA-N 5-bromo-n-(3,4-dihydroxybutoxy)-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CCONC(=O)C1=CC(Br)=C(F)C=C1NC1=CC=C(I)C=C1F CRYWQMLPWHZGMV-UHFFFAOYSA-N 0.000 description 1
- CIQRXTUAEQXFOQ-UHFFFAOYSA-N 5-bromo-n-(3,4-dihydroxybutoxy)-4-fluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Br)C=C1C(=O)NOCCC(O)CO CIQRXTUAEQXFOQ-UHFFFAOYSA-N 0.000 description 1
- UAUVEAUNLPTPMF-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-3-methoxypropoxy)benzamide Chemical compound COCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl UAUVEAUNLPTPMF-UHFFFAOYSA-N 0.000 description 1
- QKFGQKKVPARDFV-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl QKFGQKKVPARDFV-UHFFFAOYSA-N 0.000 description 1
- WCLPOMPCVIDEID-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl WCLPOMPCVIDEID-UHFFFAOYSA-N 0.000 description 1
- HGTLKMUCRJBICZ-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxybutoxy)benzamide Chemical compound CCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl HGTLKMUCRJBICZ-UHFFFAOYSA-N 0.000 description 1
- KANXQACMPJXDAO-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(2-hydroxypentoxy)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl KANXQACMPJXDAO-UHFFFAOYSA-N 0.000 description 1
- DZYORQGQSNIHNV-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl DZYORQGQSNIHNV-UHFFFAOYSA-N 0.000 description 1
- NMXVTFQPCBHSOU-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl NMXVTFQPCBHSOU-UHFFFAOYSA-N 0.000 description 1
- JSWJNRTUPIPGIK-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl JSWJNRTUPIPGIK-UHFFFAOYSA-N 0.000 description 1
- UZNBOWDGRAWIMB-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C(Cl)=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(O)CC1 UZNBOWDGRAWIMB-UHFFFAOYSA-N 0.000 description 1
- GXWBRZVIMVVFOJ-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C(Cl)=C(F)C=C(NC=2C(=CC(I)=CC=2)Cl)C=1C(=O)NOCC1(CO)CC1 GXWBRZVIMVVFOJ-UHFFFAOYSA-N 0.000 description 1
- PUTLYXOLDAXSPZ-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-4-fluoro-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl PUTLYXOLDAXSPZ-UHFFFAOYSA-N 0.000 description 1
- FCNSWXLBRAZLLK-UHFFFAOYSA-N 5-chloro-2-(2-chloro-4-iodoanilino)-n-(3,4-dihydroxybutoxy)-4-fluorobenzamide Chemical compound OCC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1Cl FCNSWXLBRAZLLK-UHFFFAOYSA-N 0.000 description 1
- GHVCOMMFVXKSPB-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(1-hydroxypropan-2-yloxy)benzamide Chemical compound OCC(C)ONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F GHVCOMMFVXKSPB-UHFFFAOYSA-N 0.000 description 1
- LQWBVTRGPHLFEW-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-3-methoxypropoxy)benzamide Chemical compound COCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F LQWBVTRGPHLFEW-UHFFFAOYSA-N 0.000 description 1
- UGSHKHJQFHIBBW-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F UGSHKHJQFHIBBW-UHFFFAOYSA-N 0.000 description 1
- ODRATJMTXWBARF-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxy-4-methylpentoxy)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F ODRATJMTXWBARF-UHFFFAOYSA-N 0.000 description 1
- LUYRETDKRMCFLG-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxybutoxy)benzamide Chemical compound CCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F LUYRETDKRMCFLG-UHFFFAOYSA-N 0.000 description 1
- KOTQFVLSRKAHNY-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxypentoxy)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F KOTQFVLSRKAHNY-UHFFFAOYSA-N 0.000 description 1
- OEKYIQATVIAAQD-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxy-2-methoxypropoxy)benzamide Chemical compound COC(CO)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F OEKYIQATVIAAQD-UHFFFAOYSA-N 0.000 description 1
- ACJUDTFSQACDDJ-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxy-3-methylbutoxy)benzamide Chemical compound CC(C)(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F ACJUDTFSQACDDJ-UHFFFAOYSA-N 0.000 description 1
- ZXIBGQVVLNTGGW-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxybutoxy)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F ZXIBGQVVLNTGGW-UHFFFAOYSA-N 0.000 description 1
- AAWRCROXDXKPCG-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-(3-hydroxypentoxy)benzamide Chemical compound CCC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F AAWRCROXDXKPCG-UHFFFAOYSA-N 0.000 description 1
- LOOMSEXYDSSZAU-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[(1-hydroxycyclopropyl)methoxy]benzamide Chemical compound C=1C(Cl)=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(O)CC1 LOOMSEXYDSSZAU-UHFFFAOYSA-N 0.000 description 1
- DCLASIVFFRWWIC-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound C=1C(Cl)=C(F)C=C(NC=2C(=CC(I)=CC=2)F)C=1C(=O)NOCC1(CO)CC1 DCLASIVFFRWWIC-UHFFFAOYSA-N 0.000 description 1
- BNTZVMZZDMLAIT-UHFFFAOYSA-N 5-chloro-4-fluoro-2-(2-fluoro-4-iodoanilino)-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]benzamide Chemical compound OCC1CC1CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F BNTZVMZZDMLAIT-UHFFFAOYSA-N 0.000 description 1
- ILXBBTOMPUATPS-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(2-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)C(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1C ILXBBTOMPUATPS-UHFFFAOYSA-N 0.000 description 1
- MQYBMXZRKAIMRU-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(2-hydroxy-4-methylpentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(C)CC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1C MQYBMXZRKAIMRU-UHFFFAOYSA-N 0.000 description 1
- WNSUJCHDSVGCAY-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(2-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1C WNSUJCHDSVGCAY-UHFFFAOYSA-N 0.000 description 1
- CHAGBTPMRUUGGN-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(2-hydroxypentoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CCCC(O)CONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1C CHAGBTPMRUUGGN-UHFFFAOYSA-N 0.000 description 1
- OABXVKLFHAEPMF-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(3-hydroxy-3-methylbutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Cl)C=C1C(=O)NOCCC(C)(C)O OABXVKLFHAEPMF-UHFFFAOYSA-N 0.000 description 1
- ZUKTYIGWNVOJAN-UHFFFAOYSA-N 5-chloro-4-fluoro-n-(3-hydroxybutoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1C ZUKTYIGWNVOJAN-UHFFFAOYSA-N 0.000 description 1
- NWXLCUCGIWXKKH-UHFFFAOYSA-N 5-chloro-4-fluoro-n-[(1-hydroxycyclopropyl)methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Cl)C=C1C(=O)NOCC1(O)CC1 NWXLCUCGIWXKKH-UHFFFAOYSA-N 0.000 description 1
- LQGHDKGKJZHIPK-UHFFFAOYSA-N 5-chloro-4-fluoro-n-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Cl)C=C1C(=O)NOCC1(CO)CC1 LQGHDKGKJZHIPK-UHFFFAOYSA-N 0.000 description 1
- JPAVQZWKYCBYRH-UHFFFAOYSA-N 5-chloro-4-fluoro-n-[[2-(hydroxymethyl)cyclopropyl]methoxy]-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Cl)C=C1C(=O)NOCC1C(CO)C1 JPAVQZWKYCBYRH-UHFFFAOYSA-N 0.000 description 1
- MDFILRMZCIASQO-UHFFFAOYSA-N 5-chloro-n-(3,4-dihydroxybutoxy)-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CCONC(=O)C1=CC(Cl)=C(F)C=C1NC1=CC=C(I)C=C1F MDFILRMZCIASQO-UHFFFAOYSA-N 0.000 description 1
- YQBLGMKTPKMTTB-UHFFFAOYSA-N 5-chloro-n-(3,4-dihydroxybutoxy)-4-fluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(Cl)C=C1C(=O)NOCCC(O)CO YQBLGMKTPKMTTB-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000008822 Ankylosis Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 1
- CVCJPBRSHMCVML-UHFFFAOYSA-N CCC(CONC(=O)C1=C(C(=CC=C1)F)NC2=C(C=C(C=C2)I)C)O Chemical compound CCC(CONC(=O)C1=C(C(=CC=C1)F)NC2=C(C=C(C=C2)I)C)O CVCJPBRSHMCVML-UHFFFAOYSA-N 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 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
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical class OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 102100023275 Dual specificity mitogen-activated protein kinase kinase 3 Human genes 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108010046732 HLA-DR4 Antigen Proteins 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 101001115394 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 3 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 206010023198 Joint ankylosis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010011078 Leupeptins Proteins 0.000 description 1
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 1
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 101150076359 Mhc gene Proteins 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 108010036222 Pepstatins Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 238000003723 Smelting Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005021 aminoalkenyl group Chemical group 0.000 description 1
- 125000005014 aminoalkynyl group Chemical group 0.000 description 1
- 125000005001 aminoaryl group Chemical group 0.000 description 1
- 125000005124 aminocycloalkyl group Chemical group 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 201000004983 autoimmune atherosclerosis Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- QZRWJJLUUOMZIT-UHFFFAOYSA-N chloro-dimethyl-pentylsilane Chemical group CCCCC[Si](C)(C)Cl QZRWJJLUUOMZIT-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- IAQRGUVFOMOMEM-ARJAWSKDSA-N cis-but-2-ene Chemical compound C\C=C/C IAQRGUVFOMOMEM-ARJAWSKDSA-N 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 229950002314 closilate Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 229940125773 compound 10 Drugs 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
- 238000005520 cutting process Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 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 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- KYYUCZOHNYSLFV-UHFFFAOYSA-N diethyl cyclopropane-1,1-dicarboxylate Chemical compound CCOC(=O)C1(C(=O)OCC)CC1 KYYUCZOHNYSLFV-UHFFFAOYSA-N 0.000 description 1
- 229940079920 digestives acid preparations Drugs 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- QCIDBNKTKNBPKM-UHFFFAOYSA-N dihydroxybenzamide Natural products NC(=O)C1=CC=CC(O)=C1O QCIDBNKTKNBPKM-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 description 1
- 208000022602 disease susceptibility Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000005357 flat glass Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- JDXWDWYCUKQTCI-UHFFFAOYSA-N n,n-dihydroxybenzamide Chemical compound ON(O)C(=O)C1=CC=CC=C1 JDXWDWYCUKQTCI-UHFFFAOYSA-N 0.000 description 1
- QEOYDJZPMVJDIK-UHFFFAOYSA-N n-(3,4-dihydroxybutoxy)-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CCONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F QEOYDJZPMVJDIK-UHFFFAOYSA-N 0.000 description 1
- UXHYAEFTSVZZRP-UHFFFAOYSA-N n-(3,4-dihydroxybutoxy)-4-fluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCCC(O)CO UXHYAEFTSVZZRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 229950005216 napadisilate Drugs 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical class CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- WTLOGKMDQWEFOK-UHFFFAOYSA-N oxolane;triphenylphosphane Chemical compound C1CCOC1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WTLOGKMDQWEFOK-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
-
- 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
- A61P17/06—Antipsoriatics
-
- 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
- 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
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- A61P37/02—Immunomodulators
-
- 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
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- 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
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
本发明涉及4-碘苯氨基苯氧肟酸衍生物的氧合酯、其药物组合物和使用方法。本发明还涉及4-碘苯氨基苯氧肟酸衍生物的氧合酯的结晶形式、其药物组合物和使用方法。
Description
发明领域
本发明涉及4-碘苯氨基苯氧肟酸衍生物的氧合酯(oxygenatedester)、其药物组合物和使用方法。本发明还涉及4-碘苯氨基苯氧肟酸衍生物的氧合酯的结晶形式、其药物组合物和使用方法。
发明背景
MAPK/ERK激酶(“MEK”)是双重特异性的激酶,例如参与免疫调节、炎症和增殖性疾病,例如癌症和再狭窄。
增殖性疾病是由细胞内信号发送***或某些蛋白质的信号转导机理的缺陷所导致的。缺陷包括信号发送级联中一种或多种信号发送蛋白的内在活性或细胞浓度的改变。细胞可以产生与其自身受体结合的生长因子,导致自分泌环,后者继续刺激增殖。细胞内信号发送蛋白的突变或过度表达可以引起细胞内的伪致有丝***信号。有些最常见的突变发生在编码已知蛋白质Ras的基因中,这是一种G蛋白,当与GTP结合时被激活,当与GDP结合时被灭活。上面提到的生长因子受体和很多其他致有丝***受体当被激活时,引起Ras从GDP结合状态转化为GTP结合状态。这种信号是大多数细胞类型增殖的绝对的先决条件。这种信号发送***、尤其是Ras-GTP复合体失活作用中的缺陷在癌症中是普遍的,引起Ras下游的信号发送级联被慢性激活。
被激活的Ras继而引起丝氨酸/苏氨酸激酶级联的活化作用。已知需要活性Ras-GTP用于自身活化作用的一组激酶是Raf家族。它们继而激活MEK(例如MEK1和MEK2),后者然后激活MAP激酶ERK(ERK1和ERK2)。有丝***原对MAP激酶的活化作用似乎是增殖所必需的;这种激酶的组成型活化作用足以诱导细胞的转化作用。下游Ras信号发送的阻滞、例如利用优势阴性Raf-1蛋白能够完全抑制从细胞表面受体或致癌性Ras突变体诱导的有丝***发生。尽管Ras本身不是蛋白激酶,不过它参与Raf和其他激酶的活化作用,最可能的是通过磷酸化作用机理。一旦被激活,Raf和其他激酶在两个紧邻的丝氨酸残基上磷酸化MEK,在MEK-1的情况下是S218和S222,它们是MEK作为激酶的活化作用的先决条件。MEK继而在酪氨酸残基Y185和苏氨酸残基T183上磷酸化MAP激酶,二者间隔单一的氨基酸。这种双磷酸化作用激活MAP激酶至少100倍。被激活的MAP激酶然后能够催化大量蛋白质的磷酸化作用,包括若干转录因子和其他激酶。很多这些MAP激酶的磷酸化作用在有丝***水平上激活靶蛋白,例如激酶、转录因子或另一种细胞蛋白。除了Raf-1和MEKK以外,其他激酶也激活MEK,MEK本身似乎是一种信号整合激酶。目前的认识是MEK对MAP激酶的磷酸化作用是高度特异性的。事实上,迄今已经证明除MAP激酶ERK以外再没有MEK的底物,MEK不磷酸化基于MAP激酶磷酸化作用序列的肽,或者甚至不磷酸化变性的MAP激酶。MEK还似乎在磷酸化MAP激酶之前与之紧密缔合,提示了MEK对MAP激酶的磷酸化作用可能需要在先的这两种蛋白质之间的强相互作用。这种需要和MEK的不寻常的特异性都提示它可能在其作用机理上有别于其他蛋白激酶,这种差异足以发现可能通过变构机理而非通常的ATP结合位点阻滞作用来发挥作用的选择性MEK抑制剂。
已经发现,本发明的化合物是MEK的抑制剂,可用于治疗各种增殖性疾病状态,例如涉及MEK机能亢进的病症以及受MEK级联调节的疾病。
发明概述
本发明提供下式化合物
其中
R1是氢、卤素或硝基;
R2是氢或氟;
R3是氢或氟;
R4是氢、碘、溴、氯或氟;
R5是氢、卤素、羟基、C1-8烷基、C1-8烷氧基、三氟甲基或氰基;
n是1至5;
R6、R7、R8、R9和R10独立地是氢、C1-8烷基、C3-8环烷基、羟基、C1-8烷氧基、全卤代(C1-3)烷基、羟基(C1-8)烷基、(C1-5)烷氧基(C1-5)烷基、[(C1-4)烷基]2氨基甲基、(C2-7)杂环(C1-5)烷基或芳氧基(C1-5)烷基,或者可以独立地连接构成3-10元环,可选地含有另外的杂原子,选自由O、S、NH和N-烷基组成的组,其中对于n>1 R7和R8是独立地加以选择的;
Ra和Rb独立地是氢或C1-4烷基;
W是O或NRa;
R11是氢、C1-8烷基、C2-6链烯基、C3-8环烷基、羟基(C1-8)烷基、(C1-5烷氧基(C1-5)烷基、苯基、C2-7杂芳基、(C1-8)烷基羰基、(苯基)羰基、(苯基)(C1-3烷基)羰基或三氟(C1-6)烷基;
其中上述烷基、烷氧基、环烷基、杂芳基和苯基可以可选地被1至5个取代基取代,取代基独立地选自由羟基、氨基、单烷基氨基、二烷基氨基、卤素、氰基、(C1-3)烷氧基、COOR、OCORa、CONRaRb、NRaCORb、SO、SO2、SO4和SO2NRaRb组成的组;
及其药学上可接受的盐、(C1-6)酰胺和(C1-6)酯;
其条件是若R11是苯基,n是1,则W不能是O;
进一步的条件是该化合物不是
5-溴-N-(2-二乙氨基-乙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-N-(2-二甲氨基-丙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;或
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2-二甲氨基-乙氧基)-3,4-二氟-苯甲酰胺。
本发明还提供下式化合物
其中
R1是氢或卤素;
R3是氢或氟;
R4是氢、碘、溴、氯或氟;
R5是氢、卤素或C1-8烷基;
n是1至5;
R6、R7、R8、R9和R10独立地是氢、C1-8烷基、羟基、C1-8烷氧基、全卤代(C1-3)烷基、(C2-7)杂环(C1-5)烷基或芳氧基(C1-5)烷基,或者可以独立地连接构成3-10元环,可选地含有另外的杂原子,选自由O、S、NH和N-烷基组成的组,其中对于n>1 R7和R8是独立地加以选择的;
Ra和Rb独立地是氢或C1-4烷基;
W是O或NRa;
R11是氢、C1-8烷基、C2-6链烯基、(C1-5)烷氧基(C1-5)烷基、苯基、(C1-8)烷基羰基或三氟(C1-6)烷基;
其中上述烷基、烷氧基、环烷基、杂芳基和苯基可以可选地被1至5个取代基取代,取代基独立地选自由羟基、氨基、单烷基氨基、二烷基氨基、卤素、氰基、(C1-3)烷氧基、COOR、OCORa、CONRaRb、NRaCORb、SO、SO2、SO4和SO2NRaRb组成的组;
及其药学上可接受的盐、(C1-6)酰胺和(C1-6)酯;
其条件是若R11是苯基,n是1,则W不能是O;
进一步的条件是该化合物不是
5-溴-N-(2-二乙氨基-乙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-N-(2-二甲氨基-丙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;或
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2-二甲氨基-乙氧基)-3,4-二氟-苯甲酰胺。
本发明还提供药物组合物,包含式I或Ia化合物和药学上可接受的载体。
另外,本发明提供在需要时治疗患者增殖性疾病的方法,包含给以治疗有效量的式I或Ia化合物。
本发明还提供式I或Ia化合物在药物制造中的用途,该药物用于治疗增殖性疾病。
此外,本发明提供在需要时治疗患者癌症、再狭窄、牛皮癣、自体免疫疾病、动脉粥样硬化、骨关节炎、类风湿性关节炎、心衰、慢性疼痛和神经病性疼痛的方法,包含给以治疗有效量的式I或Ia化合物。
本发明还提供式I或Ia化合物在药物制造中的用途,该药物用于治疗癌症、再狭窄、牛皮癣、自体免疫疾病、动脉粥样硬化、骨关节炎、类风湿性关节炎、心衰、慢性疼痛和神经病性疼痛。
另外,本发明提供用于在需要时治疗患者癌症的方法,包含给以治疗有效量的式I或Ia化合物与放射疗法或至少一种化疗剂的组合。
另一方面,本发明提供结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:7.1,19.2或32.1。
本发明还提供结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:7.1,19.2和32.1。
另外,本发明提供结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:7.1,14.1,15.3,15.8,16.9,18.1,19.2,20.3,21.4,22.3,23.4,24.5,25.5,26.2,26.8,27.8,28.3,29.5,32.1,33.2,33.6,40.0,42.9和44.1。
还由本发明所提供的是结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:11.6,12.6或24.9。
本发明还提供结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:11.6,12.6和24.9。
另外,本发明提供结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:11.6,12.6,15.6,17.3,17.9,20.3,21.1,22.1,24.9,25.9,26.7,27.8,30.1,30.9,33.8,35.4,38.2,39.3,40.8,41.6,43.6和47.0。
另外,本发明提供结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:10.6,13.7,19.0或23.7。
另外,本发明提供结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.6,13.7,19.0和23.7。
还由本发明所提供的是结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.6,13.7,14.6,17.3,18.0,18.2,98.0,19.3,20.1,21.0,21.9,22.4,23.7,24.0,24.9,26.3,27.6,28.0,30.1,32.1,32.3,32.9,35.8和37.7。
此外,本发明提供结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.5或19.6。
本发明还提供结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.5和19.6
另外,本发明提供结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.5,10.7,16.5,19.6,22.0,22.5,23.6,24.1,25.0,26.2,27.6,29.1,30.5,31.7,33.3和39.0。
另外,本发明提供结晶I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射值含有利用CuKα线辐射测量的至少一个下列2θ值:10.5,13.7,19.0或23.6。
还由本发明所提供的是结晶I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.5,13.7,19.0和23.6。
此外,本发明提供结晶I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.548,13.703,17.887,18.958,20.122,21.950,22.321,23.640,24.803,26.244,27.570,28.000,29.566,32.234,32.769,35.804,37.641,41.402,41.956和44.600。
本发明还提供结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.6或19.6。
另外,本发明提供结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.6和19.6
另外,本发明提供结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线衍射粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.6,10.7,16.5,19.6,20.9,22.0,23.7,24.2,25.0,26.2,27.7,28.0,29.1,31.7,32.8,33.3,34.1,42.0和42.3。
附图的简要说明
参照简要描述如下的附图1至6,下列非限制性实例进一步描述本发明。
图1
I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约350计数每秒(cps))。
图2
II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约1200cps)。
图3
I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约600cps)。
图4
II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约1250cps)。
图5
I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约2600cps)。
图6
II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的衍射图(Y-轴=0至最大强度约700cps)。
发明的详细说明
某些术语是如下所定义的,适用于全文。
术语“卤素”或“卤代”在本发明中表示氟、溴、氯和碘原子或氟代、溴代、氯代和碘代。术语氟和氟代例如被理解为在这里是等价的。
烷基例如“C1-8烷基”,包括具有自由化合价的脂族链(也就是含有氢和碳原子的烃基或烃基团结构)。烷基被理解为包括直链和分支的结构。实例包括甲基、乙基、丙基、异丙基、丁基、正丁基、异丁基、叔丁基、戊基、异戊基、2,3-二甲基丙基、己基、2,3-二甲基己基、1,1-二甲基戊基、庚基、辛基等。术语“C1-8烷基”在其定义内包括术语“1-6烷基”、“C1-5烷基”、“C1-4烷基”和“C1-3烷基”。
烷基可以被1、2、3个或更多取代基取代,它们独立地选自卤代(氟代、氯代、溴代或碘代)、氰基、羟基、氨基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、芳氧基、芳基烷氧基、杂环基团和(杂环基团)氧基。具体实例包括氟甲基、羟乙基、2,3-二羟基乙基、(2-或3-呋喃基)甲基、环丙基甲基、苄氧基乙基、(3-吡啶基)甲基、(2-噻吩基)乙基、羟丙基、氨基环己基、2-二甲氨基丁基、甲氧基甲基、N-吡啶基乙基、二乙氨基乙基和环丁基甲基。
本文所用的术语“烷氧基”表示与氧原子连接的直链或支链烷基链。本文所用的术语“C1-8烷氧基”表示与氧原子连接的具有一至八个碳原子的直链或支链烷基链。典型的C1-8烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基等。术语“C1-8烷氧基”在其定义内包括术语“C1-6烷氧基”和“C1-4烷氧基”。
链烯基是烷基的类似物,但是具有至少一条双键(两个相邻的sp2碳原子)。根据双键和取代基——如果有的话——的位置,双键的几何学可以是E或Z、顺式或反式。类似地,炔基具有至少一条叁键(两个相邻的sp碳原子)。不饱和的链烯基或炔基可以分别具有一条或多条双键或叁键,二者的混和;象烷基一样,不饱和的基团可以是直链或支链的,它们可以如上关于烷基所述被取代,也例如本文所述。链烯基、炔基和取代形式的实例包括顺式-2-丁烯基、反式-2-丁烯基、3-丁炔基、3-苯基-2-丙炔基、3-(2’-氟苯基)-2-丙炔基、3-甲基(5-苯基)-4-戊炔基、2-羟基-2-丙炔基、2-甲基-2-丙炔基、2-丙烯基、4-羟基-3-丁炔基、3-(3-氟苯基)-2-丙炔基和2-甲基-2-丙烯基。式I中,术语“链烯基”包括C2-6链烯基或C2-4链烯基。
环烷基例如C3-10环烷基,表示含有3至10个原子的饱和烃环结构。典型的C3-10环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
术语“芳基”表示不饱和的芳族碳环基团,具有单一的环(例如苯基)、多个环(例如联苯)或多个稠合环,其中至少一个是芳香性的(例如1,2,3,4-四氢萘基、萘基、蒽基或菲基)。芳基可以可选地被1至5个取代基取代,取代基独立地选自由羟基、氨基、单烷基氨基、二烷基氨基、卤素、氰基、(C1-3)烷氧基、COOR、OCORa、CONRaRb、NRaCORb、SO、SO2、SO4和SO2NRaRb组成的组,其中Ra和Rb独立地是氢或C1-4烷基。
本文所用的术语“芳氧基”表示与氧原子连接的芳基。
本文所用的术语“杂环”、“C2-7杂环”“C2-9杂环”或“C2-7杂芳基”在本发明中表示稳定的5-、6-或7-元单环或7-至10-元二环的杂环,它是饱和的或不饱和的,由碳原子和一至四个杂原子组成,杂原子选自由氮、氧或硫组成的组。杂环可以连接在提供稳定结构的任意杂原子或碳原子上。
包括但不限于杂芳基的杂环基团包括:呋喃基、(异)噁唑基、异噁唑基、噻吩基、噻唑基、吡咯基、咪唑基、1,3,4-***基、四唑基、吡啶基、嘧啶基、哒嗪基、吲哚基和它们的非芳族对应物。杂环基团的进一步实例包括噻吩基、哌啶基、喹啉基、异噻唑基、哌啶基、吗啉基、哌嗪基、四氢呋喃基、四氢吡咯基、吡咯烷基、八氢吲哚基、八氢苯并噻吩基、八氢苯并呋喃基、(异)喹啉基、萘啶基、苯并咪唑基和苯并噁唑基。
取代的烃基团的更一般形式包括羟基烷基、羟基链烯基、羟基炔基、羟基环烷基、羟基芳基和关于前缀氨基-、卤代-(例如氟代-、氯代-或溴代)、硝基-、烷基-、苯基-、环烷基-等的对应形式,或取代基的组合。因此,按照式(I),取代的烷基包括但不限于羟基烷基、烷氧基烷基、氨基烷基、硝基烷基、卤代烷基、氰基烷基、烷基烷基(支链烷基,例如甲基戊基)、(环烷基)烷基、苯基烷基、烷基氨基烷基、二烷基氨基烷基、芳基烷基、芳氧基烷基、芳基烷氧基烷基、(杂环基团)烷基和(杂环基团)氧基烷基。式I因而包括羟基烷基、羟基链烯基、羟基炔基、羟基环烷基、羟基芳基、氨基烷基、氨基链烯基、氨基炔基、氨基环烷基、氨基芳基、烷基链烯基、(烷基芳基)烷基、(卤代芳基)烷基、(羟基芳基)炔基等。R6、R7、R8、R9和R10包括羟基(C1-8)烷基、(C1-5)烷氧基(C1-5)烷基、氨基烷基(例如[(C1-4)烷基]2氨基甲基)、全卤代(C1-3)烷基(例如三氟甲基或三氟乙基)、(C2-7)杂环(C1-5)烷基和芳氧基(C1-5)烷基。类似地,R10包括羟基(C1-8)烷基、(C1-5)烷氧基(C1-5)烷基和三氟(C1-6)烷基。
下示片段证明R6、R7、R8、R9和R10独立联合构成3-10元环的代表性实例,该环可选地含有另外的杂原子,选自O、S、NH或N-烷基。
下示片段阐述式I的代表性实例,其中对于n>1 R7和R8是独立地加以选择的。下示片段还显示若n>1,则R7和R8对于每个(CR7R8)单元是独立地加以选择的。
本发明包括由式I所定义的化合物的水合物和药学上可接受的盐和溶剂化物。本发明化合物可以具有足够碱性的官能团,因此与任意大量的无机和有机酸反应,生成药学上可接受的盐。
本文所用的术语“药学上可接受的盐”表示基本上对活生物体无毒的式I化合物的盐。典型的药学上可接受的盐包括通过本发明化合物与药学上可接受的无机或有机酸的反应所制备的那些盐。这类盐也已知称为酸加成盐。这类盐包括在Journal of Pharmaceutical Science,66,2-19(1977)中所列举的药学上可接受的盐,它们是为技术人员所知的。
常用于生成酸加成盐的酸是无机酸,例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等,和有机酸,例如对-甲苯磺酸、甲磺酸、苯磺酸、草酸、对-溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸等。这类药学上可接受的盐的实例是硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、溴化物、氢溴酸盐、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、抗坏血酸盐、甲酸盐、盐酸盐、二盐酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、葡萄糖醛酸盐、谷氨酸盐、苯丙酸盐、水杨酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、肉桂酸盐、马尿酸盐、硝酸盐、硬脂酸盐、邻苯二甲酸盐、对苯二甲酸盐(teraphthalate)、丁炔-1,4-二酸盐、丁炔-1,4-二羧酸盐、己炔-1,4-二羧酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、二硝基苯甲酸盐、邻-乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、对-甲苯磺酸盐、对-溴苯磺酸盐、对-氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、三氟乙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、α-羟基丁酸盐、羟乙酸盐、酒石酸盐、半酒石酸盐、苯磺酸盐、乙磺酸盐、丙磺酸盐、羟基乙磺酸盐、1-萘磺酸盐、2-萘磺酸盐、1,5-萘二磺酸盐等。优选的药学上可接受的盐是盐酸盐。
应当认可的是,构成本发明任意盐一部分的特定抗衡离子通常不是关键所在,只要该盐在整体上是药理学上可接受的,并且只要该抗衡离子不危及盐的整体性质。进一步可以理解的是这类盐可以以水合物的形式存在。
本文所用的术语“立体异构体”表示由相同的原子通过相同的键键合构成的化合物,但是具有不可互换的不同三维结构。这些三维结构被称为构型。本文所用的术语“对映体”表示两种立体异构体之一,它们的分子是彼此的非叠加镜像。术语“手性中心”表示与四个不同基团连接的碳原子。本文所用的术语“非对映体”表示不是对映体的立体异构体。术语“外消旋物”或“外消旋混合物”表示对映体的混合物。
本领域普通技术人员利用本领域熟知的标准技术可以拆分本发明化合物的对映体,例如J.Jacques等,“Enantiomers,Racemates,andResolutions”,John Wiley and Sons,Inc.,1981所述那些。拆分的实例包括重结晶技术或手性色谱法。
有些本发明化合物具有一个或多个手性中心,可以存在各种立体异构构型。作为这些手性中心的结果,本发明化合物存在外消旋物、对映体的混合物和单个的对映体,以及非对映体和非对映体的混合物。所有这类外消旋物、对映体和非对映体都属于本发明的范围。
式I化合物可以通过容易为本领域普通技术人员得到的技术和方法加以制备,例如下列流程所述方法。这些流程决不限制本发明的范围。除非另有指示,所有取代基都是如前面所定义的。试剂和原料是容易为本领域普通技术人员所得到的。
式I化合物一般是这样获得的,在碱的存在下,通过肽偶联剂的作用,连接2-(芳氨基)-苯甲酸(1)与烷氧基胺(2),如流程1所示。优选的偶联剂包括二苯基膦酰氯(DPP-Cl)、苯并***-1-基氧基-三吡咯烷基鏻六氟磷酸盐(PyBOP)、苯并***-1-基氧基-三(二甲氨基)鏻六氟磷酸盐(BOP)、N,N’-二环己基碳二亚胺(DCC)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(EDCI)或1,1’-羰基二咪唑(CDI)。优选的碱包括二异丙基乙胺、三乙胺、4-甲基吗啉、吡啶或取代的吡啶,例如4-二甲氨基吡啶或2,6-二甲基吡啶。优选的溶剂是极性非质子溶剂,例如二氯甲烷、四氢呋喃或二甲基甲酰胺。反应一般是在约-78℃至约25℃的温度下进行的,正常情况下在约2小时至约5天内完成。产物酰胺可以通过除去溶剂加以分离,例如减压蒸发,如果需要的话,进一步通过标准方法纯化,例如色谱法、结晶法或蒸馏法。
流程1:从苯甲酸到苯甲酰胺的通用制备
作为替代选择,所公开的化合物一般也如流程2所示制备的,使烷氧基胺(2)与“活化的”苯甲酸衍生物(3)接触,其中活性基团“X”代表酰卤、酸酐、混合酸酐或活化酯,例如五氟苯基酯、硝基苯基酯或硫代酸酯。优选的碱包括二异丙基乙胺、三乙胺、4-甲基吗啉、咪唑、吡啶或取代的吡啶,例如4-二甲氨基吡啶或2,6-二甲基吡啶。优选的溶剂是极性非质子溶剂,例如二氯甲烷、四氢呋喃或二甲基甲酰胺。下列实施例进一步例证这些合成策略,它们适合于常规的或组合的合成方法(平行合成)。
流程2:从“活化的”苯甲酸衍生物到苯甲酰胺的通用制备
流程3概述了优选的组合方法,其中式I化合物是这样获得的,在聚合物承载的(PS)4-甲基吗啉(5)的存在下,在二甲基甲酰胺中,在机械摇动的同时,使过量五氟苯基酯(4)与烷氧基胺(2)反应。反应约16至72小时后,加入聚合物承载的胺(6)和二氯甲烷。机械搅拌另外若干小时后,通过过滤、溶剂蒸发和色谱纯化得到靶标物I。
流程3:从苯甲酸五氟苯基酯到苯甲酰胺的通用组合制备
关于其中R11=氢的式I化合物的制备,优选的合成模式可以采用式(2)试剂,其中R6、R7、R8、R9、R10是如上式I所定义的,R11是标准的羟基(W=O)或氨基(W=NRa)保护基团。在这类情形中,可以修改上述通用流程1-3,以包括所述保护基团的标准除去过程。适合的保护基团包括但不限于乙烯基醚、甲硅烷基醚、缩醛、丙酮化物和氨基甲酸酯。下面概述这类修改的实例。
如流程4所述,优选的式IIa化合物可以这样获得,使苯甲酸(1)与乙烯基醚(7)、肽偶联剂(例如PyBOP)和碱(例如二异丙基乙胺)反应,得到乙烯基醚酰胺(8)。进一步用酸处理乙烯基醚(8),得到式IIa化合物。
流程4:羟基化苯甲酰胺的代表性制备,使用乙烯基醚作为羟基保护基团
如下流程5所示,优选的式IIb化合物也可以这样获得,在肽偶联剂(例如PyBOP)和叔胺碱(例如二异丙基乙胺)的存在下,使苯甲酸(1)与适合的保护基团反应,例如叔丁基二甲基甲硅烷基醚(9),得到叔丁基二甲基甲硅烷基醚酰胺(10)。进一步在质子溶剂中用酸处理甲硅烷基醚(10),得到式IIb化合物。
流程5:羟基化苯甲酰胺的代表性制备,使用甲硅烷基醚作为羟基保护基团
优选的式IVa化合物可以通过相似方法制备,如流程6所述。例如,在肽偶联剂的存在下,例如二苯基膦酰氯(DPP-Cl),在叔胺碱的存在下,例如4-甲基吗啉(NMM),用氨基甲酸酯(11)处理苯甲酸(1),得到氨基甲酸酯酰胺(12)。随后用适合的酸处理(12),例如三氟乙酸或盐酸,得到通式IVa的胺,可以被分离为酸盐,或者在标准条件下被中和,得到游离碱。
流程6:氨基-取代的苯甲酰胺的代表性制备,使用氨基甲酸叔丁酯作为氨基保护基团
采用保护基团策略的进一步实例阐述在优选的式IIIa化合物的合成中,如流程7所示。丙酮化物-酰胺(14)容易这样获得,在肽偶联剂(例如DPP-Cl)和叔碱(例如4-甲基吗啉(NMM))的存在下,连接丙酮化物(13)与苯甲酸(1)。作为替代选择,它们可以按照流程2制备,在叔胺碱(例如二异丙基乙胺)的存在下,用丙酮化物(13)处理苯甲酸五氟苯基酯(4)。丙酮化物-酰胺(14)向优选的化合物IIIa的转化可以这样完成,在标准的酸性水解条件下处理,例如对-甲苯磺酸/甲醇。
流程7:二羟基化苯甲酰胺的代表性制备,使用丙酮化物作为二醇保护基团
式I化合物还可以通过其他式I化合物的修饰加以制备。例如,其中R6=H的式I化合物(15)可以这样转化为其中R6=烷基的式I化合物(16),在碱(例如碳酸钾)的存在下,用烷基化剂(例如碘代甲烷)处理。作为替代选择,其中R11=H的式I化合物(17)可以这样转化为其中R11=烷基羰基的式I化合物(18),用酰氯(例如乙酰氯)和碱(例如三乙胺)处理。另外,其中R4=H的式I化合物(19)可以从其中R4=碘的式I化合物(20)制备。这些实例的说明参见流程8-10。
流程8:叔苯甲酰胺的代表性制备,通过N-烷基化作用
流程9:乙酸酯的代表性制备,通过乙酰化作用
流程10:芳基碘化物的代表性氢解作用
由本发明所提供的具体化合物包括:
氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-丁氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-甲氧基-乙氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-丙氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
3,4,5-三氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基-乙氧基)苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基-乙氧基)苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)-苯甲酰胺
3,4,5-三氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-丙氧基)苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
另外,权利要求书提供下列化合物:
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-乙氧基)苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4二氟-苯甲酰胺
5-氯-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺
5-氯-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺
本发明所述其他化合物包括:
4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
4-氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
N-(3,4-二羟基-丁氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
N-(2,3-二羟基-丙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-甲氧基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-4-氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-4-氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
N-(3,4-二羟基-丁氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
N-(2,3-二羟基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基-丙氧基)苯甲酰胺
4,5-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
4,5-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
N-(3,4-二羟基-丁氧基)-4,5-二氟-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
N-(2,3-二羟基-丙氧基)-4,5-二氟-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-甲氧基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-4,5-二氟苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-4,5-二氟苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
N-(3,4-二羟基-丁氧基)-4,5-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
N-(2,3-二羟基-丙氧基)-4,5-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-氯-4-氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-4-氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-氯-N-(3,4-二羟基-丁氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-N-(2,3-二羟基-丙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-4-氟苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-4-氟苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-氯-N-(3,4-二羟基-丁氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-氯-N-(2,3-二羟基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-溴-4-氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-4-氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-溴-N-(3,4-二羟基-丁氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-N-(2,3-二羟基-丙氧基)-4-氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丁氧基)苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-4-氟-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-4-氟苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
5-溴-N-(3,4-二羟基-丁氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-N-(2,3-二羟基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺
N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
N-(3,4-二羟基-丁氧基)-3,4,5-三氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
N-(2,3-二羟基-丙氧基)-3,4,5-三氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
5-氯-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3苯氧基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)苯甲酰胺
5-溴-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3吗啉-4-基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3苯氧基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基-丙氧基-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基环丁基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-3,4-二氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-戊氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(I-羟基环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(1-羟基环丁基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(1-羟甲基-丙氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-1,1-二甲基乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(1-羟甲基环丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-3,4,5-三氟苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-2-甲氧基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-戊氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-丁氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-3-甲基丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-[2-(1-羟基-环丙基)乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-1-甲基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)3,4,5-三氟-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3甲氧基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-3,4-二氟苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(1-羟基环丙基)-乙氧基]-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟基环丁基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-3,4-二氟苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-苯甲酰胺
3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
3,4-二氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
3,4,5-三氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
3,4,5-三氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4,5-三氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-N-(2-乙氧基-乙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-N-(2-乙氧基-乙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-3,4-二氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
4-氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4-氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4-氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4-氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1,1-二甲基-乙氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-4-氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4氟-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-环丙氧基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基-丁氧基)苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基-丙氧基)苯甲酰胺
4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
4,5-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
4,5-二氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺4,5-二氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-4,5-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4,5-二氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
4,5-二氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
4,5-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
4,5-二氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-4,5-二氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-3-甲基-丁氧基)苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(1-羟基环丁基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-4,5-二氟-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-戊氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-[2-(1-羟基-环丙基)乙氧基]-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4,5二氟-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基-丁氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丙基甲氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基乙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-4,5-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基-丁氧基)苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基-环丙基)乙氧基]-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-4,5-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-N-(2-乙氧基-乙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺
5-氯-4-氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-4-氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-4-氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-氯-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-4-氟-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-戊氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(1-羟基环丙基)-乙氧基]-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1-甲基丙氧基)-苯甲酰胺
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基丙氧基)-4-氟-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
5-氯-N-(2-乙氧基-乙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基环丙基)-乙氧基]-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-氯-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-氯-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-4-甲基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(1-羟基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(1-羟基-环丁基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(1-羟甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(1-羟甲基-环丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺
5-溴-N-(2-乙氧基-乙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-2-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-戊氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-3-甲基-丁氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-[2-(1-羟基-环丙基)-乙氧基]-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(2-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-1,1-二甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-4-氟-N-(3-羟基-1-甲基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟基-环丁基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2-乙氧基-乙氧基)-4-氟-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-戊氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基乙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-环丙氧基)-苯甲酰胺
5-溴-N-(2-乙氧基-乙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基-丁氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基环丙基)-乙氧基]-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-溴-N-(2,3-二羟基-1,1-二甲基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基-丁氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丙基甲氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基乙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基-丁氧基)苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基-环丙基)乙氧基]-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-戊氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丙基甲氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基-丙氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基乙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
N-(2-乙氧基-乙氧基)-3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-戊氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基丁氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基-环丙基)乙氧基]-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基丙氧基)-苯甲酰胺
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基丙氧基)-苯甲酰胺
N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4,5-三氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3甲氧基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基戊氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基-丁氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基-戊氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基-环丙基甲氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1二甲基-乙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
5-氯-N-(2-乙氧基-乙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2甲氧基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基戊氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基丁氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基-环丙基)-乙氧基]-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1二甲基-丙氧基)-苯甲酰胺
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基-丙氧基)-苯甲酰胺
5-氯-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3甲氧基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基戊氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲基丁氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-4-甲基戊氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丙基甲氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟基环丁基甲氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙氧基)-苯甲酰胺
5-溴-N-(2-乙氧基-乙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氧基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基戊氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丁氧基)苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-3-甲基丁氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[2-(1-羟基环丙基)-乙氧基]-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1,1-二甲基-丙氧基)-苯甲酰胺
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-1-甲基丙氧基)-苯甲酰胺
5-溴-N-(2,3-二羟基-1,1-二甲基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
优选的化合物是式I的那些,其中R1是氢或卤素;更优选为氢、F、Br或Cl;最优选为氢;R2和R3是氟;R4是氢、碘、溴、氯或氟;更优选为氢、碘、氯或氟;最优选为碘;R5是氟、氯或甲基;更优选为氟或氯;最优选为氟;n是1或2;或其组合。优选的化合物是选择性MEK抑制剂。其中最优选的化合物是这样的,其中R6、R7、R8、R9、R10和R11是氢,W是氧,n是1或2,以及其中R6、R7、R9、R10和R11是氢,W是氧,n是2,R8(1)是氢,R8(2)是羟基。这类化合物具有式II和III
其中
R1是氢或卤素;
R5是氟、氯或甲基;和
n是1或2。
其中
R1是氢或卤素;和
R5是氟、氯或甲基。
其他最优选的化合物是式I的那些,其中R1是氢或卤素,例如F、Br或Cl;R2和R3是氟;R4是碘;R5是氟、氯或甲基;n是1;R6、R7、R8、R9和R10是氢,W是NRa,Ra是H;R11是甲基或苯基;及
其药学上可接受的盐。这些化合物具有式IV和V
其中
R1是氢或卤素;和
R5是氟、氯或甲基。
其中
R1是氢或卤素;和
R5是氟、氯或甲基。
优选的本发明化合物包括但不限于下列化合物:
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
5-氯-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氨基-乙氧基)苯甲酰胺;盐酸盐;
N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
5-氯-N-((S)2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基乙氧基)-苯甲酰胺;
和
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺。
另一方面,本发明提供N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的结晶I型和II型(以下分别称为“化合物A的I型”和“化合物A的II型”)或其水合物、N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的结晶I型和II型(以下分别称为“化合物B的I型”和“化合物B的II型”)或其水合物、和N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的结晶I型和II型(以下分别称为“化合物C的I型”和“化合物C的II型”)或其水合物。
本发明还提供化合物A或其水合物的结晶I型和II型、化合物B或其水合物的结晶I型和II型、和化合物C或其水合物的结晶I型或II型(以下统称为“晶型”或本发明的“晶型”,另有指定除外),它们可用作药物试剂,本发明还涉及它们的制备和分离方法、包括这些化合物和药学上可接受的载体的药物组合物、和治疗的药学方法。本发明的新颖的结晶性化合物可用作MEK的抑制剂。
由本发明所提供的晶型可以通过它们的X-射线粉末衍射图形加以鉴别。
化合物A的结晶I型和II型、化合物B的结晶I型和II型、和化合物C的结晶I型和II型是通过它们的X-射线粉末衍射图谱加以鉴别的。因而,利用CuKα辐射在Rigaku Ultima+衍射仪上测量本发明晶型的X-射线粉末衍射图谱。
设备
Rigaku Ultima+衍射仪,具有IBM-兼容的界面,装有6位置自动采样器,软件是RigMeas v2.0(Rigaku,Dec.1995)和JADE 3.1(MaterialsData,Inc.)。
CuKα线辐射(40mA,40kV,λ=1.5419A)。狭缝I和II在0.5°,狭缝III在0.3°。
方法
每周运行一次硅标,以检查X-射线管校准与否。
连续的θ/2θ偶合扫描:3.00°至50.00°,以2θ计,扫描速率1°/min:1.0sec/0.04°步长。
从小瓶内取出样品,压在铝容器内的零背景硅上。样品宽度5mm。
样品是在室温下贮存和实验的。
在数据收集期间,使样品绕垂直轴旋转40rpm。
表1列举化合物A结晶I型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表1列举的是计算机生成的、未舍入的数值。
表1
2-Theta d(A) 相对强度
(>10%)
7.078 12.4779 15.2
14.123 6.2659 15.4
15.280 5.7939 58.7
15.836 5.5917 31.4
16.880 5.2481 42.2
18.082 4.9019 41.4
19.162 4.6280 67.4
20.279 4.3754 21.1
21.360 4.1565 73.6
22.325 3.9789 14.4
23.400 3.7984 79.3
24.522 3.6271 11.0
25.480 3.4929 24.6
26.159 3.4037 100.0
26.801 3.3237 48.9
27.842 3.2017 22.8
28.280 3.1531 45.4
29.475 3.0280 16.0
32.118 2.7845 19.7
33.248 2.6924 10.6
33.645 2.6615 16.3
40.008 2.2517 10.6
42.885 2.1071 12.1
44.095 2.0520 12.8
表2列举化合物A结晶II型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表2列举的是计算机生成的、未舍入的数值。
表2
2-Theta d(A) 相对强度
(>10%)
11.582 7.6344 11.2*
12.598 7.0205 13.0*
15.622 5.6678 17.1
17.302 5.1211 29.3
17.886 4.9551 13.3
20.345 4.3614 49.8
21.140 4.1991 31.0
22.137 4.0123 81.7
24.855 3.5793 100.0*
25.885 3.4391 15.1
26.699 3.3362 23.3
27.842 3.2018 23.7
30.059 2.9704 11.8
30.948 2.8871 33.4
33.799 2.6498 24.8
35.399 2.5336 16.2
38.242 2.3516 33.9
39.282 2.2916 11.3
40.755 2.2122 12.6
41.641 2.1671 11.7
43.570 2.0756 24.5
46.958 1.9334 19.5
表3列举化合物B结晶I型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表3列举的是计算机生成的、未舍入的数值。
表3
2-Theta d(A) 相对强度
(>10%)
10.560 8.3702 14.9*
13.720 6.4488 10.3*
14.619 6.0543 13.9
17.258 5.1340 12.4
17.958 4.9354 44.5
18.219 4.8654 15.8
18.998 4.6675 38.1*
19.258 4.6052 12.3
20.142 4.4050 17.7
21.002 4.2264 18.5
21.940 4.0479 53.2
22.360 3.9727 19.3
23.680 3.7541 100.0*
24.043 3.6983 16.9
24.919 3.5702 67.3
26.278 3.3886 20.1
27.603 3.2289 40.6
28.024 3.1813 30.7
30.100 2.9665 14.6
32.142 2.7825 15.8
32.298 2.7694 14.6
32.938 2.7171 14.7
35.841 2.5034 16.3
37.660 2.3865 15.6
表4列举化合物B结晶II型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表4列举的是计算机生成的、未舍入的数值。
表4
2-Theta d(A) 相对强度
(>10%)
5.482 16.1076 39.6*
10.721 8.2453 20.3
16.478 5.3751 21.9
19.563 4.5340 73.2*
22.019 4.0334 100.0
22.478 3.9521 16.1
23.621 3.7634 11.1
24.100 3.6896 31.9
24.959 3.5647 98.2
26.181 3.4010 15.1
27.621 3.2269 31.7
29.081 3.0681 17.7
30.476 2.9307 11.4
31.698 2.8204 38.9
33.263 2.6913 19.4
39.020 2.3064 10.2
表5列举化合物C结晶I型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表5列举的是计算机生成的、未舍入的数值。
表5
2-Theta d(A) 相对强度
(>10%)
10.548 8.3798 14.6*
13.703 6.4568 11.3*
17.887 4.9549 19.9
18.958 4.6772 27.3*
20.122 4.4093 10.9
21.950 4.0460 58.3
22.321 3.9796 13.4
23.640 3.7604 100.0*
24.803 3.5867 66.6
26.244 3.3929 12.1
27.570 3.2327 21.6
28.000 3.1840 31.9
29.566 3.0189 23.1
32.234 2.7748 18.3
32.769 2.7307 16.4
35.804 2.5059 13.8
37.641 2.3877 16.8
41.402 2.1791 14.4
41.956 2.1516 10.0
44.600 2.0300 13.9
表6列举化合物C结晶II型的X-射线粉末衍射图谱,以2-theta(“2θ”)、d-间距或d(A)和相对强度>10%的峰面积的相对强度表示,这些是利用CuKα线辐射在Rigaku Ultima+衍射仪上测量的。应当注意,表6列举的是计算机生成的、未舍入的数值。
表6
2-Theta d(A) 相对强度
(>10%)
5.550 15.91107 21.8*
10.763 8.2128 22.3
16.485 5.3729 11.8
19.636 4.5173 73.5*
20.922 4.2425 20.6
22.043 4.0291 54.0
23.683 3.7538 18.0
24.153 3.6817 52.6
24.996 3.5595 100.0
26.236 3.3939 11.4
27.680 3.2201 25.2
28.037 3.1799 22.4
29.120 3.0641 21.5
31.718 2.8187 36.4
32.794 2.7287 13.3
33.314 2.6872 10.8
34.085 2.6282 13.6
41.999 2.1494 14.6
42.278 2.1359 10.3
本发明晶型可以存在无定形以及水合的形式。一般而言,水合的形式等价于未水合的形式,也打算涵盖在本发明的范围内。
本发明提供化合物A结晶I型的制备方法,包含在生成化合物A结晶I型的条件下使化合物A从在溶剂中的溶液中结晶出来。
生成化合物A结晶I型的精确条件可以凭经验确定,这仅可能给出大量已被发现适合于实施的方法。所需I型可以这样获得,将固体悬浮在适合的溶剂中,例如乙醇,再用水沉淀;将固体溶于少量沸腾着的溶剂,例如乙醇,再向沸腾着的溶剂加入水;将固体溶于少量沸腾着的溶剂,例如乙酸乙酯,再向沸腾着的溶剂加入适合的溶剂,例如庚烷,下列实施例39A有更充分的描述。
本发明提供化合物A结晶II型的制备方法,包含在生成化合物A结晶II型的条件下使化合物A从在溶剂中的溶液中结晶出来。
生成化合物A结晶II型的精确条件可以凭经验确定,这仅可能给出大量已被发现适合于实施的方法。所需II型可以这样获得,将固体悬浮在适合的溶剂中,例如乙酸乙酯/己烷或庚烷-CH2Cl2(1∶1),下列实施例39有更充分的描述。
本发明提供化合物B结晶I型的制备方法,包含在生成化合物B结晶I型的条件下使化合物B从在溶剂中的溶液中结晶出来。
生成化合物B结晶I型的精确条件可以凭经验确定,这仅可能给出大量已被发现适合于实施的方法。所需I型可以这样获得,将固体悬浮在己烷-AcOEt中。下列实施例49描述更详细的方法。
本发明提供化合物B结晶II型的制备方法,包含在生成化合物B结晶II型的条件下使化合物B从在溶剂中的溶液中结晶出来。
生成化合物B结晶II型的精确条件可以凭经验确定,这仅可能给已被发现适合于实施的方法。所需II型可以这样获得,将固体悬浮在乙酸乙酯和庚烷中,或者将固体悬浮在己烷-AcOEt中,下列实施例49和49A有更充分的描述。
本发明提供化合物C结晶I型的制备方法,包含在生成化合物C结晶I型的条件下使化合物C从在溶剂中的溶液中结晶出来。
生成化合物C结晶I型的精确条件可以凭经验确定,这仅可能给出已被发现适合于实施的方法。所需I型可以这样获得,将固体悬浮在己烷-AcOEt中。下列实施例50描述更详细的方法。
本发明提供化合物C结晶II型的制备方法,包含在生成化合物C结晶II型的条件下使化合物C从在溶剂中的溶液中结晶出来。
生成化合物C结晶II型的精确条件可以凭经验确定,这仅可能给出已被发现适合于实施的方法。所需II型可以这样获得,将固体悬浮在乙酸乙酯和庚烷中,或者将固体悬浮在己烷-AcOEt中,下列实施例50和50A有更充分的描述。
本文所用的术语“患者”表示任意的温血动物,例如但不限于人、马、狗、豚鼠或小鼠。优选地,患者是人。
用于本发明目的的术语“冶疗”表示预防或防止指定的病症,一旦该病症已经确立,改善或消除该病症。
选择性MEK1或MEK2抑制剂是这样的化合物,它们分别抑制MEK1或MEK2酶,基本上不抑制其他酶,例如MKK3、PKC、Cdk2A、磷酸酶激酶、EGF与PDGF受体激酶和C-src。一般而言,选择性MEK1或MEK2抑制剂关于MEK1或MEK2的IC50是关于上述其他酶之一的IC50的至少五十分之一(1/50)。优选地,选择性抑制剂的IC50是一种或多种上述酶的IC50的至少1/100,更优选1/500,进而更优选1/1000、1/5000或以下。
所公开的组合物可用于预防和治疗涉及MEK机能亢进的疾病或病症以及受MEK级联调节的疾病或病症。实例包括但不限于中风、脓毒性休克、心衰、骨关节炎、类风湿性关节炎、器官移植排斥、和各种肿瘤,例如卵巢、肺、胰腺、脑、***和结肠直肠的肿瘤。
本发明进一步涉及用于治疗增殖性疾病的方法,例如癌症、再狭窄、牛皮癣、自体免疫疾病和动脉粥样硬化。本发明的其他方面包括用于治疗与MEK有关的(包括与ras有关的)癌症的方法,无论该癌症是实体性的还是造血性的。癌症的实例包括脑癌、乳腺癌、肺癌(例如小细胞肺癌)、卵巢癌、胰腺癌、***癌、肾癌、结肠直肠癌、***、急性白血病和胃癌。本发明的进一步方面包括用于治疗或减少下列症状的方法:异种移植(细胞、皮肤、肢体、器官或骨髓移植)排斥、骨关节炎、类风湿性关节炎、囊性纤维变性、糖尿病并发症(包括糖尿病性视网膜病和糖尿病性肾病)、肝肿大、心肥大、中风(例如急性局灶性缺血性中风和普遍性脑缺血)、心衰、脓毒性休克、气喘、阿尔茨海默氏病和慢性或神经病性疼痛。本发明的化合物还可用作抗病毒剂,用于治疗病毒感染,例如HIV、肝炎(B)病毒(HBV)、人***瘤病毒(HPV)、巨细胞病毒(CMV)和EB病毒(EBV)。这些方法包括对需要这类治疗或患有这类疾病或病症的患者给以治疗有效量的所公开的化合物——包括晶型——或其药物组合物。
用于本发明目的的术语“慢性疼痛”包括但不限于神经病性疼痛、自发性疼痛、和与慢性酒精中毒、维生素缺乏、***或甲状腺机能减退有关的疼痛。慢性疼痛与大量病症有关,包括但不限于炎症、关节炎和术后疼痛。
本文所用的术语“神经病性疼痛”与大量病症有关,包括但不限于炎症、术后疼痛、幻肢痛、灼伤痛、痛风、三叉神经痛、急性疱疹与疱疹后疼痛、灼痛、糖尿病性神经病、丛撕脱(plexus avulsion)、神经瘤、脉管炎、病毒感染、挤压伤、收缩伤、组织损伤、肢体切断、术后疼痛、关节炎疼痛、和外周神经***与中枢神经***之间的神经损伤。
本发明还以联合治疗的方法为特征,例如用于治疗癌症的方法,其中该方法进一步包括提供放射疗法或化疗法,例如利用有丝***抑制剂,例如紫杉烷或长春花属(vinca)生物碱。有丝***抑制剂的实例包括紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、长春新碱、长春碱、长春瑞滨和长春氟宁(vinflunine)。其他治疗组合包括本发明的MEK抑制剂与抗癌剂,例如顺铂、5-氟尿嘧啶或5-氟-2-4(1H,3H)-嘧啶二酮(5FU)、氟他胺和吉西他滨。
根据患者的需要,可以在所公开的化合物给药之前、同时或之后给以化疗法或放射疗法。
根据已知的方法,本领域技术人员将能够确定本发明化合物对患者给药的适当的治疗有效量或剂量,所要考虑的因素例如年龄、体重、一般健康状况、所给药的化合物、给药途径、需要治疗的疼痛或病症类型和其他药物治疗的存在。一般而言,有效量或治疗有效量将在约0.1与约1000mg/kg每天之间,优选在约1与约300mg/kg体重之间,关于正常体重的成年受治疗者的每日剂量将在约10与约5000mg之间。按照所公开的方法,可以给以商业上可得到的胶囊剂或其他制剂(例如液体和膜衣片),规格为100mg、200mg、300mg或400mg。
本发明的化合物、包括晶型优选地在给药前加以配制。因此,本发明的另一方面是药物组合物,包含式I化合物和药学上可接受的载体。在制备本发明的组合物时,通常将活性成分、例如式I化合物与载体混合,或者用载体稀释,或者包封在载体内。剂量单元剂型或药物组合物包括片剂、胶囊剂、丸剂、粉剂、颗粒剂、水性与非水性口服溶液与悬液、和肠胃外溶液,包装在适用于分成单个剂量的容器内。
剂量单元剂型可以适用于各种给药方法,包括控释制剂,例如皮下植入物。给药方法包括口服、直肠、肠胃外(静脉内、肌内、皮下)、脑池内、***内、腹膜内、膀胱内、局部(滴剂、粉剂、软膏剂、凝胶剂或霜剂)和吸入(颊或鼻用喷雾剂)。
肠胃外制剂包括药学上可接受的水性或非水性溶液、分散系、悬液、乳液和用于制备它们的无菌粉末。载体的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇)、植物油、和可注射的有机酯,例如油酸乙酯。保持流动性的方法可以利用包衣、例如卵磷脂,表面活性剂,或者保持适当的粒径。用于固体剂型的载体包括(a)填充剂或补充剂,(b)粘合剂,(c)湿润剂,(d)崩解剂,(e)溶解迟延剂,(f)吸收促进剂,(g)吸附剂,(h)润滑剂,(i)缓冲剂,和(j)推进剂。
组合物还可以含有助剂,例如防腐剂、润湿剂、乳化剂和分散剂;抗微生物剂,例如对羟基苯甲酸酯、氯丁醇、苯酚和山梨酸;等渗剂,例如糖或氯化钠;吸收延长剂,例如单硬脂酸铝和明胶;和吸收增强剂。
下列实施例代表如上一般性描述的本发明化合物的典型合成。这些实施例仅供例证,决不限制本发明。试剂和原料容易为本领域普通技术人员所得到。
制备例1
5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸
在-78度下,向搅拌着的1.88g(0.00791mol)2-氨基-5-碘甲苯的10ml四氢呋喃溶液加入6ml(0.012mol)2.0M二异丙氨基化锂的四氢呋喃/庚烷/乙基苯(Aldrich)溶液。将所得绿色悬液剧烈搅拌10分钟,然后加入1.00g(0.00392mol)5-溴-2,3,4-三氟苯甲酸的15ml四氢呋喃溶液。随后除去冷却浴,将反应混合物搅拌18小时。浓缩混合物,将浓缩物用100ml稀(10%)盐酸水溶液处理。所得悬液用***萃取(2×150ml),合并有机萃取液,干燥(MgSO4),在真空中浓缩,得到橙色固体。将该固体用沸腾着的二氯甲烷研制,冷却至环境温度,过滤收集。将固体用二氯甲烷冲洗,在真空烘箱(80℃)内干燥,得到1.39g(76%)黄绿色粉末;mp 259.5-262℃。
1H NMR(400MHz,DMSO):δ9.03(s,1H),7.99(dd,1H,J=7.5,1.9Hz),7.57(dd,1H,J=1.5Hz),7.42(dd,1H,J=8.4,1.9Hz),6.70(dd,1H,J=8.4,6.0Hz),2.24(s,3H);19F NMR(376MHz,DMSO):δ-123.40 to -123.479(m);-139.00 to -139.14(m);IR(KBr)1667(C=O伸缩)cm-1;MS(CI)M+1=469.分析计算/实验C14H9BrF2INO2:
C,35.93/36.15;H,1.94/1.91;N,2.99/2.70;Br,17.07/16.40;F,8.12/8.46;I,27.11/26.05.
制备例
下表7中的制备例2至25是利用例1的通用方法制备的。
制备例26
5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯
向5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸(如WO 99/01426所述制备)(1.61g,3.4mmol)与吡啶(0.31ml,3.83mmol)的无水二甲基甲酰胺(7ml)溶液加入三氟乙酸五氟苯基酯(0.71ml,4.13mmol)。将所得溶液在环境温度下搅拌18小时。将反应混合物用***(100ml)稀释,用水(40ml)、0.1M盐酸水溶液(40ml)、饱和碳酸氢钠水溶液(40ml)和饱和盐水(40ml)洗涤。将有机层经无水硫酸镁干燥,在减压下浓缩,得到泡沫,在硅胶上纯化。用己烷-乙酸乙酯(19∶1)洗脱,得到5-溴-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯(1.95g,89%),为淡黄色粉末。 1H NMR(400MHz,CDCl3)δ8.59(s,1H),8.24(d,J=5.8Hz,1H),7.54(s,1H),7.45(d,J=8.4Hz,1H),6.70(dd,J=8.4,5.3Hz,1H),2.26(s,3H).
制备例27-46是利用制备例26的通用方法制备的。
制备例27
5-氯-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯
1H-NMR(400MHz,CDCl3)δ8.58(s,1H),8.12(dd,J=7.5,2.0Hz,1H),7.54(s,1H),7.46(dd,J=8.3,1.5Hz,1H),6.70(dd,J=8.3,5.4Hz,1H),2.28(s,3H);19F-NMR(376MHz,CDCl3)δ-125.1(dd,J=17.7,5.0Hz,1F),-139.1(d,J=17.7Hz,1F),-152.6(d,J=17.7Hz,2F),-156.9(t,J=20.3Hz,1H),-161.9(t,J=20.2Hz,2H);MS(APCI-)=587.9.
制备例28
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯 1H-NMR(400MHz,CDCl3)δ8.59(s,1H),8.04(dd,J=7.5,7.0Hz,1H),7.53(s,1H),7.45(d,J=8.4Hz,1H),6.77(m,1H),6.70(dd,J=7.2,6.9Hz,1H),2.27(s,3H);MS(APCI-)=554.0
制备例29
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯
MP:108.5-110.6℃;1H-NMR(400MHz,CDCl3)δ8.35(s,1H),7.89(ddd,J=10.4,8.0,2.2Hz,1H),7.53(s,1H),7.44(dd,J=8.2,1.9Hz,1H),6.64(dd,J=8.2,5.5Hz,1H),2.27(s,3H);19F-NMR(376MHz,CDCl3)δ-137.25(d,J=16.8Hz,1F),-144.18(dd,J=21.4,10.7Hz,1F),-145.55(td,J=21.4,7.6Hz,1F),-152.31(d,J=18.3Hz,2F),-156.60(t,J=21.4Hz,1F),-161.62(t,J=18.3Hz,2F).分析计算/实验C20H8NO2F8I:C,41.91/41.52;H,1.41/1.32;N,2.44/2.36;F,26.52/26.34;I,22.14/22.19.
制备例30
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-苯甲酸五氟苯基酯
MP:98.2-99.2℃;1H-NMR(400MHz,CDCl3)δ8.50(s,1H),7.93(ddd,J=10.1,8.0,2.2Hz,1H),7.70(d,J=1.7Hz,1H),7.48(dd,J=8.7,1.7Hz,1H),6.62(t,J=7.6Hz,1H)19F-NMR(376MHz,CDCl3)δ-134.42(d,J=18.3Hz,1F),-141.59(dd,J=21.4,9.2Hz,1F),-145.26(td,J=21.4,7.6Hz,1F),-152.26(d,J=18.3Hz,2F),-156.46(t,J=21.4Hz,1F),-161.53(t,J=18.3Hz,2F).分析计算/实验C19H5NO2F8ClI:C,38.45/38.39;H,0.85/0.91;N,2.36/2.32;Cl,5.97/6.32;F,25.60/25.68;I,21.38/21.32.
制备例31
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
1H-NMR(400MHz,CDCl3)δ8.74(s,1H),8.15(dd,J=7.3,2.0Hz,1H),7.71(d,J=2.0Hz,1H),7.49(dd,J=8.4,2.0Hz,1H),6.68(dd,J=8.4,7.1Hz,1H);MS(APCI-)=607.8.
制备例32
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
收率,1.99g(61%);mp.112-114℃;1H-NMR(400MHz,CDCl3)δ8.75(s,1H),8.28(dd,J=7.0,2.2Hz,1H),7.50(dd,J=8.4,1.9Hz,1H),7.713(d,J=1.9Hz,1H),6.68(dd,J=8.4,7.0Hz,1H);19F-NMR(376MHz,CDCl3)δ-116.43(dd,J=19.8,6.1Hz,1F),-135.59(dd,J=18.3,6.1Hz,1F),-152.2(d,J=16.8Hz,2F),-156.47(t,J=21.4Hz,1F),-161.53(t,J=18.3Hz,2F).分析计算/实验C19H5NO2F7BrClI:C,34.87/34.72;H,0.77/0.65;N,2.14/2.07;F,20.32/20.68;Cl,5.42/6.06;Br,12.21/11.67;I,19.39/19.75.
制备例33
2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
收率,2.15g(75%);mp.108.5-110.0℃;1H-NMR(400MHz,CDCl3)δ8.77(br s,1H),8.07(br s,1H),7.69(br s,1H),7.48(br d,J=7.0Hz,1H),6.91(br d,J=7.2Hz,1H),6.67(br s.,1H);19F-NMR(376MHz,CDCl3)δ-123.74(s,1F),-139.17(d,J=16.8Hz,1F),-152.35(d,J=21.4Hz,2F),-156.96(t,J=21.4Hz,1F),-161.81(t,J=21.4Hz,2F).分析计算/实验C19H6NO2F7ClI:C,39.65/39.32;H,1.05/0.91;N,2.43/2.35;F,23.10/22.85;Cl,6.16/6.92;I,22.05/22.50.
制备例34
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.85-7.91(m,1H),7.35-7.43(m,2H),6.67-6.73(m,1H););MS(APCI-)=575.9.
制备例35
5-溴-4-氟-2-(4-碘-2-甲基苯氨基)-苯甲酸五氟苯基酯
1H-NMR(400MHz,丙酮-d6)δ9.04(br.s.,1H),8.44(d,1H,J=7.81Hz),7.74(d,1H,J=1.22Hz),7.64(dd,1H,J=8.31,1.96Hz),7.19(d,1H,8.3Hz),6.67(d,1H,J=11.48Hz),2.22(s,3H).19F-NMR(376MHz,丙酮-d6)δ-97.1(t),-155.0(t),-160.2(t),-165.1(t).MS(APCI-)415.8m/z,429.9m/z,447.9m/z,615.8m/z.
制备例36
3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.04(ddd,J=9.3,5.6,2.2Hz,1H),7.429dd,J=10.0,1.9Hz,1H),7.38(d,J=8.8Hz,1H),6.84(td,J=9.1,6.8Hz,1H),6.77(td,J=8.5,5.1Hz,1H);19F NMR(376MHz,CDCl3)δ-124.3,-125.1,-143.5,-152.6,-157.3,-162.1;MS(APCI-)=557.9.
制备例37
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H NMR(400MHz,丙酮-d6)δ8.60(s,1H),8.39(ddd,J=7.1,2.3,0.7Hz,1H),7.58(dd,J=10.5,1.7Hz,1H),7.49(dt,J=7.5,1.5Hz,1H),7.06(td,J=8.5,4.4Hz,1H);19F NMR(376MHz,丙酮-d6)δ-120.5,-127.1,-141.5,-154.7,-159.8,-164.8;MS(APCI-)=635.8,637.8.
制备例38
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.10(dd,J=7.5,2.3Hz,1H),7.44(dd,J=10.0,1.7Hz,1H),7.41(dd,J=8.4,1.1Hz,1H),6.76(td,J=8.3,4.6Hz,1H);19F NMR(376MHz,CDCl3)δ-124.6,-124.9,-140.3,-152.5,-156.8,-161.9;MS(APCI-)=591.8,593.8.
制备例39
4,5-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H-NMR(400MHz,丙酮-d6)δ8.99(br.s.),8.17(dd,1H,J=10.99,8.79Hz),7.69(dd,1H,J=10.0,1.95Hz),7.63(m,1H),7.38(t,1H,J=8.55Hz),7.04(qd,1H,J=6.84,1.47Hz).19F-NMR(376MHz,丙酮-d6)δ-123.0(t),-125.7(p),-150.8(m),-155.1(d),-160.1(t),-165.0(t).MS(APCI-)355.9m/z,391.9m/z,558.0m/z.分析计算C14H10F2INO2:C,40.81;H,1.08;N,2.50.实验:C,40.92;H,1.00;N,2.32.
制备例40
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯
1H-NMR(400MHz,丙酮-d6)δ9.11(br.s.),8.2(dd,1H,J=11.24,8.79Hz),7.9(d,1H,J=1.95Hz),7.73(dd,1H,J=8.55,2.2Hz),7.45(d,1H,J=8.55Hz),7.17(dd,1H,J=13.18,6.83Hz).19F-NMR(376MHz,丙酮-d6)δ-96.8,-122.4,-155.0,-160.0,-165.0.MS(APCI-)415.8m/z(d),453.8m/z(d),617.8m/z(d).分析计算C13H7BrF2INO2:C,34.39;H,0.98;N,2.26.实验:C,36.61;H,0.99;N,2.09.
制备例41
2-(2-氯-4-碘-苯氨基)-4,5-二氟-苯甲酸五氟苯基酯
1H-NMR(400MHz,丙酮-d6)δ9.11(br.s.),8.2(dd,1H,J=11.24,8.79Hz),7.9(d,1H,1.95Hz),7.73(dd,1H,J=8.55,2.2Hz),7.45(d,1H,J=8.55Hz),7.17(dd,1H,J=13.18,6.83Hz).19F-NMR(376MHz,丙酮-d6)δ-125.5(p),-150.1(m),-155.1(d),-160.0(t),-164.9(t).MS(APCI-)355.9m/z,389.9m/z,407.9m/z,573.9m/z.
制备例42
4,5-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯
1H-NMR(400MHz,丙酮-d6)δ8.92(br.s.),8.14(dd,1H,J=11.23,8.79Hz),7.75(d,1H,J=1.46Hz),7.64(dd,1H,J=8.31,2.2Hz),7.2(d,1H J=8.31Hz),6.76(dd,1H,J=13.19,6.84Hz),2.24(s,3H).19F-NMR(376MHz,丙酮-d6)δ-125.78(p),-152.41(m),-155.1(d),-160.2(t),-165.0(t).MS(APCI-):355.9m/z,369.9m/z,386.9m/z(d),554.0m/z.
制备例43
2-(4-溴-2-氟-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
m.p.100.9-101.5℃;1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.07(ddd,J=9.3,5.9,2.0Hz,1H),7.54(dd,J=11.0,2.2Hz,1H),7.35-7.22(cm,2H),7.04(td,J=8.9,2.0Hz,1H);19F-NMR(376MHz,DMSO-d6)δ-125.8(t,J=10.1Hz);-126.7(m),-145.3(d,J=20.2Hz),-153.3(d,J=20.2Hz),-157.8(t,J=22.7Hz),-162.9(t,J=21.5Hz);MS(APCI-)=510.0/512.0.
制备例44
2-(4-氯-2-氟-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
m.p.99.0-99.4℃;1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.07(ddd,J=9.0,5.8,2.0Hz,1H),7.45(dd,J=11.2,2.2Hz,1H),7.30(dt,J=7.3,9.2Hz,1H),7.19-7.08(m,2H);19F NMR(376MHz,DMSO-d6)δ-125.6(t,J=10.1Hz),-126.7(m,1H),-145.6(d,J=15.2Hz),-153.3(d,J=20.2Hz);-157.7(t,J=22.8Hz),-162.8(t,J=20.2Hz);MS(APCI-)=466.0.
制备例45
2-(2,4-二氟-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.07(ddd,J=9.0,5.9,2.0Hz,1H),7.34-7.12(cm,3H),7.01(m,1H);19F NMR(376MHz,DMSO-d6)δ-116.9(s),-122.6(t,J=10.1Hz),-126.7(m),-147.9(d,J=20.2Hz),-153.5(d,J=20.2Hz),-157.7(t,J=22.8Hz),-162.8(t,J=20.2Hz);MS(APCI-)=450.0.
制备例46
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯
m.p.92.5-93.2℃;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.21(dd,J=7.7,2.1Hz,1H),7.34-7.24(m,2H),7.02(m,1H);19F NMR(376MHz,DMSO-d6)δ-116.7(m),-122.4(m),-128.1(dd,J=20.2,7.6Hz),-143.4(d,J=17.7Hz),-153.2(d,J=20.2Hz),-157.4(t,J=22.7Hz),-162.8(t,J=20.2Hz);MS(APCI-)=483.9.
制备例47
O-(2-乙烯氧基-乙基)-羟胺
A部分:2-(2-乙烯氧基-乙氧基)-异吲哚-1,3-二酮的合成
将乙二醇乙烯基醚(9.88g,112mmol)、三苯膦(29.4g,112mmol)和N-羟基邻苯二甲酰亚胺(18.22g,111.7mmol)在300ml无水四氢呋喃中合并,冷却至0℃(冰浴)。历经15分钟滴加偶氮二羧酸二乙酯(18.0ml,114mmol),使所得反应混合物历经18小时温热至环境温度。浓缩反应混合物至糊状物,过滤固体,用氯仿洗涤。进一步浓缩滤液,再次过滤,用氯仿洗涤固体。浓缩其余氯仿溶液至油状物。将该油溶于绝对乙醇(75ml)。用玻璃棒刮擦,诱发结晶。收集晶体,从热乙醇中重结晶,得到2-(2-乙烯氧基-乙氧基)-异吲哚-1,3-二酮的无色针晶(13.8g,53%): 1H NMR(400MHz,CDCl3)δ7.85(m,2H),7.75(m,2H),6.46(dd,J=14.3,6.7Hz,1H),4.45(m,2H),4.16(dd,J=14.4,2.2Hz),4.02(m 3H).
B部分:O-(2-乙烯氧基-乙基)-羟胺的合成
将2-(2-乙烯氧基-乙氧基)-异吲哚-1,3-二酮(13.8g,59.2mmol)溶于二氯甲烷(45ml)。滴加甲基肼(3.2ml,60mmol),将所得溶液在环境温度下搅拌30分钟。将所得悬液用二***(150ml)稀释,过滤。在真空中浓缩滤液。蒸馏残留的油(bp 60-65℃@20mmHg),得到胺,为无色液体(4.6g,75%): 1HNMR(400MHz,CDCl3)δ6.49(dd,J=14.3,6.7Hz,1H),5.59(br s,J=2H),4.19(dd,J=14.3,2.2Hz,1H),4.01(dd,J=6.8,2.2Hz,1H),3.90-3.83(m,4H);13C NMR(100MHz,CDCl3)δ151.7,86.8,73.7,66.0.
制备例48-51是利用制备例47A部分的通用方法制备的。
制备例48
O-(2-甲氧基-乙基)-羟胺
1H NMR(400MHz,CDCl3)δ5.21(br s,2H),3.82(m,2H),3.54(m,2H),3.37(s,3H).
制备例49
3-氨基氧基-2,2-二甲基-丙-1-醇
BP 148℃@20mmHg;1H NMR(400MHz,CDCl3)δ3.50(s,2H),3.37(s,2H),0.86(s,6H).
制备例50
O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺
1H NMR(400MHz;CDCl3)δ5.50(bs,1H),4.32(m,1H),4.04(t,J=6.81Hz,1H),3.72(m,2H),3.67(m,1H),1.41(s,3H),1.34(s,3H);MS(APCI+)=148.
制备例51
O-[2-(2-甲氧基-乙氧基)-乙基]-羟胺
BP 95-100℃@20mmHg;1H NMR(400MHz,DMSO-d6)δ5.96(br s,2H),3.62(t,J=4.3Hz,2Hz),3.55-3.47(m,4H),3.42(m,2H)3.24(s,3H);MS(APCI+)=136.1.
制备例52
2-氨基氧基-乙醇
2-氨基氧基-乙醇是利用文献方法制备的:Dhanak,D.;Reese,C.B.J.Chem.Soc.,Perkin Trans.1 1987,2829。
制备例53
2-氨基氧基-丙-1-醇
2-氨基氧基-丙-1-醇是按照文献方法制备的(Cannon,J.G;Mulligan,P.J.;Garst,J.E.;Long,J.P.;Heintz,S.J Med.Chem.1973,16,287)。
1H NMR(400MHz,CDCl3)δ5.41(br s,2H),3.77(m,1H),3.58(dd,J=11.7,2.8Hz,1H),3.52(dd,J=11.7,6.9Hz,1H),1.02(d,J=6.4Hz,3H).
制备例54
3-氨基氧基-丙-1-醇
3-氨基氧基-丙-1-醇是利用文献方法制备的(Ludwig,B.J.;Reisner,D.B.;Meyer M.;Powell,L.S.;Simet,L.;Stiefel,F.J.J.Med Chem.1970,13,60)。
1H NMR(400MHz,CDCl3)δ3.84(t,J=5.8Hz,2H),3,74(t,J=5.8Hz,2H),1.85(五重峰,J=5.8Hz,2H).
制备例55
O-(2,2-二甲基-[1,3]二氧戊环-4-基乙基)-羟胺
向剧烈搅拌着的1,2,4-丁三醇(5.8g,54.6mmol)的二氯甲烷(20ml)悬液加入2,2-二甲氧基丙烷(6.8ml,54.6mmol)和催化性的对-甲苯磺酸。5分钟后,溶液变为均相,搅拌另外30分钟。然后在真空中浓缩反应混合物,得到(2,2-二甲基-[1,3]二氧戊环-4-基)乙醇(7.72g,96.7%)。在0℃下,向搅拌着的(2,2-二甲基-[1,3]二氧戊环-4-基)乙醇(6.95g,47.5mmol)、三苯膦(12.5g,47.5mmol)与N-羟基邻苯二甲酰亚胺的新蒸馏四氢呋喃(200ml)溶液缓慢加入(历经20分钟)偶氮二羧酸二乙酯。将深红色溶液在0℃下搅拌2小时,然后温热至室温,同时搅拌17小时。在真空中浓缩黄色溶液,溶于氯仿(100ml)。过滤固体,浓缩滤液。这种过滤重复两次。在硅胶上纯化其余黄色的油,用己烷-乙酸乙酯(4∶1)洗脱,得到2-[2-(2,2-二甲基-[1,3]二氧戊环-4-基)-乙氧基]-异吲哚-1,3-二酮(8.1g,58.7%)。在0℃下,向搅拌着的2-[2-(2,2-二甲基-[1,3]二氧戊环-4-基)-乙氧基]-异吲哚-1,3-二酮(0.86g,2.95mmol)的二氯甲烷(10ml)溶液加入甲基肼(0.16ml,2.95mmol)。使所得溶液温热至室温,搅拌3天。将所得悬液用***(20ml)稀释,过滤。在真空中浓缩滤液,得到O-(2,2-二甲基-[1,3]二氧戊环-4-基乙基)-羟胺(0.36g,75.3%):
1H NMR(400MHz;CDCl3)δ4.18(五重峰,1H,J=5.9),4.07(dd,1H,J=5.9,7.8),3.86(t,2H,J=6.2),3.56(t,1H,J=7.6),1.89(m,2H),1.36(s,3H),1.20(s,3H);MS(APCI+)=162.
制备例56
1-氨基氧基-3-吗啉-4-基-丙-2-醇
A步:2-(2-羟基-3-吗啉-4-基-丙氧基)-异吲哚-1,3-二酮的合成
向N-羟基邻苯二甲酰亚胺(17.1g,105mmol)与4-环氧乙烷基甲基-吗啉(14.3g,100mmol)的无水二甲基甲酰胺(200ml)溶液加入三乙胺(15.0ml,108mmol)。将所得深红色反应混合物加热至85℃达18小时。在真空中除去溶剂后,将残余物用乙酸乙酯(200ml)稀释,用水(3×100ml)和盐水(2×75ml)洗涤。有机层经无水硫酸镁干燥,在真空中浓缩。残余物经过硅胶色谱纯化(氯仿-甲醇,19∶1),得到2-(2-羟基-3-吗啉-4-基-丙氧基)-异吲哚-1,3-二酮(7.96g,25%):
1HNMR(400MHz,CDCl3)δ7.84(m,2H),7.77(m,2H),4.26(dd,J=10.8,3.4Hz,1H),4.18-4.10(m,2H),3.72(m,4H),2.70-2.47(m,6H);MS(APCI+)=307.2.
B步:1-氨基氧基-3-吗啉-4-基-丙-2-醇的合成
将2-(2-羟基-3-吗啉-4-基-丙氧基)-异吲哚-1,3-二酮(7.96g,26.0mmol)的二氯甲烷(50ml)溶液冷却至0℃,用甲基肼(1.45ml,27.3mmol)处理。将反应混合物在0℃下搅拌5分钟,在环境温度下搅拌2小时。加入***(200ml),过滤多相溶液,收集沉淀,用***(300ml)洗涤。在真空中浓缩***溶液,残余物经过硅胶色谱纯化。用氯仿-甲醇(4∶1)洗脱,得到1-氨基氧基-3-吗啉-4-基-丙-2-醇(3.21g,70%),为无色固体。重结晶(***-二氯甲烷)得到无色针晶:mp 83-85℃;
1H NMR(400MHz,DMSO-d6)δ5.96(br s,2H),4.56(d,J=4.4Hz,1H),3.81(m,1H),3.53(表观t,J=4.6Hz,4H),3.50-3.38(m,2H),2.41-2.30(m,4H),2.29-2.17(m,2H).分析计算/实验C7H16N2O3:C,47.71/47.54;H,9.15/9.23;N,15.90/15.65.
制备例57-62是利用制备例56的通用方法制备的。
制备例57
1-氨基氧基-3-苯氧基-丙-2-醇
m.p.67.5℃;1H NMR(400MHz,DMSO-d6)δ7.27(m,2H),6.91(m,3H),6.06(s,2H),5.07(d,J=3.7Hz,1H),4.02(m,1H),3.92(dd,J=10.0,4.3Hz,1H),3.84(dd,J=10.0,6.1Hz,1H),3.59(m,2H);MS(APCI+)=183.0.
制备例58
1-氨基氧基-丁-2-醇
1H NMR(400MHz,CDCl3)δ5.49(br s,2H),3.78(m,1H),3.65(dd,J=11.2,2.4Hz,1H),3.54-3.45(m,2H),1.42(m,2H),0.91(t,J=7.6hz,3H);MS(APCI+)=105.9.
制备例59
1-氨基氧基-丙-2-醇
BP 85-87℃@20mmHg;1H NMR(400MHz,DMSO-d6)δ5.96(br s,2H),4.58(d,J=3.9Hz,1H),3.80(m,1H),3.41-3.28(m,2H),0.99(d,J=6.4Hz,3H).
制备例60
1-氨基氧基-2-甲基-丙-2-醇
1H NMR(400MHz,CDCl3)δ4.84(br s,2H),3.50(s,2H),1.15(s,6H).
制备例61
1-氨基氧基-3-甲氧基-丙-2-醇
1H NMR(400MHz;DMSO-d6)δ5.95(2H,br,NH2),4.76(1H,br,-OH),3.72-3.78(1H,m),3.36-3.46(2H,m),3.19-3.26(2H,m),3.19(3H,s);MS(APCI+)=121.9.
制备例62
1-氨基氧基-4,4,4-三氟-丁-2-醇
1H NMR(400MHz;CDCl3)δ5.40(2H,br,NH2),3.60-4.10(3H,m);MS(APCI+)=145.9.
制备例63
反式-(2-氨基氧基甲基-环丙基)-甲醇
A步:在0℃下,历经15分钟向氢化锂铝(7.6g,0.3mol)的四氢呋喃(150ml)溶液滴加反式-1,2-环丙烷二羧酸二乙酯(18.6g,0.1mol)。从冷却浴中除去所得反应混合物,在回流下加热20小时。将反应混合物冷却至0℃,小心地用水(7.7ml)、10%氢氧化钠水溶液(7.7ml)和水(23ml)使反应骤停。过滤所得固体,滤液经硫酸钠干燥,在减压下浓缩。在减压下蒸馏残留的油,得到反式-(2-羟甲基-环丙基)-甲醇(7.5g,73%),为无色液体:b.p.142-144℃@20mmHg。
B步:将反式-(2-羟甲基-环丙基)-甲醇(7.5g,73mmol)、三苯膦(19.3g,73mmol)、N-羟基邻苯二甲酰亚胺(73mmol)的无水四氢呋喃(200ml)溶液冷却至0℃,用偶氮二羧酸二乙酯处理。使所得混合物自然温热至室温,搅拌过夜。浓缩反应混合物至1/8体积,过滤。经过过滤的沉淀用***洗涤,合并洗液和滤液,在真空中浓缩。将粗产物溶于二氯甲烷。加入甲基肼(73mmol),将反应混合物在环境温度下搅拌过夜。过滤除去所得沉淀。浓缩滤液,得到另外的沉淀,也过滤除去之。浓缩最终的滤液,在减压下蒸馏,得到反式-(2-氨基氧基甲基-环丙基)-甲醇(3.84g,45%),为无色的油:bp 183℃@20mmHg;
1H NMR(400MHz;CDCl3)δ3.80(br,NH2),3.50-3.70(2H,m),3.30-3.42(2H,m),0.95-1.15(2H,m),0.40-0.60(2H,m);MS(APCI+)=117.9
制备例64
(1-氨基氧基甲基-环丙基)-甲醇
A步:在0℃下,历经1小时向搅拌着的氢化锂铝的四氢呋喃(150ml)悬液滴加1,1-环丙烷二羧酸二乙酯(25g,0.13mol)。加入完全后,将反应混合物在回流下加热另外18小时。冷却混合物至0℃,先后用水(10g)、10%氢氧化钠水溶液(10g)和水(30g)处理。过滤混合物,滤液经碳酸钾干燥,在减压下浓缩。蒸馏,得到(1-羟甲基-环丙基)-甲醇(8.8g,66%),为无色粘性的油:1H NMR(400MHz;CDCl3)δ3.57(4H,s),3.26(2H,s),0.48(4H,s).
B步:将(1-羟甲基-环丙基)-甲醇(4.08g,0.04mol)、N-羟基邻苯二甲酰亚胺(6.53g,0.04mol)和三苯膦(10.50g,0.04mol)在无水四氢呋喃(100ml)中合并,在0℃下搅拌1.5小时。在0℃下加入偶氮二羧酸二乙酯(6.97g,0.04mol),将反应混合物在室温下搅拌过夜。反复从氯仿中浓缩反应混合物和过滤所得沉淀(三苯膦氧化物),得到粗产物,进一步经过硅胶色谱纯化。用己烷/乙酸乙酯(3∶2)洗脱,得到2-(1-羟甲基-环丙基甲氧基)-异吲哚-1,3-二酮(5.63g,57%),为白色固体:
1H NMR(400MHz;CDCl3)δ7.82-7.85(2H,m),7.74-7.78(2H,m),4.19(2H,s),3.72(2H,s),0.63(4H,s)
C步:在0℃下,向搅拌着的2-(1-羟甲基-环丙基甲氧基)-异吲哚-1,3-二酮(5.63g,22.8mmol)的二氯甲烷(60ml)溶液加入甲基肼(1.1g,23.8mmol)。将反应混合物在室温下搅拌过夜,过滤,在减压下浓缩。蒸馏,得到纯的1-氨基氧基甲基-环丙基)-甲醇(2.9g,71%),为无色的油:bp 140℃@20mmHg;
1H NMR(400MHz;CDCl3)δ4.00(br s,NH2),3.61(2H,s),3.43(2H,s),0.49(4H,s);MS(APCI+)=117.9.
制备例65
O-[3-(叔丁基-二甲基-甲硅烷氧基)-丙基]-羟胺
A步:向搅拌着的N-羟基邻苯二甲酰亚胺(20.6g,123mmol)的二甲基甲酰胺(95ml)溶液加入二异丙基乙胺(43ml,246mmol)。5分钟后,加入3-溴丙醇(11.5ml,127mmol),将反应混合物加热至80℃达18小时。将冷却后的溶液用乙酸乙酯(700ml)稀释,用水(4×500ml)和饱和盐水(2×500ml)洗涤,经硫酸钠干燥,浓缩至油状物,放置后固化,得到2-(3-羟基-丙氧基)-异吲哚-1,3-二酮(17.5g,65%),为黄褐色固体:
1H NMR(400MHz,CDCl3)δ7.81(m,2H),7.74(m,2H),4.36(t,2H,J=5.6Hz),3.92(t,2H,J=5.9Hz),1.98(五重峰2H,J=5.9Hz).
B步:向2-(3-羟基-丙氧基)-异吲哚-1,3-二酮(17.5g,79.1mmol)与咪唑(5.92g,86.1mmol)的二氯甲烷(200ml)溶液加入叔丁基二甲基甲硅烷基氯(13.2g,86.1mmol)。30分钟后,将反应转移至分液漏斗,与稀盐酸水溶液(400ml)一起摇动。将有机层用饱和碳酸氢钠水溶液洗涤,经硫酸镁干燥,在真空中浓缩,得到2-[3-(叔丁基-二甲基-甲硅烷氧基)-丙氧基]-异吲哚-1,3-二酮(26.3g,99%),为粘性液体:
1H NMR(400MHz,CDCl3)δ7.76(m,2H),7.67(m,2H),4.25(t,2H,J=5.9Hz),3.77(t,2H,J=6.0Hz),1.91(五重峰,2H,J=6.1Hz),0.82(s,9H),0.00(s,6H).
C步:将2-[3-(叔丁基-二甲基-甲硅烷氧基)-丙氧基]-异吲哚-1,3-二酮(26.3g,78.3mmol)的二氯甲烷(120ml)溶液冷却至0℃,用甲基肼(16.1g,78.3mmol)处理。将反应混合物在0℃下搅拌30分钟,过滤。在减压下浓缩滤液,再次溶于***,冷冻(4℃)过夜。过滤除去所得结晶性物质,在减压下浓缩滤液,得到O-[3-(叔丁基-二甲基-甲硅烷氧基)-丙基]-羟胺(15.95g,99%),为无色的油: 1HNMR(400MHz,CDCl3)δ4.69(br s,2H),3.74(t,J=6.3Hz,2H),3.67(t,J=6.3Hz,2H),1.78(五重峰,J=6.3Hz,2H),0.88(s,9H),0.00(s,6H);MS(APCI+)=206.1.分析计算/实验C3H23NO2Si:C,52.64/52.22;H,11.29/10.94;N,6.82/6.46.
制备例66
O-[4-(叔丁基-二苯基-甲硅烷氧基)-丁基]-羟胺
A步:在N2气氛和18℃下,历经2小时向1,4-丁二醇(5g,55mmol)的二氯甲烷(10ml)与二异丙基乙胺(10ml)溶液滴加叔丁基氯代二苯基硅(5ml,18mmol)。将所得溶液在室温下搅拌4小时,在减压下浓缩。经过柱色谱纯化,用己烷/乙酸乙酯(1/1)洗脱,得到4-(叔丁基-二苯基-甲硅烷氧基)-丁-1-醇(10.2g,85%),为无色的油:
1H NMR(400MHz,CDCl3)δ7.62-7.71(4H,m);7.32-7.43(6H,m),3.63-3.69(4H,m),1.83(1H,br s),1.59-1.71(4H,m),1.03(9H,s).
B步:在0℃下,将4-(叔丁基-二苯基-甲硅烷氧基)-丁-1-醇(10.0g,30.5mmol)、三苯膦(8.0g,30mmol)和N-羟基邻苯二甲酰亚胺(4.97g,30.5mmol)在无水四氢呋喃(200ml)中合并,将所得溶液在0℃下搅拌1小时。在0℃下加入偶氮二羧酸二乙酯(5.31g,30.5mmol),使反应混合物逐渐温热至室温,搅拌过夜。在减压下浓缩反应混合物,将残余物溶于氯仿。继而产生沉淀,过滤除去白色固体。浓缩滤液,用柱色谱纯化(己烷/乙酸乙酯(3/1)),得到2-[4-(叔丁基-二苯基-甲硅烷氧基)-丁氧基]-异吲哚-1,3-二酮(11.06g,77%),为无色晶体:
1H NMR(400MHz,DMSO-d6)δ7.84(4H,s),7.59(4H,dd,J=7.6,1.0Hz),7.39-7.43(6H,m),4.13(2H,t,J=6.4Hz),3.68(2H,t,J=5.8Hz),1.67-1.78(4H,m),0.95(9H,s).
C步:将2-[4-(叔丁基-二苯基-甲硅烷氧基)-丁氧基]-异吲哚-1,3-二酮(11.1g,23.4mmol)的二氯甲烷(100ml)溶液用甲基肼处理。反应混合物搅拌过夜,过滤。浓缩滤液,经过柱色谱纯化(己烷/乙酸乙酯(3.5/1)),得到O-[4-(叔丁基-二苯基-甲硅烷氧基)-丁基]-羟胺(7.2g,90%),为无色的油: 1H NMR(400MHz,CDCl3)δ7.62-7.66(4H,m),7.33-7.42(6H,m),3.64-3.68(4H),1.54-1.70(4H,m),1.02(9H,s);MS(APCI+)=344.2.
制备例67
2-氨基氧基-2-甲基-丙-1-醇
A步:向搅拌着的N-羟基氨基甲酸叔丁酯(2.38g,17.87mmol)的绝对乙醇(50ml)溶液加入氢氧化钾(1.2g,21.45mmol)和2-溴异丁酸乙酯(3.15ml,21.45mmol)。将反应混合物在回流下加热17小时。滤出固体,浓缩滤液。使所得残余物在二***与水之间分配。含水层用***萃取两次。收集有机层,经Na2SO4干燥,过滤,在真空中浓缩,得到2-Boc-氨基氧基-2-甲基-丙酸乙酯,为澄清的油(4.2g,95%):
1H NMR(400MHz;CDCl3)δ7.34(bs,1H),4.16(q,2H,J=13.9,6.6),1.45(s,6H),1.42(s,9H),1.16(t,3H,J=7.1);MS(APCI-)=246.0.
B步:将2-Boc-氨基氧基-2-甲基-丙酸乙酯(2.54g,10.27mmol)溶于新蒸馏的THF(100ml),冷却至0℃,加入2.0M硼氢化锂的THF溶液(10.3ml,20.54mmol)。除去冰浴,将反应加热至回流。17小时后,将反应冷却至0℃,用甲醇使反应骤停,在真空中浓缩。使所得残余物在乙酸乙酯与1M氢氧化钠溶液之间分配。将有机层用1M氢氧化钠溶液洗涤两次,用饱和氯化钠溶液洗涤两次,收集,经Na2SO4干燥,过滤,在真空中浓缩,得到2-Boc-氨基氧基-2-甲基-丙-1-醇(1.50g,71%),为白色固体: 1H NMR(400MHz;CDCl3)δ6.84(bs,1H),3.37(s,2H),1.45(s,9H),1.18(s,6H);MS(APCI-)=204.0.
C步:将2-Boc-氨基氧基-2-甲基-丙-1-醇(0.21g,1.02mmol)溶于甲醇(5ml),充入无水氯化氢气体达1分钟。搅拌1小时后,在真空中浓缩反应混合物,向所得残余物加入二***,得到白色固体。将该固体用二***洗涤若干次,在真空中干燥,得到2-氨基氧基-2-甲基-丙-1-醇,为盐酸盐(0.091g,63%)。
1H NMR(400MHz;CDCl3)δ3.61(s,2H),1.16(s,6H);MS(APCI+)=105.9.
制备例68
O-(2,2-二甲基-[1,3]二噁烷-5-基)-羟胺
A步:2,2-二甲基-[1,3]二噁烷-5-醇是如前所述制备的(Forbes,D.C.等;Synthesis;1998,6,879-882)。 1H NMR(400MHz;DMSO-d6)δ4.91(d,1H,J=5.1),3.70-3.75(m,2H),3.41-3.46(m,3H),1.30(s,3H),1.24(s,3H);MS(APCI+)=132.9.
B步:在0℃下,向搅拌着的2,2-二甲基-[1,3]二噁烷-5-醇(1.50g,11.35mmol)、N-羟基邻苯二甲酰亚胺(1.85g,11.35mmol)与三苯膦(2.98g,11.35mmol)的无水四氢呋喃(30ml)溶液加入偶氮二羧酸二乙酯(2.3ml,14.75mmol)。使所得溶液温热至室温。搅拌3小时后,在真空中浓缩混合物,加入氯仿,生成白色固体。滤出固体,收集滤液,浓缩。残余物经由二氧化硅柱色谱纯化(4∶1己烷/乙酸乙酯),得到2-(2,2-二甲基[1,3]二噁烷-5-基氧基)-异吲哚-1,3-二酮,为澄清晶体(1.74g,2步55%): 1H NMR(400MHz;DMSO-d6)δ7.83(s,4H),4.11-4.12(m,1H),4.04-4.09(m,2H),3.92-3.96(m,2H),1.32(s,3H),1.25(s,3H);MS(APCI+)=278.0.
C步:在0℃和氮下,向搅拌着的2-(2,2-二甲基[1,3]二噁烷-5-基氧基)-异吲哚-1,3-二酮(1.72g,6.20mmol)的二氯甲烷(15ml)溶液加入甲基肼(0.36ml,6.82mmol),温热至室温。搅拌两小时后,在真空中浓缩反应混合物,加入二***。滤出固体,收集滤液,浓缩,得到O-(2,2-二甲基-[1,3]二噁烷-5-基)羟胺,为黄色的油(0.97%,100%)。
1H NMR(400MHz;DMSO-d6)δ5.98(bs,2H),3.84-3.87(m,2H),3.66-3.68(m,2H),3.30-3.35(m,1H),1.29(s,3H),1.22(s,3H);MS(APCI+)=147.9.
制备例69
O-(2,2,5,5-四甲基-[1,3]二氧戊环-4-基甲基)-羟胺
A步:向搅拌着的N-羟基邻苯二甲酰亚胺(Aldrich,1.63g,10.0mmol)的无水乙醇(50ml)溶液加入1-溴-3-甲基-丁-2-烯(Aldrich,1.4ml,12.0mmol)和氢氧化钾(0.67g,12.0mmol)。将反应在50℃下搅拌4小时后,在真空中浓缩,然后溶于乙酸乙酯,用水分配。将有机层用水洗涤两次,用饱和氯化钠溶液洗涤两次,收集,经Na2SO4干燥,过滤,在真空中浓缩,得到白色固体。收集固体,经由二氧化硅柱纯化,用含10%甲醇的二氯甲烷洗脱,得到2-(3-甲基-丁-2-烯基氧基)-异吲哚-1,3-二酮(0.53g,23%):
1H NMR(400MHz;DMSO-d6)δ7.81(s,4H),5.38(t,1H,J=1.5),4.57(d,2H,J=7.6).1.67(s,3H),1.62(s,3H);MS(APCI+)=232.0
B步:将2-(3-甲基-丁-2-烯基氧基)-异吲哚-1,3-二酮溶于叔丁醇/THF/H2O溶液(10ml/3ml/1ml),加入N-甲基吗啉N-氧化物(0.085g,0.73mmol)和催化量的锇酸钾二水合物。搅拌17小时后,将反应用饱和焦硫酸氢钠溶液稀释,用乙酸乙酯分配。将有机层用饱和焦硫酸氢钠溶液洗涤两次,用饱和氯化钠溶液洗涤两次,收集,经Na2SO4干燥,过滤,在真空中浓缩,得到2-(2,3-二羟基-3-甲基-丁氧基)-异吲哚-1,3-二酮,为澄清的油,加入二氯甲烷(10ml)、2,2-二甲氧基丙烷(0.12ml,0.75mmol)和催化量的对-甲苯磺酸。搅拌17小时后,在真空中浓缩反应,在乙酸乙酯与水之间分配。将有机层用水洗涤两次,用饱和氯化钠溶液洗涤一次,收集,经Na2SO4干燥,过滤,在真空中浓缩,得到2-(2,2,5,5-四甲基-[1,3]二氧戊环-4-基甲氧基)-异吲哚-1,3-二酮,为浅褐色固体(0.158g,77.1%): 1H NMR(400MHz;DMSO-d6)δ7.82s,(4H),4.12-4.26(m,2H),4.04-4.07(m,1H),1.22(s,9H),1.17(s,3H),0.97s(3H).
C步:将2-(2,2,5,5-四甲基-[1,3]二氧戊环-4-基甲氧基)-异吲哚-1,3-二酮(0.158g,0.52mmol)溶于二氯甲烷(3ml),冷却至0℃,加入甲基肼(30μl,0.57mmol)。除去冰浴,将反应在环境温度下搅拌1小时。将反应混合物用二***稀释,滤出固体,在真空中浓缩滤液,得到O-(2,2,5,5-四甲基-[1,3]二氧戊环-4-基甲基)-羟胺,为黄色的油(0.042g,46%)。1H NMR(400MHz;DMSO-d6)δ6.06(bs,2H),3.84-3.87(m,1H),3.50-3.59(m,2H),1.26(s,3H),1.19(s,3H),1.16(s,3H),0.94(s,3H);MS(APCI+)=176.9.
制备例70
(S)-(+)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇
A步:在环境温度下,向搅拌着的D-甘露糖醇(1.82g,10.0mmol)的四氢呋喃(21ml)与二甲基甲酰胺(9ml)溶液加入对-甲苯磺酸一水合物(0.02g,0.1mmol),然后加入2,2-二甲氧基丙烷(2.8ml,0.023mol)。将反应混合物在室温下搅拌18小时,然后加入另外的2,2-二甲氧基丙烷(0.3ml,2.4mmol)。将悬液加热至40-45℃,搅拌2小时。加入碳酸氢钠(1.8g,0.016mol)中和酸,将混合物搅拌30分钟。过滤过量Na2CO3,用四氢呋喃(5ml)洗涤。浓缩滤液。向剩余浅黄色油加入甲苯(15ml),将混合物在3-5℃下搅拌直至生成浅黄色胶状固体。将该固体过滤,用己烷洗涤(2×5ml)。将产物在真空烘箱内干燥18小时,得到1,2∶5,6-二-O-异亚丙基-D-甘露糖醇(1.24g,47.3%),为灰白色固体,mp 110-113℃。
B步:向1,2:5,6-二-O-异亚丙基-D-甘露糖醇(50g,0.191mol)的水(700ml)溶液加入固体碳酸氢钠(20g)。将所得溶液搅拌直至全部固体溶解,然后在冰水浴中冷却。分批向溶液缓慢加入固体高碘酸钠(81.5g,0.381mol)。观察到有气体放出。将白色混合物在环境温度下搅拌2小时。加入固体氯化钠(30g),将混合物搅拌15分钟。过滤白色固体。在冰水浴中冷却滤液。缓慢加入固体硼氢化钠。有气泡放出。使混合物温热至环境温度,搅拌过夜。乳状混合物变为澄清的溶液。水性溶液用二氯甲烷萃取(3×)。将有机溶液用盐水洗涤,经硫酸镁干燥。在真空中除去溶剂,得到(S)-(+)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇,为无色的油,在高真空和环境温度下干燥过夜,34.82g(60%);MS(APCI+)=133(M++1)
制备例71
(R)-(+)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇
A步:向L-抗坏血酸(83.9g,0.477mol)的水(600ml)溶液加入Pd/C(10%,8.3g)。将混合物在Parr氢化器内、在48psi和18℃下氢化62小时。过滤反应混合物,在真空中浓缩滤液,在50℃真空烘箱内干燥18小时后,得到L-古洛糖酸γ-内酯(81.0g,96%),为灰白色固体:m.p.182-184℃。
B步:将L-古洛糖酸γ-内酯(25.0g,140.3mmol)溶于四氢呋喃(140ml)与二甲基甲酰胺(200ml)的混合物。加入对-甲苯磺酸一水合物(2.67g,14.0mmol),将反应混合物在冰水浴中冷却至0-5℃。滴加2,2-二甲氧基丙烷(22.4ml,182.4mmol),将反应混合物在环境温度下搅拌18小时。将混合物用固体碳酸钠(24.0g)中和,搅拌1小时。过滤固体,用四氢呋喃洗涤。在真空下除去THF,在高真空下蒸馏除去DMF。将所得橙色固体用甲苯(300ml)研制,过滤,用甲苯(20ml)洗涤,在40℃真空烘箱内干燥3天,得到5,6-异亚丙基-L-古洛糖酸γ-内酯(28.9g,94%),为淡橙色固体:mp 155-158℃;MS(APCI+)=219.0(M++1)
C步:在3-5℃下,向搅拌着的5,6-O-异亚丙基-L-古洛糖-1,4-内酯(15.16g,69.5mmol)的水(0.3L)悬液分小部分加入固体高碘酸钠。将混合物的pH用1N氢氧化钠水溶液调至5.5。将悬液在环境温度下搅拌2小时,然后用氯化钠(20.0g)饱和,过滤。在3-5℃下,向滤液分小部分加入硼氢化钠(10.5g,0.278mol)。将反应混合物在环境温度下搅拌18小时。加入丙酮(100ml),破坏过量的硼氢化钠,继续搅拌30分钟。在减压下除去丙酮,水性残余物用二氯甲烷(3×300ml)和EtOAc(3×300ml)萃取。合并有机层,肼硫酸镁干燥,过滤,蒸发,得到(R)-(+)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇(5.07g,55.7%),为无色澄清液体:MS(APCI+)=132.9(M++1)
制备例72
(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺和(S)-O-(2,2-二甲基
-[1,3]二氧戊环-4-基甲基)-羟胺的制备
(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺和(S)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺是利用下列方法分别从(S)-(+)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇和(R)-(-)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇制备的:
A步:在氮气氛下,向装有机械搅拌器和加液漏斗的3L圆底烧瓶内加入N-羟基邻苯二甲酰亚胺(68.0g,0.416mol)和四氢呋喃(1.2L)。向该溶液加入三苯膦(109.2g,0.416mol)和(R)-或(S)-(2,2-二甲基-[1,3]二氧戊环-4-基)-甲醇(55.0g,0.416mol)。将混合物冷却至3-5℃,滴加偶氮二羧酸二乙酯(85.2ml,0.541mol),同时保持内部温度低于15℃。使反应混合物温热至环境温度,搅拌18小时。在减压下蒸发四氢呋喃。向剩余橙色固体加入二氯甲烷(0.5L),将混合物搅拌1小时。过滤白色固体(Ph3PO),用二氯甲烷(0.1L)洗涤。除去溶剂,向所得固体加入乙醇(0.5L)。将混合物在3-5℃下搅拌2小时。过滤白色固体,用少量冷EtOH洗涤,在40℃真空烘箱内干燥,得到(S)-或(R)-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-异吲哚-1,3-二酮(112.5g,97%),为白色固体:1H NMR(CDCl3):δ1.33(s,3H),1.99(s,3H),3.96(m,1H),4.15(m,2H),4.30(m,1H),4.48(m,1H),7.59(m,2H),7.84(m,2H);MS(APCI+)=278(M++1).
B步:在3-5℃下,向搅拌着的(S)-或(R)-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-异吲哚-1,3-二酮(74.9g,0.27mol)的二氯甲烷(480ml)溶液滴加甲基肼(15.8ml,0.29mol)。悬液的颜色从黄色变为白色。除去冷却浴,将混合物在环境温度下搅拌2小时。在旋转蒸发器上浓缩所得悬液。向白色固体加入***(0.5L),将所得混合物在环境温度下搅拌1.5小时。过滤白色沉淀,用***(0.2L)洗涤。在旋转蒸发器上浓缩滤液,得到(S)-或(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺(39.0g,98.3%): 1H NMR(CDCl3):δ1.35(s,3H),1.42(s,3H),3.73(m,3H),4.05(m,1H),4.33(m,1H),5.39(m,2H);MS(APCI+)=148.1(M++1)
制备例73
O-(2-苯氨基-乙基)-羟胺;盐酸盐
O-(2-苯氨基-乙基)-羟胺是利用制备例48的通用方法从2-苯氨基乙醇制备的,从醚合氯化氢中沉淀,分离盐酸盐。
1H NMR(DMSO-d6):δ7.12(t,J=7.7Hz,2H),6.72-6.61(m,3H),4.16(t,J=5.4Hz,2H),3.35(t,J=5.4Hz,2H);MS(APCI+)=153.1(M++1).
制备例74
(2-氨基氧基-乙基)-甲基-氨基甲酸叔丁酯
A步:(2-羟基-乙基)-甲基-氨基甲酸叔丁酯是如前人所述制备的:Mewshaw,R.E.等,J.Med.Chem.1999,42,2007。
B步:历经45分钟向搅拌着的(2-羟基-乙基)-甲基-氨基甲酸叔丁酯(7.10g,40.5mmol)、N-羟基邻苯二甲酰亚胺(7.17g,44.0mmol)与三苯膦(11.5g,43.8mmol)的四氢呋喃(150ml)溶液滴加偶氮二羧酸二乙酯。将所得反应混合物在环境温度下搅拌22小时,在真空中浓缩至浓稠的油。加入氯仿(200ml),冷却所得溶液,进行1,2-肼二羧酸二乙酯的沉淀。过滤沉淀,浓缩滤液,进一步用己烷稀释。加入三苯膦氧化物的单晶。过滤除去所得三苯膦氧化物的单晶,在真空中浓缩滤液,经过硅胶色谱纯化,得到[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基氧基)-乙基]-甲基-氨基甲酸叔丁酯(12.8g,98%),为无色的油:
1H NMR(400MHz,DMSO-d6)δ7.86(bs,4H),8.55(bs,H),4.24(t,J=5.5Hz,2H),3.50 br t,J=5.4Hz,2H),2.92和2.88(brs,3H),1.39和1.36(br s,9H).
C步:将[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基氧基)-乙基]-甲基-氨基甲酸叔丁酯(4.50g,14.0mmol)的二氯甲烷(40ml)溶液用甲基肼(0.78ml,14.7mmol)处理,将反应混合物在环境温度下搅拌6小时。加入***(80ml),将非均相溶液放置过夜。过滤除去沉淀,用***(80ml)洗涤。进一步浓缩滤液,过滤所得沉淀,浓缩第二份滤液,得到(2-氨基氧基-乙基)-甲基-氨基甲酸叔丁酯(2.83g),为粘性的油:
1H NMR(400MHz,CDCl3)δ3.73(t,J=5.2Hz,2H),5.45(br s,NH2),3.46和3.42(br s,2H),2.86 br s,3H),1.25(br s,9H);MS(APCI+)=191.1.
实施例1
3,4,5-三氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
A步:向2-(4-碘-2-甲基-苯氨基)-3,4,5-三氟-苯甲酸(3.60g,8.84mmol)、O-(2-乙烯氧基乙基)羟胺(1.09g,10.5mmol)与二异丙基乙胺(2.80ml,16.0mmol)的二氯甲烷(50ml)溶液加入苯并***-1-基氧基-三吡咯烷基鏻-六氟磷酸盐(5.26g,10.1mmol)。将所得溶液在环境温度下搅拌90分钟。将反应混合物用***(100ml)稀释,用水(3×50ml)和饱和盐水(50ml)洗涤。有机层经无水硫酸镁干燥,在真空中浓缩。残余物经过硅胶色谱纯化,得到2-(4-碘-2-甲基-苯氨基)-3,4,5-三氟-N-(2-乙烯氧基乙氧基)苯甲酰胺(3.17g,73%),为淡黄色泡沫。
B步:将2-(4-碘-2-甲基-苯氨基)-3,4,5-三氟-N-(2-乙烯氧基乙氧基)苯甲酰胺(3.00g,6.09mmol)的乙醇(80ml)溶液用1M盐酸水溶液(16ml,16mmol)处理。将所得溶液在环境温度下搅拌2.5小时。加入水(50ml),过滤浆液。将固体用乙醇-水(1∶1,150ml)洗涤,从甲醇-丙酮中重结晶,得到N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-3,4,5-三氟-苯甲酰胺(2.12g,75%):m.p.205-207℃(分解);
1H NMR(400MHz,DMSO-d6)δ11.85(br s,1H),8.13(s,1H),7.54(dd,J=8.9,8.7Hz,1H),7.47(d,J=1.0Hz,1H),7.32 9d,J=8.5Hz,1H),6.41(dd,J=8.1,5.0Hz,1H),4.69(br s,1H),3.79(br s,2H),3.52(br s,2H),2.20(s,3H);MS(APCI+)=467.1;MS(APCI-)=465.1;分析计算/实验C16H14F3IN2O3:C,41.22/41.28;H,3.03/2.91;N,6.01/5.79.
实施例2-11是利用实施例1的通用方法制备的。
实施例2
3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
MP181-183℃;1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(s,1H),7.49(s,1H),7.40(dd,7.3,6.6Hz,1H),7.35(dd,J=8.3,1.7Hz,1H),7.16(dt,J=7.3,9.3Hz,1H),6.46(dd,J=8.5,5.6Hz,1H),4.70(br s,1H),3.81(br s,2H),3.54(br s,2H),2.21(s,3H);MS(APCI+)=449.1;MS(APCI-)=447.1;分析计算/实验C16H15F2IN2O3:C,42.88/42.94;H,3.37/3.39;N,6.25/6.05.
实施例3
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
方法A:利用实施例1的通用方法:
m.p.173-175℃;1H NMR(400MHz,DMSO-d6)δ11.93(br s,1H),8.85(br s,1H),7.76(d,J=1.7Hz,1H),7.48(dd,J=8.6,1.7Hz,1H),7.44(dd,J=8.5,6.2Hz,1H),7.25(dt,J=8.5,9.3Hz,1H),6.58(dd,J=8.5,6.4Hz,1H),4.70(br s,1H),3.86(br s,2H),3.56(br d,J=3.9Hz,2H);MS(APCI+)=469.0;MS(APCI-)=467.0;分析计算/实验C15H12ClF2IN2O3:C,38.45/38.60;H,2.58/2.53;N,5.98/5.91;F,8.11/8.08;I,27.08/27.43.
方法B:向2-(2-氯-4-碘-苯氨基)-3,4-二氟苯甲酸五氟苯基酯(10.0g,17.4mmol)的无水二甲基甲酰胺(36ml)溶液加入2-(氨基氧基)-乙醇(1.6g,20.8mmol)和N,N-二异丙基乙胺(6.0ml,34.8mmol)。将所得溶液在环境温度下搅拌16小时。浓缩反应混合物至20%体积,然后用乙酸乙酯(360ml)稀释。所得溶液用水(6×60ml)和盐水(2×60ml)洗涤。有机层经无水硫酸镁干燥,在减压下浓缩,得到白色固体,在硅胶上纯化。用乙酸乙酯-甲醇(9∶1)洗脱,得到2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺(7.31g,90%),为白色固体。从甲醇中重结晶,得到分析纯的物质,在各方面都等同于通过方法A制备的物质。
实施例4
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.88(br s,1H),9.81(s,1H),7.85(d,J=2.0Hz,1H),7.64(m,1H),7.60(dd,J=8.5,1.9Hz,1H),7.31(d,J=8.3Hz,1H),7.00(dd,J=11.7,2.5Hz,1H),6.75(td,J=8.5,2.5Hz,1H),4.73 br s,1H),3.90(t,J=4.6Hz,2H),3.60(br t,J=4.2Hz,2H);MS(APCI+)=451.0;MS(APCI-)=449.0;分析计算/实验C15H13ClF1IN2O3:C,39.98/40.07;H,2.91/2.83;N,6.22/6.11.
实施例5
4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
1H NMR(400MHz,CDCl3)δ9.16(br s,1H),8.67(s,1H),7.60(d,J=1.7Hz,1H),7.51(dd,J=8.4,1.7Hz,1H),7.37(dd,J=7.8,6.6Hz,1H),7.02(d,8.3Hz,1H),6.59(dd,J=12.2,2.4Hz,1H),6.41(m,1H),4.08(t,J=4.2Hz,2H),3.80(t,J=4.2Hz,2H),2.22(s,3H);MS(APCI+)=431.0;MS(APCI-)=429.0.
实施例6
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-乙氧基)-苯甲酰胺
收率;96%;m.p.183-184.5℃;1H-NMR(400MHz;DMSO-d6)δ8.46(s,1H),7.73(d,1H,J=1.7Hz),7.58(m,1H),7.44(dd,1H,J=8.5,2.0Hz),6.54(dd,1H,J=8.5,5.4Hz),4.70(宽峰s,1H),3.84(m,2H),3.54(s,2H);19F-NMR(376MHz;DMSO-d6)δ-137.03(d,1F,J=20.2Hz),-141.04(s,1F),-154.73(s,1F);MS(APCI+)486.9(M+1,100);MS(APCI-)484.9(M-1,50),424.9(100);IR(KBr)3337(O-H伸缩),1652(C=O伸缩),1502·cm-1.分析计算/实验C15H11ClF3IN2O3:C,37.02/37.16;H,2.28/2.29;N,5.76/5.49.
实施例7
5-氯-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-苯氨基)-苯甲酰胺
收率;21%;m.p.174-176℃;1H-NMR(400MHz;DMSO-d6)δ11.72(s,1H),8.47(s,1H),7.53(d,1H,J=7.1Hz),AB[7.43(d,2H,J=8.3Hz),6.63(d,2H,J=7.6Hz)],4.67(s,1H),3.74(s,2H),3.49(s,2H);19F-NMR(376MHz;DMSO-d6)δ-134.59(s,1F),-139.07(d,1F,J=17.7Hz);MS(APCI+)469.0(M+1,100);MS(APCI-)467.0(M-1,40),406.9(100);IR(KBr)1636cm-1(C=O伸缩).分析计算/实验C15H12ClF2IN2O3:C,38.45/38.61;H,2.58/2.43;N,5.98/5.94.
实施例8
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
收率;96%;m.p.117-119℃;1H-NMR(400MHz;DMSO-d6)δ11.83(s,1H),9.62(s,1H),7.69(d,1H,J=10.5Hz),7.60(m,1H),7.49(d,1H,J=8.6Hz),7.27(m,1H),6.84(d,1H,J=11.2Hz),6.70(m,1H),4.73(宽峰s,1H),3.90(m,2H),3.60(m,2H);19F-NMR(376MHz;DMSO-d6)δ-106.74(s,1F),-124.58(s,1F);MS(APCI+)435.0(M+1,100);MS(APCI-)433.0(M-1,82),373.0(100);IR(KBr)1638(C=O伸缩),1597cm-1.分析计算/实验C15H13F2IN2O3:C,41.49/41.52;H,3.02/2.97;N,6.45/6.18.
实施例9
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
方法A:利用实施例32的通用方法:收率;54%;m.p.155-156℃;1H-NMR(400MHz;DMSO-d6)δ11.83(s,1H),8.69(s,1H),7.56(dd,1H,J=11.0,1.5Hz),7.36(m,2H),7.19(m,1H),6.65(m,1H),3.82(s,2H),3.55(s,2H);19F-NMR(376MHz;DMSO-d6)δ-128.18(s,1F),-133.11(s,1F),-144.16(s,1F);MS(APCI+)453.0(M+1,100);MS(APCI-)451.0(M-1,100);IR(KBr)3349(O-H伸缩),1641(C=O伸缩),1610cm-1.分析计算/实验C15H12F3IN2O3:C,39.84/39.99;H,2.67/2.81;N,6.20/6.20.
实施例10
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
收率;96%;m.p.180-180.5℃;1H-NMR(400MHz;DMSO-d6)δ11.89(s,1H),8.68(s,1H),7.59(m,2H),7.34(d,1H,J=8.8Hz),6.72(m,1H),4.70(宽峰s,1H),3.82(m,2H),3.55(s,2H);19F-NMR(376MHz;DMSO-d6)δ-127.72(s,1F),-134.13(s,1F),-140.35(d,1F,J=17.7Hz);MS(APCI+)487.0(M+1,100);MS(APCI-)484.9(M-1,63),424.9(100);IR(KBr)3333(O-H伸缩),1643(C=O伸缩),1609,1490cm-1.分析计算/实验C15H11ClF3IN2O3:C,37.02/37.30;H,2.28/2.23;N,5.76/5.69.
实施例11
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
收率;100%;m.p.189-190℃;1H-NMR(400MHz;DMSO-d6)δ11.89(s,1H),8.70(s,1H),7.69(d,1H,J=6.1Hz),7.57(d,1H,J=10.7Hz),7.34(d,1H,J=7.8Hz),6.73(m,1H),4.70(宽峰s,1H),3.81(s,2H),3.54(s,2H);19F-NMR(376MHz;DMSO-d6)δ-126.43(s,1F),-127.65(s,1F),-140.20(d,1F,J=17.7Hz);MS(APCI+)533.0(95),531.0(M+1,100);MS(APCI-)531.0(40),529.0(M-1,42),470.9(95),468.9(100);IR(KBr)3341(O-H伸缩),1647(C=O伸缩),1606,1509,1484cm-1.分析计算/实验C15H11BrF3IN2O3:C,33.93/33.89;H,2.09/2.02;N,5.27/5.13.
实施例12
4,5-二氟-N-(2-羟基-乙氧基-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
在室温下,向4,5-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯(2.96g,0.533mmol)的二甲基甲酰胺溶液加入二异丙基乙胺(0.184ml,1.1mmol)。将反应搅拌过夜后,浓缩反应混合物至约一半体积。将溶液用***(30ml)稀释,然后用水(4×10ml)和盐水(10ml)洗涤。醚层经硫酸镁干燥,过滤所得混合物。在真空中除去滤液溶剂,得到油性固体。该油性固体经过快速色谱纯化(35g硅胶),用含乙酸乙酯的己烷梯度洗脱。在真空中除去溶剂,得到固体,在真空泵上干燥过夜。从己烷-丙酮中重结晶,得到4,5-二氟-N-(2-羟基乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺,为固体(0.107g,45%):
m.p.151.2-152.5C;1H-NMR(400MHz,(CD3)2CO)δ9.22(br.S,1H),7.63(m,2H),7.53(dd,1H,J=8.3,1.95Hz),7.14(d,1H,J=8.3Hz),6.41(m,1H),4.03(t,2H,J=4.4Hz),3.69(t,2H,J=4.88Hz),2.23(s,3H);19F-NMR(376MHz,(CD3)2CO)δ-132.75,-152.61;MS 478.9m/z(APCI+);476.9m/z(APCI-).分析计算C16H15F2IN2O3:C,42.88;H,3.39;N,6.25.实验:C,42.79;H,3.19;N,6.02.
实施例13至20是利用实施例12的通用方法制备的。
实施例13
5-溴-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.208.2-209.6C;1H-NMR(400MHz,(CD3)2CO)δ8.62(br.S,1H),7.79(dd,1H,J=7.08,1.47Hz),7.55(s,1H),7.42(d,1H,J=8.79Hz),6.65(dd,1H,J=8.30,5.86Hz),4.02(t,2H,J=4.64Hz),3.67(t,2H,J=4.64Hz),2.32(s,3H);19F-NMR(376MHz,(CD3)2CO)δ-126.85,-139.3(d,J=15.16Hz).分析计算C16H14BrF2IN2O3:C,36.46;H,2.68;N,5.31;F,7.21;Br,15.16;I,24.08. 实验:C,36.67;H,2.62;N,5.23;F,7.23;Br,15.32;I,23.3.
实施例14
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.190.2-200.2C;1H-NMR(400MHz,(CD3)2CO)δ11.11(br s,1H),8.92(brs.,1H),7.84(dd,1H,J=6.84,2.2Hz),7.76(d,1H,J=1.95Hz),7.54(dd,1H,J=8.54,6.59Hz),6.77(dd,1H,J=8.54,6.59Hz),4.40(t,2H,J=4.39Hz),3.69(t,2H,J=4.89Hz).19F-NMR(376MHz,(CD3)2CO)δ-126.16,-137.47(d,J=17.69Hz);MS 546.9m/z,548.9m/z(AP+);544.9m/z,546.9m/z(AP-).分析计算C15H11BrClF2IN2O3:C,32.91;H,2.03;N,5.12;F,6.94;Br,14.58;I,23.18.实验:C,32.94;H,1.95;H,5.30;F,6.87;Br,14.79;I,22.91.
实施例15
5-氯-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.199.1-200.8C;1H-NMR(400MHz,(CD3)2CO)δ8.57(br.S,1H),7.68(dd,1H,J=7.32,2.2Hz),7.55(s,1H),7.41(dd,1H,J=8.3,1.71Hz),6.64(dd,1H,J=8.3,5.86),4.02(t,2H,J=4.63Hz),3.67(t,2H,J=4.88Hz),2.32(s,3H).19F-NMR(376MHz,(CD3)2CO)δ-134.75,-139.56(t,J=15.17Hz);MS 483.0m/z(AP+);481.0m/z(AP-).分析计算C16H14ClF2IN2O3:C,39.82;H,2.92;N,5.8;F,7.87;Cl,7.35;I,26.29.实验:C,39.91;H,2.92;N,6.0;F,7.91;Cl,7.39;I,27.06.
实施例16
5-溴-4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.154.4-156.4;1H-NMR(400MHz,(CD3)2CO)δ9.42(br.s,1H),7.86(d,1H,J=7.57Hz),7.66(d,1H,J=1.46Hz),7.56(dd,1H,J=8.3,2.2Hz),7.16(d,1H,J=8.55Hz),6.8(dd,1H,J=11.72,6.59Hz),4.04(t,2H,J=7.9,4.4Hz),3.69(t,2H,J=6.84,4.64Hz),2.23(s,3H).19F-NMR(376MHz,(CD3)2CO)δ-103.3;MS508.9m/z,510.9m/z(AP+);506.9m/z,508.9m/z(AP-).分析计算C16H15BrFIN2O3:C,37.75;H,2.97;N,5.50.实验:C,37.68;H,2.7;H,5.31.
实施例17
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
1H-NMR(400MHz,(CD3)2CO)δ11.01(br.s,1H),9.53(br.s,1H),7.79(br.s,1H),7.67(br.s,1H),7.59(br.d,1H,J=7.82Hz),7.32(d,1H,J=8.55Hz),7.26(br.s,1H),4.03(br.s,2H),3.7(br.s,2H);19F-NMR(376MHz,(CD3)2CO)δ-132.54,-149.93;MS 469.0(AP+);467.0(AP-).
实施例18
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.189.6-190.6C;1H-NMR(400MHz,(CD3)2CO)δ11.00(br s,1H),9.39(br.s,1H),7.65(dd,1H,J=11.23,8.79Hz),7.59(dd,1H,J=10.26,1.96Hz),7.51(m,1H),7.31(t,1H,J=8.8Hz),7.13(m,1H),4.02(t,2H,J=4.64Hz),3.69(t,2H,J=4.89Hz);19F-NMR(376MHz,(CD3)2CO)δ-125.9(d,J=50.55Hz),-132.74,-151.05;MS 453.0m/z(AP+);451.0m/z(AP-).分析计算C15H12F3IN2O3:C,39.84;H,2.67;N,6.20.实验:C,40.22;H,2.62;N,6.03.
实施例19
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.173-175C;1H-NMR(400MHz,(CD3)2CO)δ9.59(br.s.),7.89(d,1H,J=7.57Hz),7.62(dd,1H,J=10.26,1.95Hz),7.55(m,1H),7.34(t,1H,J=8.64Hz),7.03(d,1H,J=11.48Hz),4.04(d,2H,J=4.39Hz),3.70(d,2H,J=4.64Hz);19F-NMR(376MHz,(CD3)2CO)δ-103.07,-124.7(d,J=53.1Hz);MS 512.8m/z,514.8m/z(AP+);510.9m/z,512.9m/z(AP-).分析计算C15H12BrF2IN2O3·0.17C4H8O2·0.13C6H14:C,36.66;H,2.84N,5.19.实验:C,36.65;H,2.57;N,5.16.
实施例20
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.=178-181℃;1NMR(400MHz;DMSO-d6)δ12.00(s,1H),8.80(s,1H),7.76(s,1H),7.66(d,1H,J=7.1),7.47(d,1H,J=8.5),6.66(t,1H,J=7.6),4.70(bs,1H),3.85(m,2H),3.56(m,2H);MS(APCI+)=502.9/504.9. 分析计算/实验C15H11Cl2F2IN2O3:C 35.81/35.69,H 2.20/2.25,N 5.57/5.22,F 7.55/7.72.
实施例21-24和26-27是利用实施例38的通用方法制备的。
实施例21
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.=185-187℃;1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),8.32(s,1H),7.53(m,2H),7.30(d,1H,J=8.5),6.60-6.55(m,1H),4.69(bs,1H),3.80(bs,2H),3.50(bs,2H);MS(APCI+)=471.0.分析计算/实验C15H11F4IN2O3:C,38.32/38.38;H,2.36/2.15;N,5.96/5.76;F,16.16/15.87.
实施例22
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)苯甲酰胺
m.p.146.1-146.4℃;1H NMR(400MHz,DMSO-d6)δ11.82(1H,s),8.71(1H,s),7.47(1H,dd,J=11.1Hz,2.1Hz),7.30-7.40(1H,m),7.15-7.20(2H,m),6.76-6.81(1H,m),4.69(1H,br s),3.80(2H,t,J≤4.0Hz),3.52(2H,t,J≤4.0Hz).分析计算/实验C15H12F3BrN2O3:C,44.47/44.58;H,2.99/2.88;N,6.91/6.72;F,14.07/14.01;Br,19.72/19.60.
实施例23
2-(4-溴-2-氟-苯氨基)-4,5-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.190.8-192.5℃;1H NMR(400MHz,丙酮-d6)δ9.40(br s,1H),7.67(1H,dd,J=11.48Hz,8.79Hz),7.48(2H,m),7.37(1H,m),7.12(1H,m),4.05(2H,t,J=4.64Hz),3.71(2H,t,J=4.64Hz).分析计算/实验C15H12BrF3N2O3:C,44.47/45.55;H,2.99/2.98;N,6.91/6.29.
实施例24
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.142.1-142.5℃;1H NMR(400MHz,DMSO-d6)δ11.83(1H,s),8.72(1H,s),7.36-7.39(2H,m),7.16(1H,dd,J=16.5Hz,9.4Hz),7.07(1H,dd,J=8.5Hz,1.3Hz),6.82-6.88(1H,m),4.69(1H,br s),3.80(2H,t,J=4.6Hz),3.52(2H,t,J=4.6Hz).分析计算/实验C15H12ClF3N2O3;C,49.95/50.18;H,3.35/3.21;N,7.77/7.70;F,15.80/15.70;Cl 9.83/9.94.
实施例25
3,4-二氟-2-(2-氟-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺
利用实施例86的通用方法从3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基乙氧基)-苯甲酰胺制备。m.p.129.6-130.4℃;1H NMR(400MHz,DMSO-d6)δ11.85(1H,s),8.72(1H,s),7.36-7.39(1H,m),6.82-7.18(5H,m),4.69(1H,br s),3.82(2H,t,J=4.7Hz),3.53(2H,t,J=4.7Hz).分析计算/实验C15H13F3N2O3:C,55.22/55.16;H,4.02/3.97;N,8.59/8.51;F,17.47/17.15.
实施例26
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.161.6-162.4℃;1H NMR(400MHz,DMSO-d6)δ11.89(1H,s),8.69(1H,s),7.56(1H,dd,J=7.5Hz,1.9Hz),7.21-7.27(1H,m),6.94-7.06(1H,m),6.89-6.92(1H,m),4.69(1H,br s),3.81(2H,t,J=4.6Hz),3.53(2H,t,J=4.6Hz).分析计算/实验C15H11ClF4N2O3:C,47.57/47.74;H,2.93/2.83;N,7.40/7.31;F,20.07/19.76;Cl,9.36/9.39.
实施例27
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺
m.p.141.1-141.6℃;1H NMR(400MHz,DMSO-d6)δ11.84(1H,s),8.73(1H,s);7.34-7.37(1H,m),7.11-7.27(1H,m),7.04-7.09(1H,m),6.89-6.99(2H,m),4.70(1H,br s),3.82(2H,t,J=4.9Hz),3.53(2H,t,J=4.8Hz).分析计算/实验C15H12F4N2O3:C,52.33/52.34;H,3.51/3.39;N 8.14/8.01;F,22.07/21.93.
实施例28
4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
A步:在环境温度下,向4-氟-2-(4-碘-2-甲基-苯氨基)苯甲酸(3.32g,8.95mmol)在二氯甲烷中的混合物加入二异丙基乙胺(2.82ml,16.2mmol)。向所得溶液加入O-[3-(叔丁基-二甲基-甲硅烷氧基)-丙基]-羟胺(2.19g,10.65mmol)和PyBOP。搅拌1.5小时后,将溶液用***(100ml)稀释,用水(3×50ml)和盐水(50ml)洗涤,经硫酸镁干燥,过滤,在真空中浓缩,得到胶状物。经过色谱纯化,历经45分钟用100%己烷至含30%乙酸乙酯的己烷梯度洗脱。合并各部分,在真空中除去溶剂,得到黄色的胶。在真空泵上干燥约18小时,得到N-[3-(叔丁基-二甲基-甲硅烷氧基)-丙氧基]-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺,为固体(4.06g,81%)。 1H-NMR(400MHz,CDCl3)δ9.3(br.s.,1H),9.0(br.s.,1H),7.58(s,1H),7.49(dd,1H,J=8.3,1.95Hz)),7.36(br.t,1H,=5.71Hz),7.05(d,1H,J=8.3Hz),6.65(dd,1H,J=11.96,2.44Hz),6.4(br.t.,J=7.1Hz),4.14(t,2H,J=5.61Hz),3.812(t,2H,J=5.62Hz),2.28(s,3H),1.94(p,2H,J=5.86Hz),0.9(s,9H),0.08(s,6H).19F-NMR(376MHz,CDCl3)δ-105.25.MS(AP+)559.2m/z,(AP-)557.1m/z.
B步:在环境温度下,向N-[3-(叔丁基-二甲基-甲硅烷氧基)-丙氧基}-4-氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺(4.0g,7.27mmol)的甲醇(5ml)溶液加入5M H2SO4的甲醇溶液(0.073ml,0.364mmol)。搅拌1小时后,向反应加入另外的5M H2SO4的甲醇溶液(0.035ml,0.182mmol)。搅拌2小时后,将反应用饱和NaHCO3(aq)(约1.5ml)调至pH7,然后加入水(35ml)。含水层用乙酸乙酯萃取(1×20ml,2×10ml)。合并萃取液,用盐水洗涤,经硫酸镁干燥。过滤所得混合物,在真空中除去滤液溶剂,得到油状物,在真空泵上干燥经过周末。该油经过快速色谱纯化,在50分钟内用100%己烷至100%乙酸乙酯梯度洗脱。合并各部分,在真空中除去溶剂,得到固体,在真空泵上干燥约6小时。使固体在己烷与乙酸乙酯的混合物中重结晶,得到4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺,为固体(2.4g,74%):
m.p.120.8-122.4C;1H-NMR(400MHz,(CD3)2CO)δ10.91(br s,1H),9.59(br.S,1H),9.68(m,2H),7.57(d,1H,J=8.54Hz),7.18(d,1H,J=8.34Hz),6.72(m,1H);6.53(m,1H);4.12(t,2H,J=6.11Hz),3.71(t,2H,J=5.86Hz),2.26(s,3H),1.86(m,2H);19F-NMR(376MHz,(CD3)2CO)δ-108.14;MS 445.1m/z(AP+),443.1m/z(AP-).分析计算C17H18FIN2O3:C,45.96;H,4.08;N,6.31;F,4.28;I,28.57.实验:C,45.78;H,3.88;N,6.14;F,4.30;I,28.27.
实施例29-33是利用实施例28的通用方法制备。
实施例29
5-氯-3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.155.2-156.6C;1H-NMR(400MHz,(CD3)2CO)δ10.98(br s,1H),8.70(br.S,1H),7.66(dd,1H,J=7.33,1.95Hz),7.55(s,1H),7.42(dd,1H,J=8.54,1.95Hz),6.64(dd,1H,J=8.55,6.11Hz),4.08(t,2H,J=6.11Hz),3.67(t,2H,J=6.10Hz),2.32(s,3H),1.83(m,2H);19F-NMR(376MHz,(CD3)2CO)δ-135.0,-139.63(d,J=17.67Hz);MS 497.1m/z(AP+);495.1m/z(AP-).分析计算C17H16ClF2IN2O3:C,41.11;H,3.25;N,5.64;F,7.65;Cl,7.14;I,25.55.实验:C,41.09;H,3.07;N,5.46;F,7.63;Cl,7.24;I,25.57.
实施例30
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丙氧基)-苯甲酰胺
m.p.158.8-160.8C;1H-NMR(400MHz,(CD3)2CO)δ10.90(br s,1H),9.93(br.S,1H),7.84(d,1H,J=1.95Hz),7.72.(dd,1H,J=8.55,1.96Hz),7.65(dd,1H,J=8.55,1.96Hz),7.39(d,1H,J=8.54Hz),7.05(dd,1H,J=11.72,2.44Hz),6.67(td,1H,J=8.55,2.69Hz),4.13(t,2H,J=6.34Hz),3.71(t,2H,J=6.10Hz),1.86(m,2H).19F-NMR(376MHz,(CD3)2CO)δ-108.0;.MS 465.1m/z(AP+),463.1m/z(AP-). 分析计算C16H15ClFIN2O3:C,41.36;H,3.25;N,6.03;F,4.09;Cl,7.63;I,27.31.实验:C,41.41;H,3.13;N,5.84;F,4.10;Cl,7.62;I,27.41
实施例31
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)-苯甲酰胺
m.p.120-121℃;1NMR(400MHz;DMSO-d6)δ11.90(bs,1H),8.91(bs,1H),7.76(bs,2H),7.47(d,1H,J=8.1),6.67(m,1H),4.48(bs,1H),3.89(bs,2H),3.47(bs,2H),1.73(m,2H);MS(APCI+)=560.8/562.8.分析计算/实验C16H13BrClF2IN2O3:C 34.22/34.45,H 2.33/2.36,N 4.99/4.91,F 6.77/6.72.
实施例32
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)-苯甲酰胺
m.p.151.8-152.4℃;1H NMR(400MHz,DMSO-d6)δ11.74(1H,s),8.71(1H,s),7.56(1H,d,J=11.0Hz),7.20-7.30(2H,m),7.16-7.22(1H,m),6.62-6.68(1H,m),4.46(1H,br s),3.83(2H,t,J=5.6Hz),3.46(2H,t,J=4.6Hz),1.67-1.70(2H,m). 分析计算/实验C16H14F3IN2O3:C,41.22/41.27;H,3.03/2.87;N,6.01/5.92;F,12.23/11.97;I,27.22/27.44.
实施例33
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(4-羟基-丁氧基)-苯甲酰胺
m.p.131.4-131.9℃;1H NMR(400MHz,DMSO-d6)δ11.71(1H,s),8.68(1H,s),7.54(1H,d,J=11.0Hz),7.20-7.36(2H,m),7.14-7.18(1H,m),6.60-6.66(1H,m),4.38(1H,br s),3.74(2H,t,J=6.1Hz),3.36(2H,t,J=4.2Hz),1.41-1.55(4H,m). 分析计算/实验C17H16F3IN2O3:C,42.52/42.91;H,3.36/3.27;N,5.83/5.58;F,11.87/11.61;I,26.43/26.67.
实施例34
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺
A步:向搅拌着的5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸五氟苯基酯(5.80g,9.51mmol)的新蒸馏四氢呋喃(40ml)溶液加入O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺(1.54g,10.5mmol)和二异丙基乙胺(1.8ml,10.5mmol)。20小时后,使混合物在乙酸乙酯与水之间分配。有机层用水洗涤两次,用饱和盐水溶液洗涤两次。收集有机层,经Na2SO4干燥,过滤,在真空中浓缩。残余物在乙酸乙酯/己烷中重结晶纯化,得到5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-苯甲酰胺,为白色固体(3.7g,67.9%):
1H NMR(400MHz;CDCl3)δ9.82(bs,1H),8.10(bs,1H),7.68(s,1H),7.47(bs,1H),7.40-7.43(m,1H),6.44-6.47(m,1H),4.40(bs,1H),3.97-4.20(m,3H),3.77(t,1H,J=8.0),1.44(s,3H),1.37(s,3H);MS(APCI+)=573.0/575.0.
B步:向搅拌着的5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-苯甲酰胺(3.7g,6.45mmol)的甲醇(20ml)与水(2ml)溶液加入对-甲苯磺酸(0.12g,0.65mmol)。20小时后,在真空中浓缩反应。使所得残余物在乙酸乙酯与水之间分配。有机层用饱和NaHCO3溶液洗涤两次,用饱和盐水溶液洗涤两次。收集有机层,经Na2SO4干燥,过滤,在真空中浓缩。残余物用甲醇/水结晶纯化,在40℃真空烘箱内干燥固体,得到5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺:
m.p.=152-154℃;1NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.83(s,1H),7.76(s,1H),7.66(d,1H,J=6.8),7.47(d,1H,J=8.5),6.68(t,1H,J=6.6),4.83(bs,1H),4.60(bs,1H),3.89-3.92(m,1H),3.68-3.76(m,2H),3.30(2H,部分被HD0所覆盖);MS(APCI+)=533.0/535.0;分析计算/实验C16H13Cl2F2IN2O4:C,36.05/36.23;H,2.46/2.40;N,5.25/5.03;F,7.13/7.14.
实施例35-37是利用实施例34所述通用方法制备的。
实施例35
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.=67-69℃;1H NMR(400MHz,CDCl3)δ7.51(s,1H),7.46(d,1H,J=6.3),7.38(d,1H,J=8.5),6.44(dd,1H,J=8.3,4.9),3.94-3.98(m,2H),3.89(m,1H),3.74(A of abx,1H,J=11.7,3.9),3.61(B of abx,1H,J=11.5,4.9),2.30(s,3H);MS(APCI+)=513.0/515.0.分析计算/实验C17H16ClF2IN2O4:C,39.83/39.90;H,3.15/3.23;N,5.46/5.03;F,7.41/7.20.
实施例36
5-氯-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.=135-138℃;1H NMR(400MHz,DMSO-d6)δ11.86(bs,1H),8.55(bs,1H),7.85(s,1H),7.60(d,1H,J=7.1),7.51(s,1H),7.35(d,1H,J=8.5),6.53(dd,1H,J=8.3,5.4),4.51-4.52(m,2H),3.86-3.88(m,2H),3.53(bs,1H),3.23-3.28(cm,1H),2.20(s,3H),1.73-1.77(cm,1H),1.45-1.48(cm,1H);MS(APCI+)=527.0.分析计算/实验C18H18ClF2IN2O4:C,41.05/41.12;H,3.44/3.41;N,5.32/5.13;F,7.21/6.83.
实施例37
5-氯-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺
m.p.=146-148℃;1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.84(s,1H),7.76(s,1H),7.65(d,1H,J=7.1),7.47(d,1H,J=8.8),6.67(dd,1H,J=8.3,6.3),4.54-4.50(m,2H),3.93(t,2H,J=6.3),3.54(t,1H,J=4.2),3.28-3.20(m,2H),1.76(cm,1H),1.52-1.47(cm,1H);MS(APCI+)=547.0/549.0.分析计算/实验C17H15Cl2O4:C,37.32/37.26;H,2.76/2.62;N,5.12/4.99;F,6.94/7.07.
实施例38
N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
在-15℃下,向搅拌着的3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸(4.52g,11.5mmol)的新蒸馏四氢呋喃(20ml)溶液加入二苯基膦酰氯(2.85ml,14.95mmol)。将所得反应混合物在-15℃下搅拌30分钟。加入N-甲基吗啉(1.26ml,11.5mmol),继续在-15℃下搅拌90分钟。然后向反应加入O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)羟胺(2.03g,13.8mmol),在-15℃下搅拌30分钟。加入N-甲基吗啉(1.9ml,17.25mmol),使反应温热至室温。17小时后,将混合物用乙酸乙酯稀释,用饱和NaHCO3溶液分配两次,然后用水分配两次,用饱和盐水溶液分配两次。收集有机层,经硫酸钠干燥,过滤,在真空中浓缩。所得残余物经过二氧化硅柱色谱纯化,用3∶1己烷/乙酸乙酯洗脱。收集相应的部分,在真空中干燥,从乙酸乙酯/己烷中结晶,得到N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺(4.12g,68.6%),为浅褐色固体:
m.p.=114-115℃;1NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.62(s,1H),7.53-7.55(m,1H),7.31-7.37(m,2H),7.17(dd,1H,J=16.9,9.3),6.60-6.65(m,1H),4.22(t,1H,J=6.1),3.96(t,1H,J=8.3),3.76-3.77(m,2H),3.63(t,1H,J=4.9),1.26(s,3H),1.21(s,3H);MS(APCI+)=522.9;分析计算/实验C19H18F3IN2O4:C,43.70/43.88;H,3.47/3.43;N,5.36/5.20;F,10.91/10.87.
实施例39
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(化合物A的II型)
在环境温度下,向搅拌着的N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(3.03g,5.81mmol)的甲醇(30ml)与水(3ml)溶液加入对-甲苯磺酸(0.11g,0.581mmol)。18小时后,加入另外0.11g对-甲苯磺酸和2ml水。另外24小时后,在真空中浓缩反应混合物。使残余物在乙酸乙酯与水之间分配。有机层用饱和NaHCO3溶液洗涤两次,用饱和盐水溶液洗涤两次。收集有机层,经Na2SO4干燥,过滤,在真空中浓缩,得到浅褐色固体,从乙酸乙酯/己烷中结晶,得到N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺,为白色固体。
m.p.=135.5-137.3℃;1NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.69(s,1H),7.54(dd,1H,J=10.9,1.5),7.32-7.38(m,2H),7.17(dd,1H,J=16.8,9.0),6.61-6.66(cm,1H),4.82(bs,1H),4.58(bs,1H),3.84-3.85(m,1H),3.71-3.64(cm,2H),3.33(2H,部分被HD0所覆盖);MS(APCI+)=483.0;分析计算/实验C16H14F3IN2O4:C,39.85/40.12;H,2.93/2.84;N,5.81/5.65;F,11.82/11.47.
作为替代选择,将N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的粗白色固体悬浮在庚烷-CH2Cl2(1∶1)中。比例是6ml溶剂每克固体。将悬液在环境温度下搅拌30分钟。过滤固体,在45℃真空(20mmHg)烘箱内干燥18小时,得到白色晶体,mp 131-132℃。
实施例39A
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺(化合物A的I型)
在环境温度下,向搅拌着的N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(0.907g,1.74mmol)的甲醇(1ml)溶液加入对-甲苯磺酸(0.032g,0.17mmol)。搅拌18小时后,在真空中浓缩反应混合物,使所得残余物在乙酸乙酯与水之间分配。有机层用水洗涤两次,用饱和盐水溶液洗涤一次。收集有机层,经Na2SO4干燥,过滤,在真空中浓缩,得到浅褐色固体,将其溶于乙醇,用水沉淀,得到N-(2,3-二羟基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,为白色固体(0.387g)。
m.p.=83-85℃;1NMR(400MHz,DMSO-d6)11.87(s,1H),8.69(s,1H),7.56(d,1H,J=11.0),7.33-7.39(m,2H),7.19(dd,1H,J=16.6,9.0),6.62-6.68(cm,1H),4.82(d,1H,J=4.2),4.58(t,1H,J=5.5),3.84-3.87(m,1H),3.66-3.72(m,2H),3.3(2H,部分被HD0所覆盖);MS(APCI+)=483.0;分析计算/实验C16H14F3IN2O4·0.3H2O:C,39.41/39.02;H,3.02/2.93;N,5.75,5.81;F,11.69/11.68.
作为替代选择,将粗固体N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺溶于少量沸腾着的乙醇(95%)。向该沸腾着的溶剂加入水,直至轻微浑浊。将混合物冷却至环境温度,然后在0℃下经过18小时。过滤所生成的固体,在45℃真空(20mmHg)烘箱内干燥18小时,mp 81-84℃。
此外,将粗固体N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺溶于少量沸腾着的乙酸乙酯,向该溶液加入庚烷直至轻微浑浊。将混合物冷却至环境温度,然后在0℃下经过18小时。过滤所生成的固体,在45℃真空(20mmHg)烘箱内干燥18小时,mp 86℃。
实施例40-48的化合物是利用实施例38和39所述的方法制备的。
实施例40
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=172-174℃;1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.69(s,1H),7.67(d,1H,J=6.8),7.56(d,1H,J=10.7),7.34(d,1H,J=8.3),6.73(cm,1H),4.81(m,1H),4.58-4.57(m,1H),3.86-3.84(m,1H),3.70-3.67(m,2H),3.30(2H,部分被HD0所覆盖);MS(APCI+)=561.0.分析计算/实验C16H13BrF3IN2O4:C,34.25/34.27;H,2.34/2.22;N,4.99/4.75.
实施例41
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=152-155℃;1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.66(s,1H),7.58-7.55(m,2H),7.34(d,1H,J=8.1Hz),6.72(cm,1H),4.81(d,1H,J=4.1Hz),4.58(t,1H,J=5.9Hz),3.87-3.84(m,1H),3.70-3.68(m,2H),3.33(2H,部分被HD0所覆盖);MS(APCI+)=517.0.分析计算/实验C16H13ClF3IN2O4:C37.20/36.88,H 2.54/2.43,N 5.42/5.14,F 11.03/11.70.
实施例42
N-(2,3-二羟基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=173-175℃;1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.59(s,1H),7.69(d,1H,J=10.3),7.58(t,1H,J=7.8),7.49(d,1H,J=8.5),7.27(t,1H,J=8.5),6.82(d,1H,J=11.5),6.69(t,1H,J=7.8),3.94-3.92(m,1H),3.78-3.71(m,2H),3.4(2H,under HDO);MS(APCI+)=465.0.
实施例43
N-(2,3-二羟基-丙氧基)-3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=157-160℃;1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.32(s,1H),7.53-7.48(m,2H),7.29(d,1H)J=8.3),6.58-6.55(m,1H),4.80(d,1H,J=3.0),4.57(t,1H,J=5.9),3.83-3.81(m,1H),3.67-3.65(m,2H),3.30(2H,under HDO);MS(APCI+)=500.9.分析计算/实验C16H13F4IN2O4:C,38.42/38.48;H,2.62/2.54;N,5.60/5.55;F,15.19/14.96.
实施例44
2-(4-溴-2-氟-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺按照N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(实施例39)的方式制备:
m.p.110-117℃(dec).分析计算/实验C16H14BrF3BrN2O4:C,44.16/43.86;H,3.24/2.97;N,6.44/6.13;F,13.10/12.76;Br,18.36/18.64.
实施例45
2-(4-氯-2-氟-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺
m.p.114.0-114.9℃;1H NMR(400MHz,DMSO-d6)δ11.87(1H,s),8.74(1H,s),7.38(1H,dd,J=11.3Hz,2.3Hz),7.36(1H,m),7.07-7.20(2H,m),6.84-6.90(1H,m),4.83(1H,br s),4.59(1H,br s),3.84-3.87(1H,m),3.65-3.72(2H,m),3.20-3.40(2H,m).分析计算/实验C16H14F3ClN2O4:C,49.18/49.09;H,3.61/3.56;N,7.07/7.03;F,14.59/14.45;Cl,9.07/9.16.
实施例46
N-(2,2-二甲基-[1,3]二噁烷-5-基氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=154-155℃;1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.64(s,1H),7.55(dd,1H,J=10.7,1.7),7.40(t,1H,J=7.1),7.33(d,1H,J=8.3),7.21-7.14(m,1H),6.69-6.65(m,1H),3.95(A of AB,2H,J=10.7),3.80(B of AB,2H,J=12.2),3.65(bs,1H),1.33(s,3H),1.25(s,3H);MS(APCI+)=523.1;分析计算/实验C19H18F3IN2O4:C,43.70/43.76;H,3.47/3.44;N,5.36/5.21;F,10.91/10.73.
实施例47
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺
m.p.111-114℃;1H NMR(400MHz,DMSO-d6)δ11.82(bs,1H),8.64(bs,1H),7.55(dd,1H,J=10.7,1.9),7.40(t,1H,J=7.3),7.34-7.31(m,1H),7.20(dd,1H,J=16.6,9.3),6.65-6.60(m,1H),4.64(bs,2H),3.75-3.72(m,1H),3.48-3.44(m,4H);MS(APCI+)=482.9;分析计算/实验C16H14F3IN2O4:C,39.85/39.93;H,2.93/2.93;N,5.81/5.51;F,11.82/11.72.
实施例48
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺
m.p.173-175℃;1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.56(s,1H),7.61(d,1H,J-6.3),7.55(d,1H,J=9.3),7.32(d,1H,J=9.5),6.69(m,1H),4.61(m,2H),3.73(m,1H),3.48(m,4H);MS(APCI+)=516.9/518.9.
实施例49
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(化合物B的I型)
A步:在氮气氛下,向3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸(39.3g,100.0mmol)的无水四氢呋喃溶液(500ml,0.2M)加入(R)-O-(2,2-二甲基-[1,3 ]二氧戊环-4-基甲基)羟胺(14.7g,100.0mmol),然后加入N-甲基吗啉(27.5ml,0.25mol)。橙色溶液用冰水浴冷却。滴加二苯基膦酰氯(22.9ml,0.12mol)。生成一些固体。使混合物温热至环境温度,搅拌18小时。加入水,使反应骤停,在真空重蒸发四氢呋喃。将其余的油溶于乙酸乙酯(500ml),用饱和盐水与饱和碳酸氢钠的混合物(1∶1)洗涤两次。除去乙酸乙酯,粗的油性固体经过快速色谱纯化(硅胶,己烷-丙酮/2∶1),在40℃真空烘箱内干燥20小时后,得到N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,为灰白色固体:41.7g(79.8%),m.p.124-125℃。合并不纯的部分,经过第二次柱色谱纯化,用相同的条件洗脱,得到第2批6.4g(12.3%),mp 124-125℃,总收率48.1g(92.1%)。
1H NMR(d6-DMSO):δ11.9(s,br,1H),8.7(s,br,1H),7.6(d,1H,J=10.99Hz),7.4(m,2H),7.2(m,1H),6.7(m,1H),4.2(m,1H),4.0(t,1H,J1=8.3Hz,J2=6.8Hz),3.8(m,2H),3.7(m,1H),1.3(s,3H),1.2(s,3H);19FNMR(d6-DMSO):δ-128.0,-133.1,-144.3;MS:523(M++1).
B步:将N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(22.3g,42.7mmol)悬浮在甲醇中(223ml,10ml/g),加入pTsOH-H2O(4.1g,21.35mmol)的水(22.3ml)溶液。将混合物在环境温度下搅拌18小时,在此期间全部固体溶解,得到无色澄清的溶液。浓缩该溶液,用乙酸乙酯萃取(2×300ml)。有机溶液用碳酸氢钠洗涤,经MgSO4干燥。过滤后,浓缩滤液,与庚烷共蒸发,得到泡沫样固体。向该固体加入己烷-CH2Cl2(1∶1,100ml),将混合物搅拌30分钟。生成白色固体,过滤之,用己烷洗涤。使固体从己烷-EtOAc中重结晶,在60℃真空烘箱内干燥3天后,得到N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,为白色晶体,13.57g(65.9%)。从相同的溶剂***重结晶后,从母液得到第二批5.05g。总收率为18.62g(90.4%):m.p.89-90℃(化合物B的II型)。合并晶体,用一套研钵和研棒研磨成微细粉末,在60℃真空烘箱内干燥3天:m.p.117-118℃(化合物B的I型);
[α]=-2.05°(c=1.12,甲醇);分析计算C16H14F3I1N2O4:C,39.85;H,2.93;N,5.81;F,11.82,I,26.32.实验:C,39.95;H,2.76;N,5.72;F,11.71;I,26.53.1NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.69(s,1H),7.54(dd,1H,J=10.9,1.5),7.32-7.38(m,2H),7.17(dd,1H,J=16.8,9.0),6.61-6.66(cm,1H),4.82(bs,1H),4.58(bs,1H),3.84-3.85(m,1H),3.71-3.64(cm,2H),3.33(2H,部分被HD0所覆盖).
实施例49A
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(化合物B的II型)
A步:在氮气氛和-15℃下,向3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸(2.25g,5.10mmol)的无水四氢呋喃溶液滴加二苯基膦酰氯(1.26ml,6.63mol)。搅拌20分钟后,加入N-甲基吗啉(0.70ml,6.375mmol),将反应搅拌另外20分钟。加入(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺(0.748g,5.1mmol),将反应搅拌1小时,此时加入N-甲基吗啉(0.7ml,6.37mmol)。使混合物温热至环境温度,搅拌12小时。在真空中浓缩反应,然后用EtOAc稀释。将有机层用饱和NaHCO3(2×)、盐水(1×)洗涤,经Na2SO4干燥,过滤,浓缩。从SiO2上纯化粗产物,使用4∶1己烷/EtOAc作为洗脱剂,得到1.82g(68%)红褐色固体。
B步:将N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(0.210g,0.40mmol)悬浮在10∶1甲醇/H2O中,加入pTsOH-H2O(0.008g,0.04mmol)。将混合物在环境温度下搅拌18小时,在此期间全部固体溶解,得到无色澄清的溶液。该溶液用EtOAc稀释。有机溶液用碳酸氢钠(2×)、盐水(1×)洗涤,经Na2SO4干燥。过滤后,浓缩滤液,从EtOAc和庚烷中重结晶。将该固体用庚烷-CH2Cl2(1∶1)洗涤,在60℃真空中干燥,得到N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,为白色固体(0.136g,70%)。产物在90.8℃下收缩,在115-117℃下熔化。分析显示C 40.92,H 3.16,N 5.41,F 11.30,I 23.92(6.75%EtOAc,0.96%庚烷)。
实施例50
N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(化合物C的I型)
利用上述关于N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的方法,从(S)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺和3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸制备:m.p.116-118℃(化合物C的II型);和m.p.116-118℃(化合物C的I型);
[α]=+1.77°(c=1.13,甲醇).分析计算C16H14F3I1N2O4:C,39.85;H,2.93;N,5.81;F,11.82,I,26.32.实验:C,40.01;H,2.73;N,5.84;F,11.45;I,26.42.
实施例50A
N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(化合物C的II型)
利用上述关于N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的替代方法,从(S)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺和3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸制备:mp 118-119℃。
实施例51
5-氯-2-(2-氯-4-碘-苯氨基)-N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-苯甲酰胺
利用关于N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4碘-苯氨基)-苯甲酰胺所述方法,从(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺和5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸制备:
m.p.155-156℃;[α]=-5.1°(c=3.5mg/mL,乙醇);
1NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.83(s,1H),7.76(s,1H),7.66(d,1H,J=6.8Hz),7.47(d,1H,J=8.5Hz),6.68(t,1H,J=6.6Hz),4.83(bs,1H),4.60(bs,1H),3.89-3.92(m,1H),3.68-3.76(m,2H),3.30(2H,部分被HD0所覆盖);MS(APCI+)=533.0/535.0;分析计算/实验C16H13Cl2F2IN2O4:C,36.05/36.04;H,2.46/2.25;N,5.25/5.10;F,7.13/7.18;Cl,13.30,13.50;I,23.80,24.02.
实施例52
5-氯-2-(2-氯-4-碘-苯氨基)-N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-苯甲酰胺
A步:向装有磁搅拌器的1L单颈圆底烧瓶内加入5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸(59.6g,135mmol)的无水四氢呋喃(300ml)溶液。将溶液在冰-丙酮浴中冷却至0℃。向该溶液加入二异丙基乙胺(34.8g,270mmol)、(S)-O-(2,2-二甲基[1,3]二氧戊环-4-基甲基)-羟胺(29.7g,202mmol)、1-羟基苯并***(30.93g,202mmol)和苯并***-1-基氧基三(二甲氨基)鏻六氟磷酸盐(BOP)(89.32g,202mmol)。30分钟后,除去冷却浴,将反应在环境温度下搅拌18小时。在真空中蒸发溶剂,将残余物溶于二***。将有机溶液用10%氢氧化钠水溶液(3×500ml)和盐水洗涤,干燥(MgSO4)。浓缩溶液,得到5-氯-2-(2-氯-4-碘-苯氨基)-N-((S)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-苯甲酰胺(69.9g),为淡黄色固体,直接用于下面的水解反应。
B步:向装有磁搅拌器的3L单颈圆底烧瓶内加入5-氯-2-(2-氯-4-碘-苯氨基)-N-((S)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-苯甲酰胺(69.9g,122mmol)的四氢呋喃(1.5L)溶液。加入1N盐酸水溶液(500ml),将反应混合物在环境温度下搅拌18小时。浓缩反应混合物,用乙酸乙酯萃取(3×800ml)。将有机萃取液用饱和碳酸氢钠水溶液(500ml)和盐水(500ml)洗涤,干燥(MgSO4)。将粗的淡黄色固体从乙酸乙酯/己烷中重结晶,在70℃真空烘箱内干燥,得到5-氯-2-(2-氯-4-碘-苯氨基)-N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺(35g,54%),为淡黄色晶体:
m.p.153-154℃;[α]=+3.36°(c=1.04,甲醇);1H NMR(d6-DMSO)δ12.02(s,1H),8.85(s,1H),7.74(s,1H),7.64(d,1H),7.45(d,1H),6.66(t,1H),4.82(s,1H),4.58(s,1H),3.88(m,2H),3.74(m,3H);19F NMR(d6-DMSO)δ-133.21(s,1F),-137.18(s,1F);MS(m/z):534(68),532(100),483(28),481(41),440(51).分析计算/实验C16H13Cl2F2IN2O4:C,36.05/36.36;H,2.46/2.38;N,5.25/5.30;F,7.13/7.15;Cl,13.30/13.76;I,23.80/23.83.
实施例53
5-氯-N-[(2(R),3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
利用上述关于N-[(R)-2,3-二羟基丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺所述方法从(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)羟胺和5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酸制备:
m.p.142-143℃.1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.66(s,1H),7.58-7.55(m,2H),7.34(d,1H,J=8.1Hz),6.72(cm,1H),4.81(d,1H,J=4.1Hz),4.58(t,1H,J=5.9Hz),3.87-3.84(m,1H),3.70-3.68(m,2H),3.33(2H,部分被HD0所覆盖).
实施例54
5-氯-N-[(2(S),3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
利用上述关于N-[(R)-2,3-二羟基丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺所述方法从(S)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)羟胺和5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酸制备:
m.p.157-158℃;[α]=+5.29°(c=1.02,甲醇);1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.66(s,1H),7.58-7.55(m,2H),7.34(d,1H,J=8.1Hz),6.72(cm,1H),4.81(d,1H,J=4.1Hz),4.58(t,1H,J=5.9Hz),3.87-3.84(m,1H),3.70-3.68(m,2H),3.33(2H,部分被HD0所覆盖).分析计算/实验C16H13ClF3IN2O4:C,37.20/37.47;H,2.54/2.57;N 5.42/5.32;F,11.03/11.09;Cl,6.86/6.87;I,24.56/24.80.
实施例55
2-(4-溴-2-氟-苯氨基)-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺
按照N-[2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(实施例39)的方式制备,例外如下:有机层经硫酸钠干燥,浓缩,得到白色泡沫。将其在真空(0.5mm)下加热至100℃达1小时,得到玻璃状物:m.p.52℃(收缩),70℃(熔化);
[α]=-4.4°(c=6.8,乙醇);1H NMR(400MHz,CD3OD)δ7.40[cm,1H];7.29[dd,J=11.0,2.2Hz,1H);7.16[d,J=8.5Hz,1H];6.98[dd,J=16.4,9Hz,1H];6.73[cm,1H];3.94[cm,1H];3.83[m,2H];3.55[m,2H].分析计算/实验C16H14BrF3BrN2O4:C,44.16/43.77;H,3.24/3.36;N,6.44/6.09;F,13.10/12.64;Br,18.36/18.24.
实施例56-61的化合物是利用实施例1的通用方法制备的。
实施例56
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
收率:55%;m.p.141.5-143.0℃;1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.84(s,1H),7.77(d,J=1.7Hz,1H),7.51-7.42(m,2H),7.27(ddd,J=9.0,8.8,7.8Hz,1H),6.59(dd,J=8.6,6.4Hz,1H),6.49(dd,J=14.2,6.6Hz,1H),4.19(d,J=14.1Hz,1H),4.06(br s,2H),3.98(d,J=6.6Hz,1H),3.87(br s,2H);19F NMR(376MHz,DMSO-d6)δ-132.4,-141.4;MS(APCI+)=495.1;MS(APCI-)=493.0.分析计算/实验C17H14ClF2N2O3带有0.08摩尔残余C6H14;C,41.86/41.90;H,3.04/2.91;N,5.59/5.72.
实施例57
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
收率:25%;m.p.115-116℃;1H-NMR(400MHz;DMSO-d6)δ11.96(s,1H),8.42(s,1H),7.73(d,1H,J=1.7Hz),7.59(m,1H),7.44(dd,1H,J=8.6,1.7Hz),6.54(m,1H),6.47(dd,1H,J=14.2,6.6Hz),4.15(d,1H,J=14.2Hz),4.02(s,2H),3.96(dd,1H,J=6.9,1.7Hz),3.83(s,2H);19F-NMR(376MHz;DMSO-d6)δ-137.08(d,1F,J=20.2Hz),-140.97(s,1F),-154.65(s,1F);MS(APCI+)513.0(M+1,100);MS(APCI-)511.0(M-1,65),424.9(100);IR(KBr)1647(C=O伸缩),1621,1488cm-1.分析计算/实验C17H13ClF3IN2O3:C,39.83/40.04;H,2.56/2.54;N,5.46/5.32.
实施例58
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
收率:44%;m.p.103.5-104℃;1H-NMR(400MHz;DMSO-d6)δ11.90(s,1H),9.62(s,1H),7.69(dd,1H,J=10.5,2.0Hz),7.60(m,1H),7.49(d,1H,J=8.3Hz),7.27(m,1H),6.84(d,1H,J=11.7Hz),6.70(m,1H),6.52(dd,1H,J=14.4,6.8Hz),4.20(dd,1H,J=14.4,2.0Hz),4.09(m,2H),3.98(dd,1H,J=6.8,1.7Hz),3.90(m,2H);19F-NMR(376MHz;DMSO-d6)δ-106.73(s,1F),-124.58(s,1F);MS(APCI+)461.0(M+1,100);MS(APCI-)459.0(M-1,100);IR(KBr)1641(C=O伸缩),1602cm-1.分析计算/实验C17H15F2IN2O3:C,44.37/44.42;H,3.29/3.28;N,6.09/5.89.
实施例59
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
1H-NMR(400MHz;DMSO-d6)δ11.89(s,1H),8.67(s,1H),7.57(dd,11.0,1.7Hz,1H),7.41-7.32(m,2H),7.20(m,1H),6.66(m,1H),6.46(dd,J=14.2,6.8Hz,1H),4.17(dd,J=14.2,1.5Hz,1H),4.00(br s,2H),3.97(dd,J=6.7,1.8Hz,1H),3.84(br s,2H);19F-NMR(376MHz;DMSO-d6)δ-128.1(s,1F),-133.1(s,1F),-144.3(d,17.7Hz,1F).分析计算/实验C17H14F3IN2O3:C,42.70/42.30;H,2.95/2.92;N,5.86/5.52.
实施例60
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
收率:34%;m.p.119-120℃;1H-NMR(400MHz;DMSO-d6)δ11.96(s,1H),8.64(s,1H),7.59(m,2H),7.35(d,1H,J=8.3Hz),6.71(m,1H),6.48(dd,1H,J=14.4,6.8Hz),4.17(d,1H,J=14.2Hz),3.98(m,3H),3.84(m,2H);19F-NMR(376MHz;DMSO-d6)δ-127.60(s,1F),-134.09(d,1F,J=15.2Hz),-140.45(d,1F,J=17.7Hz);MS(APCI-)511.0(M-1,100);IR(KBr)1646(C=O伸缩),1608cm-1.分析计算/实验C17H13ClF3IN2O3:C,39.83/39.78;H,2.56/2.57;N,5.46/5.36.
实施例61
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺
收率:39%;m.p.128-130℃;1H-NMR(400MHz;DMSO-d6)δ11.95(s,1H),8.67(s,1H),7.69(d,1H,J=6.4Hz),7.57(dd,1H,J=10.7,1.7Hz),7.35(d,1H,J=8.1Hz),6.72(m,1H),6.48(dd,1H,J=14.4,6.6Hz),4.17(d,1H,J=14.2Hz),3.98(m,3H),3.83(s,2H);19F-NMR(376MHz;DMSO-d6)δ-126.37(s,1F),-127.54(s,1F),-140.31(d,1F,J=17.7Hz);MS(APCI+)558.9(100),556.9(M+1,98);MS(APCI-)556.9(31),554.9(M-1,32),468.9(100);IR(KBr)1644(C=O伸缩),1607,1515,1490cm-1.分析计算/实验C7H13BrF3IN2O3:C,36.65/36.71;H,2.35/2.23;N,5.03/4.97.
实施例62-64的化合物是利用实施例12的通用方法制备的。
实施例62
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
m.p.=179-181℃;1H NMR(400MHz;DMSO-d6)δ11.36(s,1H),8.48(s,1H),7.76(d,1H,J=6.8),7.72(s,1H),7.43(d,1H,J=8.5),6.59(m,1H),4.55(t,1H),J=6.4),3.20(d,2H,J=5.9),1.09(s,6H);MS(APCI+)=574.9/576.9.分析计算/实验C17H15BrClF2IN2O3:C 35.48/35.56,H 2.63/2.53,N4.87/4.71,F 6.60/6.68.
实施例63
3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.=175-176℃;1H NMR(400MHz;DMSO-d6)δ11.29(s,1H),8.15(s,1H),7.46(s,1H),7.41(m,1H),7.32(d,1H,J=8.3),7.32(q,1H,J=16.4,8.8),6.38(m,1H),4.59(bs,1H),3.15(d,2H,J=4.9),2.17(s,3H),1.08(s,6H);MS(APCI+)=477.0.分析计算/实验C18H19F2IN2O3(0.05eq CH2Cl2):C45.12/44.73,H 4.01/3.96,N 5.83/5.54,F 7.91/7.71
实施例64
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺
收率:17%;m.p.140-153℃;1H-NMR(400MHz;DMSO-d6)δ11.94(s,1H),8.82(s,1H),7.76(d,1H,J=1.5Hz),7.48(dd,1H,J=8.5,2.0Hz),7.42(m,1H),7.25(m,1H),6.57(m,1H),4.58(s,1H),3.63(s,2H),1.12(s,6H);19F-NMR(376MHz;DMSO-d6)δ-132.53(s,1F),-141.45(d,1F);MS(APCI+)496.9(M+1,100);MS(APCI-)495.0(M-1,48),406.9(100);IR(KBr)1637cm-1(C=O伸缩).分析计算/实验C17H16ClF2IN2O3带有0.03摩尔残余丙酮:C,41.18/41.57;H,3.27/3.14;N,5.62/5.31.
实施例65-76的化合物是利用实施例38的通用方法制备的。
实施例65
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
m.p.=182-183℃;1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.38(s,1H),7.54(d,1H,J=11.0),7.39(m,1H),7.31(d,1H,J=8.1),7.24(dd,1H,J=16.9,9.5),6.59-6.56(m,1H),4.58,(m,1H),3.16(d,2H,J=6.3),1.08(s,6H);MS(APCI+)=481.0.分析计算/实验C17H16F3IN2O3(+0.47C4H8O2):C,43.47/43.86;H,3.82/3.40;N,5.37/5.60.
实施例66
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺
m.p.=178-180℃;1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.41(s,1H),7.64(d,1H,J=7.1),7.56(d,1H,J=11.0),7.33(d,1H,J=8.3),6.69-6.65(m,1H),4.57(t,1H,J=6.1),3.19(d,2H,J=6.6),1.10(s,6H);MS(APCI+)=514.9/516.9.分析计算/实验C17H15ClF3IN2O3:C,39.67/39.99;H,2.94/2.74;N,5.44/5.31;F,11.07/11.05.
实施例67
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)苯甲酰胺
m.p.156.7-156.9℃;1H NMR(400MHz,DMSO-d6)δ11.85(1H,s),8.70(1H,s),7.55(1H,dd,J=10.8Hz,1.9Hz),7.33-7.37(2H,m),7.17(1H,dd,J=16.7Hz,9.4Hz),6.62-6.67(1H,m),4.57(1H,br s),3.58(2H,s),1.09(6H,s).分析计算/实验C17H16F3IN2O3:C,42.5/42.48;H,3.36/3.21;N,5.83/5.67;F,11.87/11.51;I,26.43/26.38.
实施例68
3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.136.2-136.5℃;1H NMR(400MHz,DMSO-d6)δ11.90(1H,s),8.49(1H,s),7.50(1H,d,J=1.7Hz),7.34-7.41(2H,m),7.14(1H,dd,J=16.6Hz,9.3Hz),6.45(1H,dd,J=8.4Hz,5.6Hz),4.97(1H,s),3.69-3.79(3H,m),3.25-3.31(2H,m),3.21(3H,s),2.21(3H).分析计算/实验C18H19F2IN2O4:C,43.92/44.14;H,3.89/3.88;N,5.69/5.59;F,7.72/7.79;I,25.78/25.89.
实施例69
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺
m.p.139.5-140.1℃;1H NMR(400MHz,DMSO-d6)δ12.03(1H,s),8.83(1H,s),7.50-7.76(2H,m),7.47(1H,dd,J=8.6Hz,1.5Hz),6.65-6.69(1H,m),4.98(1H,s),3.70-3.90(3H,m),3.31(2H,m),3.22(3H,s).分析计算/实验C17H15BrClF2IN2O4:C,34.52/34.92;H,2.56/2.54;N,4.74/4.67;F,6.42/6.48;I,21.45/21.12.
实施例70
3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺
m.p.165.4-165.6℃;1H NMR(400MHz,DMSO-d6)δ11.74(1H,s),8.49(1H,s),7.47(1H,d,J=1.5Hz),7.31-7.36(2H,m),7.11(1H,dd,J=16.5Hz,9.4Hz),6.43(1H,dd,J=8.3Hz,5.6Hz),4.55(1H,br s),3.67(2H,s),3.33(2H,s),2.17(3H,s),0.36(4H,J=4.9Hz).分析计算/实验C19H19F2IN2O3:C,46.74/46.87;H,3.92/3.93;N,5.74/5.99;F,7.78/7.64;I,25.99/25.84.
实施例71
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺
m.p.152.6-153.9℃;1H NMR(400MHz,DMSO-d6)δ11.88(1H,s),8.81(1H,s),7.75(1H,s),7.69(1H,d,J=6.6Hz),7.45(1H,d,J=8.5Hz),6.63-6.67(1H,m),4.53(1H,br s),3.73(2H,s),3.33(2H,s),0.36(4H,J=4.9Hz).分析计算/实验C18H15BrClF2IN2O3:C:36.79/37.21;H,2.57/2.57;N,4.77/4.64;F,6.47/6.58;I,21.60/21.78.
实施例72
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺
m.p.175.2-175.5℃;1H NMR(400MHz,DMSO-d6)δ12.00(1H,s),8.41(1H,s),7.47(1H),7.40(1H,m),7.33(1H,d),7.12(1H,dd,J=16.6Hz,9.3Hz),6.54(1H,br s),6.44(1H,dd,J=8.3Hz,5.3Hz),4.24(1H,m),3.83-3.98(2H,m),2.18(3H,s).分析计算/实验C17H14F5IN2O3:C,39.56/39.87;H,2.73/2.66;N,5.43/5.30;F,18.40/18.32;I,24.58/24.63.
实施例73
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺
m.p.186.9-187.3℃;1H NMR(400MHz,DMSO-d6)δ12.16(1H,s),8.77(1H,s),7.80(1H,dd,J=7.0Hz,1.5Hz),7.75(1H,d,J=1.7Hz),7.47(1H,dd,J=8.6Hz,1.9Hz),6.66(1H,dd,J=8.5Hz,5.9Hz),6.55(1H,br s),4.31(1H,m),3.92-4.07(2H,m).分析计算/实验C16H10BrClF5IN2O3:C,31.22/31.52;H,1.64/1.60;N,4.55/4.46;F,15.43/15.39;I,20.62/20.87.
实施例74
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[反式-(2-羟甲基-环丙基甲氧基)]-苯甲酰胺
m.p.128.5-128.7℃;1H NMR(400MHz,DMSO-d6)δ11.71(1H,s),8.69(1H,s),7.54(1H,dd,J=10.9Hz,1.8Hz),7.32-7.36(2H,m),7.17(1H,dd,J=16.6Hz,9.3Hz),6.60-6.66(1H,m),4.43(1H,t,J=5.6Hz),3.54-3.65(2H,m),3.14-3.34(2H,m),0.85-0.89(2H,m),0.34-0.41(2H,m).分析计算/实验C18H16F3IN2O3:C,43.92/44.23;H,3.28/3.23;N,5.69/5.54;F,11.58/11.47;I,25.78/25.58.
实施例75
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-[反式-(2-羟甲基-环丙基甲氧基)]-苯甲酰胺
m.p.152.5-153.1℃;1H NMR(400MHz,DMSO-d6)δ11.76(1H,s),8.65(1H,s),7.56(1H,m),7.52-7.53(1H,m),7.32(1H,d,J=8.5Hz),6.66-6.72(1H,m),4.44-4.47(1H,m),3.54-3.62(2H,m),3.12-3.42(2H,m),0.81-0.89(2H,m),0.32-0.40(2H,m).分析计算/实验C18H15ClF3IN2O3:C,41.05/41.00;H,2.87/2.96;N,5.31/5.13;F,10.82/10.48;I,24.09/24.33.
实施例76
N-(2,3-二羟基-3-甲基-丁氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺
m.p.=180-183℃;1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.69(bs,1H),7.56(d,1H,J=10.7),7.40(m,1H),7.35(d,1H,J=9.0),7.20(dd,1H,J=16.6,8.3),6.65(m,1H),4.87(bs,1H),4.31(s,1H),4.07(d,1H,J=9.8),3.65(t,1H,J=9.8),3.44-3.41(m,1H),1.05(s,3H),0.97(s,3H);MS(APCI+)=511.1.分析计算/实验C18H18F3IN2O4(+0.22eq C4H8O2):C,42.82/43.20;H,3.76/3.61;N,5.29/5.15.
实施例77
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基-乙氧基)-苯甲酰胺
按照关于实施例1所述方式制备标题化合物。白色固体:
m.p.157.8℃;1H NMR(400MHz,DMSO-d6)δ11.3(s,1H),7.70(m,2H),7.44(dd,J=8.6Hz,1.95Hz,1H),7.01(t,J=8.1Hz,2H),6.94(t,J=9.2Hz,1H),6.47(m,4H),5.58(br t,J=5.1Hz,1H),3.91(t,J=5.6Hz,2H),3.19(q,J=5.6Hz,2H);19F NMR(376MHz,DMSO-d6)δ-139.77(s,1F),-143.39(d,J=20.2Hz,1F).
实施例78
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氨基-乙氧基)-苯甲酰胺
A步:向(2-氨基氧基-乙基)-甲基-氨基甲酸叔丁酯(0.63g,3.31mmol)与二异丙基乙胺(0.6ml,3.44mmol)的二甲基甲酰胺(10ml)溶液加入3,4-二氟-2-(4-碘-2-甲基苯氨基)-苯甲酸五氟苯基酯(1.66g,2.99mmol)。将所得反应混合物在环境温度下搅拌5小时,在减压下浓缩。将残余物用***(100ml)稀释,用水(2×25ml)和盐水(2×25ml)洗涤,经硫酸镁干燥,在真空中浓缩。残余物经过硅胶色谱纯化。用二氯甲烷洗脱,得到[2-({1-[3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基]-甲基-氨基甲酸叔丁酯(1.05g,62%),为白色泡沫:
1H NMR(400MHz,DMSO-d6)δ11.85和11.80(br s,1H),8.49(br s,1H),7.50(s,1H),7.39(m,1H),7.35(d,J=8.3Hz,1H),7.14(m,1H),6.46(dd,J=7.8,5.9Hz,1H),3.85(br s,2H),3.35(br s,2H),2.79(br s,3H),2.21(s,3H),1.36和1.33(s,9H);19F NMR(376MHz,DMSO-d6)δ-132.9,-143.3(d,J=17.7Hz);MS(APCI+)=562.1.
B步:向0℃的[2-({1-[3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基]-甲基-氨基甲酸叔丁酯(0.75g,1.3mmol)的二氯甲烷(12ml)溶液加入三氟乙酸(3.0ml,39mmol)。将所得溶液在0℃下搅拌2.5小时,用***(50ml)稀释。加入水(20ml),同时剧烈搅拌,将含水层的pH用饱和碳酸氢钠水溶液调至pH8。将多相混合物搅拌30分钟,过滤除去沉淀,用水-乙醇(2∶1)和丙酮洗涤。将固体(471mg)在真空种干燥过夜,进一步用热甲醇研制,在70℃减压下干燥,得到3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氨基-乙氧基)-苯甲酰胺(272mg),为白色粉末:
m.p.183-185(dec);1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.69(t,J=7.0Hz,1H),7.46(d,J=1.7Hz,1H),7.33(dd,J=8.6,2.0Hz,1H),6.95(app q,J=9.0Hz,1H),6.40(t,J=7.8Hz,1H),3.87(br t,J=4.4Hz,2H),2.82(br s,2H),2.47(s,3H),2.24(s,3H);19F NMR(376MHz,DMSO-d6)δ-137.7(d,J=7.6Hz),-143.3(d,J=20.2Hz).分析计算/实验C17H18F2IN3O2:C,44.50/44.61;H,4.01/3.97;N,9.01/8.72.
实施例79
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氨基-乙氧基)-苯甲酰胺,盐酸盐
A步:将3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸(3.11g,7.91mmol)的四氢呋喃(20ml)溶液用-40℃浴冷却,用N-甲基吗啉(0.87ml,7.9mmol)处理。历经5分钟滴加二苯基膦酰氯(2.00ml,10.5mmol),将反应混合物搅拌90分钟,在此期间使冷却浴的温度缓慢温热至0℃。
将反应混合物再次冷却至-40℃,加入(2-氨基氧基-乙基)-甲基-氨基甲酸叔丁酯(2.00g,10.5mmol)的四氢呋喃(6ml)溶液。另外10分钟后,加入N-甲基吗啉(1.33ml,12.1mmol)。使冷却浴的温度历经4小时温热至环境温度,将反应混合物进一步搅拌过夜。将反应用乙酸乙酯(40ml)稀释,用饱和氯化铵水溶液洗涤(2×10ml)。有机层经硫酸镁干燥,浓缩,经过硅胶色谱纯化。用35%乙酸乙酯-己烷洗脱,得到[2-({1-[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基]-甲基-氨基甲酸-叔丁酯(3.28g,73%),为灰白色泡沫:
1H NMR(400MHz,DMSO-d6)δ11.84和11.75(br s,总共1个H),8.66(br s,1H),7.54(dd,J=10.9,1.6Hz,1H),7.36(br t,J=8.8Hz,1H),7.33(br d,J=8.8Hz),7.20(m,1H),6.64(m,1H),3.85(t,J=5.2Hz,2H),3.34(br s,2H),2.81和2.79(br s,总共3个H),1.34和1.32(s,总共9个H);19F NMR(376MHz,DMSO-d6)δ-128.0(d,J=32.9Hz),-133.0,-144.2(d,J=17.7Hz);MS(APCI-)=564.1.
B步:将[2-({1-[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基]-甲基-氨基甲酸-叔丁酯(3.28g,5.80mmol)溶于醚合氯化氢溶液(20ml,1.0M二***溶液)。将所得溶液在环境温度下搅拌48小时,在此期间继而产生白色固体沉淀。加入己烷(20ml),将反应混合物剧烈搅拌另外20分钟。过滤反应混合物,用药刀打碎滤饼。将固体用己烷(50ml)和***(20ml)洗涤,在真空中干燥,得到自由流动的黄红色粉末(2.46g,85%)。从乙腈中重结晶,得到无色针晶:
m.p.173-176℃;1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.76(br s,2H),8.64(s,1H),7.55(dd,J=11.0,1.9Hz,1H),7.47(dd,J=7.1,6.3Hz,1H),7.33(d,J=8.3Hz,1H),7.23(dt,J=7.6,9.2Hz,1H),6.64(td,J=8.8,4.2Hz,1H),4.05(t,4.9Hz,2H),3.11(br s,2H),2.56(t,J=4.6Hz,3H);19F NMR(376MHz,DMSO-d6)δ-128.2(t,J=10.1Hz),-132.5(d,J=20.2Hz),-144.0(d,20.2Hz).分析计算/实验C16H16F3IN3O2Cl:C,38.31/38.20;H,3.21/3.10;N,8.38/8.34;F,11.36/11.21;Cl,7.07/7.05.
实施例80
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2,2,2-三氟-乙氨基)-乙氧基]-苯甲酰胺;盐酸盐
A步:历经30分钟向O-[2-(2,2,2-三氟-乙氨基)-乙基]羟胺(3.19g,22.3mmol,如J.Am.Chem.Soc.1979,101,4300制备)、三苯膦(6.05g,23.1mmol)与N-羟基邻苯二甲酰亚胺(3.65g,22.4mmol)的溶液滴加偶氮二羧酸二乙酯(3.60ml,22.9mmol)。将所得反应混合物在环境温度下搅拌20小时后,浓缩反应混合物,将残余物溶于60ml温热的氯仿。冷却后,继而产生1,2-肼二羧酸二乙酯结晶。过滤沉淀,浓缩滤液,进一步用***稀释。加入三苯膦氧化物的单晶,引发很多的沉淀。过滤除去所得沉淀,在真空中浓缩滤液,经过硅胶色谱纯化。用己烷-乙酸乙酯(2∶1)洗脱,得到2-[2-(2,2,2-三氟-乙氨基)-乙氧基]-异吲哚-1,3-二酮(4.05g,63%),为无色的油:
1H NMR(400MHz,CDCl3)δ7.84-7.73(m,4H),4.30(t,J=4.8Hz,2H),3.26(q,J=9.5Hz,2H),3.00(t,J=4.9Hz,2H),2.33(br s,1H);MS(APCI+)=289.0.
B步:向2-[2-(2,2,2-三氟-乙氨基)-乙氧基]-异吲哚-1,3-二酮(0.46g,1.6mmol)加入二氯甲烷(5ml),将所得溶液冷却至0℃。加入甲基肼(0.086ml,1.62mmol),将所得溶液在环境温度下搅拌1小时。加入***(20ml),过滤沉淀,在真空中浓缩滤液。加入二甲基甲酰胺(5ml),将所得溶液先后用3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酸五氟苯基酯(0.847g,1.51mmol)和二异丙基乙胺(0.60ml,3.4mmol)处理。将所得反应混合物搅拌过夜,用乙酸乙酯稀释,用水(4×)和饱和盐水洗涤,经硫酸镁干燥,在真空中浓缩。经过硅胶色谱纯化(己烷-乙酸乙酯1∶1),得到3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2,2,2-三氟-乙氨基)-乙氧基]-苯甲酰胺(0.70g,83%),为蜡状泡沫:
1H NMR(400MHz,丙酮-d6)δ10.98(br s,1H),8.69(br s,1H),7.52(br s,2H),7.39(dd,J=8.6Hz,2.0Hz,1H),7.00(m,1H),6.55(dd,J=8.6Hz,6.4Hz,1H),3.27(q,J=10.0Hz,2H),2.90(br t,J=4.9Hz,2H),2.82(br s,2H),2.30(s,3H);19F NMR(376MHz,丙酮-d6)δ-73.1(t,J=10.0Hz,3F),-133.8(s,1F),-143.2(s,1F);MS(APCI+)=530.0.
C步:盐酸盐是这样制备的,将3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2,2,2-三氟-乙氨基)-乙氧基]-苯甲酰胺(375mg,0.708mmol)的***(5ml)溶液用醚合氯化氢(2ml,1.0M***溶液)处理,加入己烷(50ml)产生沉淀。将所得固体在75℃真空中干燥过夜,得到淡黄色粉末:
1H NMR(400MHz,丙酮-d6)δ12.35(br s,1H),8.84(br s,1H),7.73(br s,1H),7.54(s,1H),7.40(dd,J=8.4Hz,1.9Hz,1H),7.00(表观 q,J=8.4Hz,1H),6.58(dd,J=8.4Hz,6.40Hz,1H),4.43(br s,2H),4.17(br q,2H),3.59(br s,2H),2.30(s,3H);19F NMR(376MHz,丙酮-d6)δ-68.39(s,3F),-133.07(s,1F),-143.20(s,1F).分析计算/实验C18H17F5IN3O2+0.86HCl:C,38.57/38.77;H,3.21/3.04;N,7.49/7.19;Cl,5.44/5.66.
实施例81
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-N-甲基-苯甲酰胺
将2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺(0.460g,1.02mmol)的二甲基甲酰胺(10ml)溶液先后用碳酸钾(0.61g,4.4mmol)和碘代甲烷(0.075ml,1.2mmol)处理。将所得反应混合物在环境温度下搅拌1小时,用过量水稀释,用乙酸乙酯萃取。将有机萃取液用盐水洗涤,经硫酸镁干燥,在真空中浓缩。硅胶色谱得到白色固体(200mg)。进一步经过C-18反相硅胶色谱纯化(30%水-乙腈),得到2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-N-甲基-苯甲酰胺(139mg,29%),为白色泡沫:
1H NMR(400MHz,丙酮-d6)δ8.45(s,1H),7.79(d,J=2.0Hz,1H),7.69(dd,J=8.8,6.6Hz,1H),7.60(dd,J=8.5,2.0Hz,1H),7.28(d,J=8.5Hz,1H),7.09(dd,J=11.4,2.3Hz,1H),6.77(td,J=8.6,2.5Hz,1H),3.90(t,J=2H),3.85(br m,OH),3.58(t,J=4.5Hz,2H),3.38(s,3H);19F-NMR(376MHz,丙酮-d6)δ-109.8(dd,J=10.1,7.6Hz);MS(APCI+)=465.0.
实施例82
乙酸2-({1-[3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基酯
向0℃的3,4,5-三氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺(0.25g,0.536mmol)的THF(10.72ml)溶液加入三乙胺(0.113ml,0.804mmol)。5分钟后,向***液加入乙酰氯(0.039ml,0.536mmol),立即生成沉淀。在0-5℃之间搅拌50分钟后,使反应混合物在水(20ml)与乙酸乙酯(20ml)之间分配。含水层用乙酸乙酯(20ml)萃取。合并有机层,经无水硫酸镁干燥。过滤所得混合物,滤饼用乙酸乙酯彻底洗涤。在真空中浓缩滤液,得到黄色的油(0.1755g)。粗油经过色谱纯化,用己烷与乙酸乙酯梯度洗脱。合并各级分,在真空中除去溶剂,得到固体。使该固体在己烷/丙酮混合物中重结晶,得到0.0221g(8%)固体;
1H NMR(400MHz,丙酮-d6):δ10.15(br s,1H),8.49(br s,1H),7.88(t,J=0.9Hz,1H),7.56(s,1H),7.43(d,J=8.3Hz,1H),6.69(dd,J=8.55,5.86Hz,1H),4.53(br s,2H),4.19(br s,2H),2.33(s,3H),1.81(br s,3H).19F NMR(375MHz,丙酮-d6):δ-139.52(br t,1F),-146.62(br q,1F),-153.43(br s,1F).分析计算/实验C18H16F3IN2O4:C,42.54/40.87;H,3.17/2.98;N,5.51/5.17.
实施例83
[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-(4-羟基-异噁唑烷-2-基)-甲酮
向搅拌着的3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸五氟苯基酯(171mg,0.306mmol)与氯化4-羟基四氢异噁唑-2-鎓(BIONET,58mg,0.46mmol)的二甲基甲酰胺(2ml)溶液加入4-甲基吗啉(0.1ml,0.91mmol)。将所得反应混合物在环境温度下搅拌3小时。加入乙酸乙酯(50ml),混合物用水(3×10ml)和饱和盐水(10ml)洗涤。萃取液经硫酸镁干燥,在真空中浓缩。色谱(10%甲醇-二氯甲烷)得到黄褐色油,放置后固化。从丙酮-***中重结晶,得到[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-(4-羟基-异噁唑烷-2-基)-甲酮(61mg,43%),为白色粉末:
m.p.122-124℃;1H NMR(400MHz,丙酮-d6)δ7.97(br s,1H),7.51-7.45(m,2H),7.38(ddd,J=8.6,1.7,1.2Hz,1H),7.12(m,1H),6.68(td,J=8.8,5.2Hz,1H),4.82(m,1H),4.71(br d,J=4.2Hz,OH),3.98(dd,J=8.8,4.2Hz,1H),3.96-3.88(m,2H),3.75(dd,J=11.8,0.9Hz,1H);19F-NMR(376MHz,丙酮-d6)δ-30.5,-135.4,-144.4.分析计算/实验C16H12F3IN2O3:C,41.40/41.52;H,2.61/2.53;N,6.03/6.05.
实施例84
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺
在10psig和室温下,将5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(0.240g,0.429mmol)与三乙胺(0.2g,1.98mmol)的四氢呋喃(16ml)溶液用Raney镍(0.12g,预先用四氢呋喃冲洗)氢化总计7小时。过滤除去催化剂,在真空中浓缩滤液。使所得残余物在乙酸乙酯与水之间分配。将有机层用水洗涤两次,用饱和盐水洗涤两次,收集,经硫酸钠干燥,过滤,在真空中浓缩。利用YMC30×100mm 5μ(C18)柱进行HPLC纯化,0-100%乙腈(3.0%正丙醇)/100-0%水(3.0%正丙醇)的流速30ml/min。收集所需级分,浓缩,在50℃真空烘箱内干燥过夜,得到5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺,为白色固体(0.054g,30%):
m.p.=143.5-144.5℃;1NMR(400MHz,DMSO-d6)δ11.95(bs,1H),8.74(bs,1H),7.68(d,1H,J=6.1Hz),7.17(t,1H,J=9.8Hz),7.01-7.04(m,1H),6.94(m,2H),4.81(m,1H),4.57(m,1H),3.86(m,1H),3.69-3.71(m,2H),3.3,(2H,underHDO);MS(APCI+)=435.0/437.0.
实施例85
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺
在50psig和室温下,将N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺(0.260g,0.539mmol)与三乙胺(2.0ml,14.3mmol)的四氢呋喃(14ml)溶液用Raney镍(0.2g湿重)氢化20小时。过滤除去催化剂,在真空中浓缩滤液。使所得残余物在乙酸乙酯与水之间分配。将有机层用饱和碳酸氢钠溶液洗涤两次,用水洗涤两次,收集,经硫酸钠干燥,过滤,在真空中浓缩。利用YMC 30×100mm 5μ(C18)柱进行HPLC纯化,0-100%乙腈(3.0%正丙醇)/100-0%水(3.0%正丙醇)的流速30ml/min。收集所需级分,浓缩。所得残余物用乙酸乙酯/水萃取。将有机层用饱和NaCl溶液洗涤,收集,在真空中干燥,得到N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺,为白色固体(0.061g,31%):
m.p.=113-115℃;1NMR(400MHz;DMSO-d6)δ11.90(s,1H),8.73(s,1H),7.37(m,1H),7.10-7.19(m,2H),7.02(t,1H,J=7.4Hz),6.84-6.93(m,2H),4.82(m,1H),4.57-4.58(m,1H),3.86-3.88(m,1H),3.67-3.73(m,2H),3.3(2H,underHDO);MS(APCI+)=357.1;分析计算/实验C16H15F3N2O4:C,53.94/53.97;H,4.24/4.37;N,7.86/7.83.
实施例86-97
实施例86至97是利用组合合成方法制备的,如下所述,通过如上所述制备的各烷氧基胺和五氟苯基酯的组合。通用方法:
A步:向一组2英钱(dram)小瓶内装入适当的五氟苯基酯二芳基胺(0.12mmol)固体,用2ml N,N-二甲基甲酰胺稀释。利用整体分配器,向每个反应瓶加入0.2克聚合物承载的吗啉树脂(商业上可从Novabiochem得到,或者通过Booth和Hodges:J.Am.Chem.Soc.,1997,119,4842的方法制备)。制备羟胺丙酮化物的N,N-二甲基甲酰胺溶液(0.8M,1.6ml),分配(0.1mmol,0.2ml)在相应的反应小瓶内。将反应用涂有特氟隆的盖子密封,在环境温度下在轨道摇动器上摇动5天。向14个反应加入0.2克聚合物承载的三(2-氨基乙基)胺(Novabiochem;另见:Booth,R.J.;Hodges,J.C.J Am.Chem.Soc.,1997,119,4842)、0.1克聚合物承载的异氰酸甲酯(Novabiochem;另见:Booth,R.J.;Hodges,J.C.J Am.Chem.Soc.,1997,119,4842)和1ml二氯甲烷。将反应容器再次密封,在环境温度下摇动另外6小时。将反应通过Specdisk 3A滤器过滤,用6ml 10%甲醇/二氯甲烷溶液冲洗,经由氮流浓缩。
B步:向所得丙酮化物苯甲酰胺加入2ml甲醇、0.05ml去离子水、约2毫克对-甲苯磺酸和0.1克甘油树脂。将反应用涂有特氟隆的盖子密封,摇动17小时。将反应通过Specdisk 3A滤器过滤,用6ml含50%甲醇的二氯甲烷洗涤,经由氮流浓缩。利用SQ1600 Combi-Flash柱对全部样本进行纯化,用乙腈/水(0.05%三氟乙酸)洗脱。利用CPI 120SEC18柱(4.6×50μm)进行LC/MS,用乙腈/水(0.05%三氟乙酸)洗脱。
实施例No. | 化合物 | 结构式 | 精确质量实测 | |
86 | 2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺 | C16H14ClF2IN2O4 | 499(APCI+) | |
87 | 2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4,5-三氟-苯甲酰胺 | C16H13ClF3IN2O4 | 517(APCI+) | |
88 | 5-溴-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺 | C16H13BrClF2IN2O4 | 577/579(APCI+) | |
89 | N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C17H17F2IN2O4 | 479(APCI+) | |
90 | N-(2,3-二羟基-丙氧基)-3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C17H16F3IN2O4 | 495(APCI-) | |
91 | 5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C17H16BrF2IN2O4 | 557/559(APCI+) | |
92 | 2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺 | C17H16ClF2IN2O4 | 513(APCI+) | |
93 | 2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4,5-三氟-苯甲酰胺 | C17H15ClF3IN2O4 | 531(APCI+) |
94 | 5-溴-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺 | C17H15BrClF2IN2O4 | 591/593(APCI+) |
95 | N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C18H19F2IN2O4 | 493(APCI+) |
96 | N-(3,4-二羟基-丁氧基)-3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C18H18F3IN2O4 | 511(APCI+) |
97 | 5-溴-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C18H18BrF2IN2O4 | 571/573(APCI+) |
实施例98-235
实施例98-235是利用组合合成方法制备的,如下所述,通过如上所述制备的各烷氧基胺和五氟苯基酯的组合。通用方法:利用整体树脂分配器向2英钱小瓶内各自装入100-110mg聚合物承载的吗啉(3.55mmol N/g)。(聚合物承载的吗啉代甲基树脂是商业上可得到的(Novabiochem),或者可以通过Booth和Hodges:J.Am.Chem.Soc.,1997,119,4842的方法制备。)将适当的小瓶先后用烷氧基胺在DMF中的0.08M储备溶液(0.6ml,0.048mmol)和五氟苯基酯在DMF中的0.12M储备溶液(0.48ml,0.0576mmol,1.2eq.)处理。将小瓶用衬以特氟隆的盖子密封,在环境温度下在轨道摇动器上搅拌。48小时后,将反应混合物用聚合物承载的三(2-氨基乙基)胺(100mg,4.28mmol/g)(Novabiochem;另见:Booth,R.J.;Hodges,J.C.J Am.Chem.Soc.,1997,119,4842)和二氯甲烷(1.0ml)处理。将小瓶再次密封,摇动另外6小时。通过Specdisk 3A滤器过滤除去固体,用10%甲醇-二氯甲烷溶液洗涤(3×2ml)。在氮流下浓缩滤液,利用SQ1600 Combiflash柱HPLC纯化,用乙腈/水(0.05%三氟乙酸)洗脱。利用CPI 120SE C18柱(0.0046×0.050mm)进行LC/MS,用乙腈/水(0.05%三氟乙酸)洗脱。
实施例No. | 化合物 | 结构式 | 精确质量(APCI+) | |
98 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基丙氧基)-苯甲酰胺 | C16H13BrClF2IN2O3 | 561/563(M+1) | |
99 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)苯甲酰胺 | C16H14ClF2IN2O3 | 483(M+1) | |
100 | 3,4,5-三氟-N-(3-羟基-丙氧基)-2-(4碘-2-甲基苯氨基)-苯甲酰胺 | C17H16F3IN2O3 | 481(M+1) | |
101 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基丙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 501(M+1) | |
102 | 5-溴-3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16BrF2IN2O3 | 541/543(M+1) | |
103 | 3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C17H17F2IN2O3 | 463(M+1) | |
104 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺 | C17H16ClF2IN2O3 | 496.9(M+1) | |
105 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基丁氧基)-苯甲酰胺 | C17H15ClF3IN2O3 | 514.9(M+1) |
106 | 3,4,5-三氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C18H18F3IN2O3 | 494.9(M+1) | |
107 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丁氧基)-苯甲酰胺 | C17H15BrClF2IN2O3 | 574.8/576.8(M+1) | |
108 | 5-溴-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C18H18BrF2IN2O3 | 554.9/556.9(M+1) | |
109 | 3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C18H19F2IN2O3 | 476.9(M+1) | |
110 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丁氧基)-苯甲酰胺 | C17H15Cl2F2IN2O3 | 530.8(M+1) | |
111 | 5-氯-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C18H18ClF2IN2O3 | 510.9(M+1) | |
112 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2羟基-丁氧基)-苯甲酰胺 | C17H16F3IN2O3 | 481.1(M+1) | |
113 | 5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺 | C17H15BrF3IN2O3 | 559.0/561.0(M+1) |
114 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺 | C17H15ClF3IN2O3 | 515.1(M+1) |
115 | 4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺 | C17H16F3IN2O3 | 481.1(M+1) |
116 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺 | C17H15ClF4N2O3 | 407.4(M+1) |
117 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺 | C17H16F4N2O3 | 373.5(M+1) |
118 | 2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺 | C17H16BrF3N2O3 | 433.3/435.3(M+1) |
119 | 5-氯-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16ClF2IN2O3 | 496.9(M+1) |
120 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | C16H14ClF2IN2O3 | 482.9(M+1) |
121 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 500.9(M+1) |
122 | 3,4,5-三氟-N-(2-羟 | C17H16F3IN2O3 | 480.9(M+1) |
基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | |||
123 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺 | C16H13BrClF2IN2O3 | 560.8/562.8(M+1) |
124 | 5-溴-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16BrF2IN2O3 | 540.8/542.8(M+1) |
125 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | C16H14ClF3N2O3 | 375.0(M+1) |
126 | 3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C17H17F2IN2O3 | 462.9(M+1) |
127 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺 | C16H13Cl2F2IN2O3 | 516.8(M+1) |
128 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺 | C16H14F3IN2O3 | 466.9(M+1) |
129 | 5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | C16H13BrF3IN2O3 | 545.0/547.0(M+1) |
130 | 5-氯-3,4-二氟-2-(2- | C16H13ClF3IN2O3 | 500.9(M+1) |
氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | |||
131 | 4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)苯甲酰胺 | C16H14F3IN2O3 | 466.9(M+1) |
132 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | C16H13ClF4N2O3 | 393.4(M+1) |
133 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺 | C16H14F4N2O3 | 359.4(M+1) |
134 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基-乙氧基)苯甲酰胺 | C16H14ClF2IN2O3 | 482.9(M+1) |
135 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-甲氧基乙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 500.9(M+1) |
136 | 3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺 | C17H17F2IN2O3 | 462.9(M+1) |
137 | 5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺 | C17H16BrF2IN2O3 | 540.8/542.8(M+1) |
138 | 3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺 | C17H16F3IN2O3 | 480.9(M+1) |
139 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基乙氧基)-苯甲酰胺 | C16H13BrClF2IN2O3 | 560.8/562.8(M+1) |
140 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基乙氧基)-苯甲酰胺 | C16H13Cl2F2IN2O3 | 516.8(M+1) |
141 | 5-氯-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺 | C17H16ClF2IN2O3 | 496.9(M+1) |
142 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 501.1(M+1) |
143 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H21ClF2IN3O4 | 568.0(M+1) |
144 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)苯甲酰胺 | C20H20BrClF2IN3O4 | 645.9/647.9(M+1) |
145 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H20ClF3IN3O4 | 585.9(M+1) |
146 | 3,4,5-三氟-N-(2-羟 | C21H23F3IN3O4 | 566.0(M+1) |
基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | |||
147 | 5-溴-3,4-二氟-N-(2-羟基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C21H23BrF2IN3O4 | 625.9/627.9(M+1) |
148 | 3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C21H24F2IN3O4 | 548.0(M+1) |
149 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H20Cl2F2IN3O4 | 601.9(M+1) |
150 | 5-氯-3,4-二氟-N-(2-羟基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C21H23ClF2IN3O4 | 582.0(M+1) |
151 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺 | C20H21F3IN3O4 | 551.9(M+1) |
152 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H20ClF3IN3O4 | 585.8(M+1) |
153 | 4,5-二氟-2-(2-氟-4- | C20H21F3IN3O4 | 551.9(M+1) |
碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺 | ||||
154 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H20ClF4N3O4 | 478.4(M+1) | |
155 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺 | C20H21ClF3N3O4 | 460.0(M+1) | |
156 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H14ClF2IN2O3 | 482.9(M+1) | |
157 | 3,4,5-三氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16F3IN2O3 | 480.9(M+1) | |
158 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丙氧基)-苯甲酰胺 | C16H13BrClF2IN2O3 | 560.8/562.8(M+1) | |
159 | 5-溴-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16BrF2IN2O3 | 540.8/542.8(M+1) | |
160 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基丙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 500.8(M+1) | |
161 | 5-氯-2-(2-氯-4-碘- | C16H13Cl2F2IN2O3 | 516.8(M+1) |
苯氨基)-3,4-二氟-N-(2-羟基丙氧基)-苯甲酰胺 | |||
162 | 3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺 | C17H17F2IN2O3 | 462.9(M+1) |
163 | 5-氯-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C17H16ClF2IN2O3 | 496.9(M+1) |
164 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H14F3IN2O3 | 466.9(M+1) |
165 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H13ClF3IN2O3 | 500.8(M+1) |
166 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H13ClF4N2O3 | 393.1(M+1) |
167 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H14F4N2O3 | 359.4(M+1) |
168 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺 | C16H14ClF3N2O3 | 375.1(M+1) |
169 | 4,5-二氟-2-(2-氟-4- | C16H14F3IN2O3 | 466.9(M+1) |
碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺 | |||
170 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺 | C17H15ClF3IN2O3 | 514.9(M+1) |
171 | 3,4,5-三氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C18H18F3IN2O3 | 494.9(M+1) |
172 | 5-溴-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C18H18BrF2IN2O3 | 554.9/556.9(M+1) |
173 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺 | C17H15BrClF2IN2O3 | 574.8/576.8(M+1) |
174 | 3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C18H19F2IN2O3 | 477.0(M+1) |
175 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺 | C17H15Cl2F2IN2O3 | 530.9(M+1) |
176 | 5-氯-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C18H18ClF2IN2O3 | 510.9(M+1) |
177 | 3,4-二氟-2-(2-氟-4- | C17H16F3IN2O3 | 481.1(M+1) |
碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺 | ||||
178 | 5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺 | C17H15BrF3IN2O3 | 559.0/561.0(M+1) | |
179 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺 | C17H15ClF3IN2O3 | 515.1(M+1) | |
180 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺 | C17H15ClF4N2O3 | 407.4(M+1) | |
181 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺 | C17H16F4N2O3 | 373.5(M+1) | |
182 | 2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺 | C17H16BrF3N2O3 | 433.3/435.3(M+1) | |
183 | 氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H18ClF2IN2O4 | 575.0(M+1) | |
184 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺 | C22H17ClF3IN2O4 | 592.9(M+1) |
185 | 3,4,5-三氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C23H20F3IN2O4 | 573.0(M+1) |
186 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3苯氧基-丙氧基)-苯甲酰胺 | C22H17BrClF2INO4 | 652.8/654.8(M+1) |
187 | 5-溴-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C23H20BrF2IN2O4 | 632.9/634.9(M+1) |
188 | 3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C23H21F2IN2O4 | 555.0(M+1) |
189 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺 | C22H17Cl2F2IN2O4 | 608.9(M+1) |
190 | 5-氯-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C23H20ClF2IN2O4 | 588.9(M+1) |
191 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧 | C22H18F3IN2O4 | 558.9(M+1) |
基)-苯甲酰胺 | ||||
192 | 5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H17ClF3IN2O4 | 592.8(M+1) | |
193 | 4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H18F3IN2O4 | 558.9(M+1) | |
194 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H17ClF4N2O4 | 485.4(M+1) | |
195 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H18F4N2O4 | 451.5(M+1) | |
196 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺 | C22H18ClF3N2O4 | 467.0(M+1) | |
197 | 3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺 | C19H21F2IN2O3 | 491.0(M+1) | |
198 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺 | C18H17ClF3IN2O3 | 528.9(M+1) | |
199 | 3,4,5-三氟-N-(3-羟基-2,2-二甲基丙氧 | C19H20F3IN2O3 | 508.9(M+1) |
基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | |||
200 | 5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺 | C18H17Cl2F2IN2O3 | 544.9(M+1) |
201 | 5-氯-3,4-二氟-N-(3-羟基-2,2-二甲基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺 | C19H20ClF2IN2O3 | 524.9(M+1) |
202 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺 | C18H18F3IN2O3 | 495.1(M+1) |
203 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺 | C18H17ClF4N2O3 | 421.4(M+1) |
204 | 3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺 | C19H21F2IN2O4 | 507(M+1) |
205 | 3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺 | C19H20F3IN2O4 | 525(M+1) |
206 | 5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-[2-(2-甲氧基- | C19H20BrF2IN2O4 | 585/587(M+1) |
乙氧基)-乙氧基]-苯甲酰胺 | |||
207 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺 | C18H18ClF2IN2O4 | 527(M+1) |
208 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺 | C18H17ClF3IN2O4 | 545(M+1) |
209 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺 | C18H17BrClF2IN2O4 | 605/607(M+1) |
210 | 3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺 | C16H10F7IN2O3 | 539.1(M+1) |
211 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟N-(3,3,3-三氟-2羟基-丙氧基)-苯甲酰胺 | C16H10ClF7N2O3 | 447.4(M+1) |
212 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺 | C16H11F7N2O3 | 413.4(M+1) |
213 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰 | C16H11ClF6N2O3 | 429.0(M+1) |
214 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟N-(2-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H15ClF4N2O3 | 419.4(M+1) |
215 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16F4N2O3 | 385.4(M+1) |
216 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16ClF3N2O3 | 401.0(M+1) |
217 | 4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16F3IN2O3 | 492.9(M+1) |
218 | 3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16F3IN2O3 | 493.5(M+1) |
219 | 3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H15F4IN2O3 | 511.1(M+1) |
220 | 5-溴-3,4-二氟-2-(2- | C18H15BrF3IN2O3 | 571.0/573.0(M+1) |
氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | |||
221 | 4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16F3IN2O3 | 493.1(M+1) |
222 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16F4N2O3 | 385.4(M+1) |
223 | 2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16BrF3N2O3 | 445.3/447.3(M+1) |
224 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H16ClF3N2O3 | 401.4(M+1) |
225 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺 | C18H15ClF4N2O3 | 419.1(M+1) |
226 | 2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺 | C17H16F4N2O4 | 389.4(M+1) |
227 | 5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺 | C17H15ClF4N2O4 | 423.4(M+1) |
228 | 2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺 | C17H16BrF3N2O4 | 449.3/451.3(M+1) |
229 | 2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺 | C17H16ClF3N2O4 | 405.4(M+1) |
230 | 3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺 | C22H19F3IN3O2 | 542.0(M+1) |
231 | 5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺 | C22H19BrF2IN3O2 | 574.0/576.0(M+1) |
232 | 2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基-乙氧基)-苯甲酰胺 | C21H17ClF2IN3O2 | 544.0(M+1) |
233 | 2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-苯氨基乙氧基)-苯甲酰胺 | C21H16ClF3IN3O2 | 562.0(M+1) |
234 | 3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺 | C22H20F2IN3O2 | 524.0(M+1) |
235 | 5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基乙氧基)-苯甲酰胺 | C21H16BrClF2IN3O2 | 622.0/624.0(M+1) |
实施例236
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((S)-3-羟基-2-甲氨基-丙氧基)-苯甲酰胺
A步:将N-Boc-O-苄基-L-丝氨酸(8.86g,30.0mmol)溶于四氢呋喃(94ml),所得溶液用0℃冰浴冷却。一次性加入甲基碘(15.0ml,241mmol)。5分钟后,在10分钟内分三次加入氢化钠(60%矿物油分散系,3.6g,90mmol)。将所得反应混合物在氮下搅拌76小时,同时保持冷却浴的温度在0℃。反应混合物用冷的(0-5℃)乙酸乙酯(150ml)稀释,历经10分钟滴加水(1.5ml)。使冷却浴温度缓慢温热至环境温度过夜。在旋转蒸发器上浓缩反应混合物至粘性的油,无需加热。使残余物在***(100ml)与水(300ml)之间分配。醚层进一步用饱和碳酸氢钠水溶液(150ml)洗涤。合并含水部分,用柠檬酸水溶液(2M)酸化至pH 3,用乙酸乙酯萃取(3×150ml)。合并萃取液,用水(2×150ml)和5%硫代硫酸钠水溶液(150ml)洗涤,经硫酸镁干燥,在旋转蒸发器上浓缩(无需加热),得到(S)-3-苄氧基-2-(叔丁氧羰基-甲基-氨基)-丙酸,为粘性无色的油(8.98g)。
B步:将A步所制备的酸(8.95g,28.9mmol)溶于甲醇(50ml)与二氯甲烷(50ml)。将所得溶液冷却至0℃。历经1小时滴加三甲代甲硅烷基重氮甲烷(2.0M己烷溶液,26ml),将所得反应混合物在0℃下搅拌另外1小时。加入另一部分三甲代甲硅烷基重氮甲烷(2.0M己烷溶液,3ml),将反应在0℃下搅拌另外30分钟。在真空中浓缩反应混合物,注意不加热溶液超过20℃。将残液溶于四氢呋喃-甲醇(3∶1,200ml),将所得溶液冷却至0℃。历经30分钟滴加硼氢化锂溶液(2.0M四氢呋喃溶液,20ml)。将反应混合物在0℃下搅拌另外1小时,在环境温度下搅拌1小时。加入另一部分硼氢化锂溶液(20ml),将反应混合物搅拌过夜。小心地加入水(30ml),同时剧烈搅拌。气体放出平息后,加入50%氢氧化钠水溶液(1ml),继续搅拌20分钟。在真空中浓缩反应混合物至约1/4体积,用乙酸乙酯(300ml)稀释,用水(50ml)、饱和氯化铵水溶液(50ml)和饱和盐水(50ml)洗涤。萃取液经硫酸镁干燥,在真空中浓缩。残留的油经过硅胶色谱纯化(含40%乙酸乙酯的己烷),得到产物((R)-1-苄氧基甲基-2-羟基-乙基)-甲基-氨基甲酸叔丁酯(6.02g,68%,从N-Boc-O-苄基丝氨酸计),为无色的油:
1HNMR(400MHz,CDCl3)δ7.39-7.28(m,5H),4.55(AB四重峰,J=8.0Hz,Δv=16.4Hz,2H),4.13(br s,1H),3.85-3.55(cm,4H),2.86(s,3H),1.45(s,9H);[α]D=+77(甲醇,c=1mg/mL);MS(APCI+)296.2(M+1,10%),222.1(M+1-C4H10O,60%),196.1(M+1-C5H8O2,100%).
C,D步:按照制备例74的方法,((R)-1-苄氧基甲基-2-羟基-乙基)-甲基-氨基甲酸叔丁酯可以转化为((S)-2-氨基氧基-1-苄氧基甲基-乙基)-甲基-氨基甲酸叔丁酯。
E步:利用实施例80A步方法,可以从((S)-2-氨基氧基-1-苄氧基甲基-乙基)-甲基-氨基甲酸叔丁酯和3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酸制备[(S)-1-苄氧基甲基-2-({1-[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-甲酰基}-氨基氧基)-乙基]-甲基-氨基甲酸叔丁酯。
F步:将E步产物用三甲基碘硅烷处理,然后用盐酸水溶液处理,得到3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((S)-3-羟基-2-甲氨基-丙氧基)-苯甲酰胺,可以分离为药学上可接受的盐。
实施例237
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((R)-3-羟基-2-甲氨基丙氧基)-苯甲酰胺
A步:将((R)-1-苄氧基甲基-2-羟基-乙基)-甲基-氨基甲酸叔丁酯用叔丁基二甲基甲氯硅烷与咪唑的二甲基甲酰胺溶液处理,得到[(S)-1-苄氧基甲基-2-(叔丁基-二甲基-甲硅烷氧基)-乙基]-甲基-氨基甲酸叔丁酯。
B步:在披活性钯碳的存在下,使A步所制备的化合物暴露于加压氢气氛下,得到[(S)-2-(叔丁基-二甲基-甲硅烷氧基)-1-羟甲基-乙基]-甲基-氨基甲酸叔丁酯。
C,D步:利用制备例74的通用方法,B步化合物可以转化为[(S)-1-氨基氧基甲基-2-(叔丁基-二甲基-甲硅烷氧基)-乙基]-甲基-氨基甲酸叔丁酯。
E步:利用实施例80A步方法,可以制备[(S)-2-(叔丁基-二甲基-甲硅烷氧基)-1-({1-[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-甲酰基}-氨基氧基甲基)-乙基]-甲基-氨基甲酸叔丁酯。
F步:将E步产物用三甲基碘硅烷处理,然后用氟化四丁铵处理,得到3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((R)-3-羟基-2-甲氨基-丙氧基)-苯甲酰胺,可以分离为药学上可接受的盐。
实施例238
(S)-与(R)-5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺
分别类似于实施例236和237,可以从5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酸制备(S)-与(R)-5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺。
实施例239
(S)-与(R)-5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺
分别类似于实施例236和237,可以从5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-苯甲酸制备(S)-与(R)-5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺。
实施例240
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氨基丙氧基)-苯甲酰胺
A步:利用实施例56的通用方法,N-(叔丁氧羰基)-N-甲基-2,3-环氧丙胺(可利用文献方法获得:Edwards,M.L;Snyder,R.D.;Stemerick,D.M.J.Med.Chem.1991,34,2414)可以转化为(3-氨基氧基-2-羟基-丙基)-甲基-氨基甲酸叔丁酯。
B,C步:利用实施例236E和F步的通用方法,可以从(3-氨基氧基-2-羟基-丙基)-甲基-氨基甲酸叔丁酯和3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酸制备3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氨基-丙氧基)-苯甲酰胺。
实施例241
测量MEK抑制作用的细胞测定法
化合物作为MEK抑制剂的评价是在这样一种测定法中进行的,该测定法测量它们抑制鼠结肠26(C26)癌细胞中MAP激酶(ERK)磷酸化作用的能力。由于ERK1和ERK2代表唯一已知的MEK底物,细胞中ERK磷酸化抑制作用的测量提供本发明化合物抑制细胞MEK的直接结果。简而言之,该测定法涉及在37℃下,将呈指数生长的C26细胞用不同浓度的供试化合物(或载体对照)处理一小时。然后洗去细胞的化合物/载体,溶于含有70mM NaCl、50mM磷酸甘油酯、10mMHEPES,pH7.4、1%Triton X-100、1mM Na3VO4、100μM PMSF、10μM亮肽素和10μM胃酶抑素的溶液。然后对上清液进行凝胶电泳和蛋白质印迹测定,使用识别双重磷酸化ERK1与ERK2的原代抗体。为了评价总的MAPK水平,随后将印迹“剥离”,用识别未磷酸化ERK1与ERK2的多克隆抗体的1∶1混合物再次探查。
表8公开了由上述方案生成的抑制数据。如果试验了若干浓度的抑制剂,那么从关于抑制作用的剂量响应曲线测定IC50值(产生50%抑制作用的浓度)。否则,报告在所测浓度下的抑制百分率。
表8:本发明化合物对ERK磷酸化的细胞抑制作用
实施例No.化合物 | IC50(μM) | 抑制%@0.1μM | 抑制%@1μM | 抑制%@10μM |
1 | 0.008 | |||
2 | 0.003 | |||
3 | 0.004 | |||
4 | 0.002 | |||
5 | 0.003 | |||
6 | 0.005 | |||
7 | 0.005 | |||
8 | 0.0003 | |||
9 | 0.00007 | |||
10 | 0.0003 |
11 | 0.002 | |||
12 | 0.022 | |||
13 | 0.002 | |||
14 | 0.002 | |||
15 | 0.001 | |||
16 | 0.02 | |||
17 | 0.045 | |||
18 | 0.002 | |||
19 | 0.001 | |||
20 | 0.003 | |||
21 | 0.0018 | |||
22 | 0.0077 | |||
23 | 0.032 | |||
24 | 0.026 | |||
25 | 0.052 | |||
26 | 0.24 | |||
27 | 0.12 | |||
28 | 0.12 | |||
29 | 0.047 | |||
30 | 0.13 | |||
32 | 0.0044 | |||
33 | 0.005 | |||
34 | 0.001 | |||
35 | 0.006 | |||
36 | 0.053 | |||
37 | 0.03 | |||
38 | >1.00 | |||
39 | 0.0004 | |||
40 | 0.0014 | |||
41 | 0.00073 | |||
42 | 0.0027 |
43 | 0.0018 | |||
44 | 0.003 | |||
45 | 0.019 | |||
46 | 0.582 | |||
47 | 0.001 | |||
48 | 0.0016 | |||
49 | 0.00033 | |||
50 | 0.00083 | |||
51 | 0.0038 | |||
52 | 0.0078 | |||
53 | 0.0012 | |||
54 | 0.0012 | |||
55 | 0.0045 | |||
58 | 0.06 | |||
61 | 0.15 | |||
62 | 0.018 | |||
63 | 0.047 | |||
64 | 0.013 | |||
65 | 0.014 | |||
66 | 0.002 | |||
67 | 0.006 | |||
68 | 0.024 | |||
69 | 0.06 | |||
70 | 0.2 | |||
71 | 0.12 | |||
72 | 0.019 | |||
73 | 0.08 | |||
74 | 0.018 | |||
75 | 0.042 | |||
76 | 0.006 | |||
77 | 0.24 |
78 | 0.23 | ||||
79 | 0.02 | ||||
80 | 0.49 | ||||
81 | 0.134 | ||||
82 | >1 | ||||
83 | 0.041 | ||||
85 | 0.054 | ||||
86 | 0.019 | ||||
87 | 0.025 | ||||
88 | 0.11 | ||||
89 | 0.012 | ||||
90 | 0.04 | ||||
91 | 89.4 | 98.9 | |||
92 | 51.8 | 92.4 | |||
93 | 4 | 79.1 | |||
94 | 0.28 | ||||
95 | 0.19 | ||||
96 | 35 | 87.1 | |||
97 | 30.1 | 91.9 | |||
98 | 0.011 | ||||
99 | 0.018 | ||||
100 | 0.058 | ||||
101 | 0.225 | ||||
102 | 0.275 | ||||
103 | 0.487 | ||||
104 | 0.024 | ||||
105 | 3.3 | 71.3 | |||
106 | 13.2 | 81.6 | |||
107 | 0.076 | ||||
108 | 74 | 94.6 | |||
109 | 0.038 |
111 | 78 | 93.4 | ||
112 | 95.2 | 95.5 | ||
113 | 89.9 | 94.6 | ||
114 | 90.5 | 97.3 | ||
115 | 94.8 | 98.5 | ||
116 | 62.8 | 75.8 | ||
117 | 0 | 66.7 | 86.9 | |
118 | 74.6 | 95.6 | ||
119 | 87.4 | 97.9 | ||
120 | 0.014 | |||
121 | 46.9 | 85.5 | ||
122 | 49.6 | 87.3 | ||
123 | 0.021 | |||
124 | 78 | 96.9 | ||
125 | 9.1 | 89 | ||
126 | 0.026 | |||
127 | 0.025 | |||
128 | 0.009 | |||
129 | 100 | 100 | ||
130 | 0.004 | |||
131 | 78.7 | 91.3 | ||
132 | 45.7 | 80.6 | ||
133 | 0 | 26.4 | ||
134 | 0.37 | |||
135 | 0 | 41.4 | ||
136 | 0.25 | |||
137 | 0.1 | |||
138 | 0 | 19.6 | ||
139 | 0.36 | |||
140 | 0.45 | |||
141 | 38 | 92.7 |
142 | 31 | 91.4 | ||
143 | 0.6 | |||
145 | 0.1 | |||
146 | 0 | 40.5 | ||
147 | 0.1 | |||
148 | 0.23 | |||
149 | 0.17 | |||
150 | 49 | 99.9 | ||
151 | 0.041 | |||
152 | 59.2 | 90.3 | ||
153 | 13.9 | 89.5 | ||
154 | 8.9 | 51 | ||
155 | 0 | 30.9 | ||
156 | 0.011 | |||
157 | 50.7 | 91.5 | ||
159 | 88.4 | 100 | ||
160 | 71.9 | 96.8 | ||
161 | 0.015 | |||
162 | 0.00785 | |||
163 | 88.9 | 95.1 | ||
164 | 0.003 | |||
165 | 0.004 | |||
166 | 0 | 31.9 | 88.7 | |
167 | 80.5 | 89.2 | ||
168 | 48.8 | 89.5 | ||
169 | 0.014 | |||
170 | 19 | 85.7 | ||
171 | 35.6 | 94.6 | ||
172 | 41.9 | 92.9 | ||
173 | 0.3 | |||
174 | 0.1 |
175 | 0.18 | ||||
176 | 14.1 | 87.7 | |||
177 | 91.6 | 95.7 | |||
178 | 61.8 | 94.9 | |||
179 | 90.4 | 99.3 | |||
180 | 34 | 58.6 | |||
181 | 0 | 65.1 | |||
182 | 13.1 | 81.9 | |||
183 | 0.053 | ||||
184 | 16.1 | 82.5 | |||
185 | 6.2 | 71.9 | |||
186 | 0.034 | ||||
187 | 13.8 | 83.3 | |||
188 | 0.044 | ||||
190 | 51.5 | 94.6 | |||
191 | 0.006 | ||||
192 | 0.007 | ||||
193 | 0.01 | ||||
194 | 0 | 0 | |||
195 | 26.7 | 82.6 | |||
196 | 10.2 | 82.8 | |||
197 | 0.051 | ||||
198 | 0 | 43.5 | |||
199 | 0.1 | ||||
200 | 0.3 | ||||
201 | 0.1 | ||||
202 | 59.7 | 94.6 | |||
203 | 0 | 37.4 | |||
206 | 0.14 | ||||
207 | 0.212 | ||||
208 | 1.029 |
210 | 79.7 | 99.2 | ||
211 | 35 | 71.9 | ||
212 | 20.1 | 85.1 | ||
213 | 6.2 | 78.7 | ||
214 | 15.4 | 38.2 | ||
215 | 11.7 | 84.8 | ||
216 | 41.2 | 87.6 | ||
217 | 26.9 | 93.1 | ||
218 | 87 | 96.9 | ||
219 | 65.3 | 96.2 | ||
220 | 35.4 | 88.8 | ||
221 | 46 | 92.4 | ||
222 | 9.6 | 55.6 | ||
223 | 5.2 | 56.7 | ||
224 | 0 | 18.1 | ||
225 | 0 | 8.7 | 36.9 | |
226 | 41.5 | 84.1 | ||
227 | 24.2 | 63 | ||
228 | 48.6 | 92.4 | ||
229 | 9.8 | 76.5 | ||
230 | 0.051 | |||
231 | 0.067 | |||
232 | 0.022 | |||
233 | 0.033 | |||
234 | 0.054 | |||
235 | 0.062 |
实施例242
角叉菜胶诱导的爪垫水肿(CFE)大鼠模型
向雄性远系繁殖的Wistar大鼠(135-150g,Charles River Labs)口服给以10ml/kg载体或供试化合物,一小时后给以经过声波处理的角叉菜胶悬液(1mg/0.1ml盐水)。将角叉菜胶注射到右后爪的跖下区。在注射后立即利用汞体积描记法测定爪体积,角叉菜胶注射后五小时再次测定。测定水肿的抑制百分率,利用线性回归计算ID40。利用单路径ANOVA和Dunnett检验评估与对照动物相比的肿胀差异。
实施例243
胶原诱导的小鼠关节炎
II型胶原诱导的小鼠关节炎(CIA)是关节炎的实验模型,具有大量与类风湿性关节炎共有的病理、免疫和遗传特征。该疾病是由100μgII型胶原对DBA/1小鼠的致免疫作用诱发的,它是关节软骨的主要组分,Freund氏完全佐剂中真皮内释放。疾病敏感性受II类MHC基因部位调节,这类似于类风湿性关节炎与HLA-DR4的关系。
在大多数致免疫小鼠中发展为进行性与炎性关节炎,以爪宽度增加高达100%为特征。供试化合物对小鼠给药的范围例如20、60、100和200mg/kg体重/天。试验的持续时间可以是若干周至几个月,例如40、60或80天。临床评分指数用于评估疾病进展,从红斑与水肿(第1阶段)、关节变形(第2阶段)到关节强硬(第3阶段)。可以见到,疾病能够影响动物的一只或全部爪子,导致每只小鼠的总分可能达到12。关节炎关节的病理组织学揭示了滑膜炎、血管翳形成和软骨与骨侵蚀。全部易患CIA的小鼠都是对II型胶原的高抗体应答者,存在对CII的显著细胞应答。
实施例244
SCW诱导的单关节关节炎
关节炎是如Schwab等,Infection and Immunity,59:4436-4442(1991)所述诱导的,并作微小修改。大鼠接受6μg经过声波处理的SCW[10μl Dulbecco′s PBS(DPBS)],在第0天向右tibiotalar关节进行关节内注射。在第21天,用100μg i.v.给药的SCW(250μl)引发DTH。关于口服化合物研究,将化合物悬浮在载体(0.5%羟丙基-甲基纤维素/0.2%Tween 80)中,声波处理,每日给药两次(10ml/kg体积),开始于用SCW进行再活化作用之前1小时。化合物的给药量在10与500mg/kg体重/天之间,例如20、30、60、100、200和300mg/kg/天。水肿量度是这样获得的,在第21天再活化作用之前测定致敏后爪的基线体积,并与随后时间点的体积进行比较,例如第22、23、24和25天。爪体积是利用汞体积描记法测定的。
实施例245
小鼠耳-心移植模型
Fey,T.A.等描述了用于移植***心脏新生心移植物到小鼠与大鼠耳廓的方法(J Pharm.and Toxic.Meth.39:9-17(1998))。将化合物溶于含有绝对乙醇、0.2%羟丙基甲基纤维素水溶液、丙二醇、Cremophor与葡萄糖的组合的溶液,或其他溶剂或悬浮载体。对小鼠口服或腹膜内给药,每日一次、两次或三次,从移植当天(第0天)到第13天或者直到抑制物已被排斥。对大鼠给药每日一次、两次或三次,从第0天到第13天。将每只动物麻醉,切开接受抑制的耳基部,仅切及背侧表皮和真皮。扩大切口,平行于头部向下至软骨,宽度足以容纳适当的大鼠用隧道或小鼠用***工具。将新生不足60小时的小鼠或大鼠幼畜麻醉,颈脱臼。从胸部取出心脏,用盐水冲洗,用解剖刀纵向对切,用无菌盐水冲洗。将供体心脏片段用***工具置于预先形成的隧道内,用轻微的压力小心地从隧道内压出空气或残液。不需要缝合、粘合、包扎或者用抗生素处理。
用实体解剖显微镜在10-20倍放大率下检查移植物,无需麻醉。可以麻醉移植心跳不可见的受移植动物,利用置于耳廓内或直接置于移植物内的Grass E-2铂真皮下针式微电极和血流速度描记评价电活性的存在。对移植物可以检查10、20、30或更多天,每天1-4次。可以对比供试化合物与对照化合物改善移植排斥症状的能力,后者例如环孢菌素、他克莫司或口服给药的来氟米特。
实施例246
利用大鼠试验评估本发明化合物的止痛活性。将角叉菜胶(含2%的0.9%氯化钠水溶液,100μl注射体积)注射到体重175至200g的大鼠单后肢的爪垫内。将大鼠置于玻璃板上,用置于注射爪正下方的卤素灯照射。测量从开始照射直到后肢从玻璃上收回的时间(秒),记为爪收回潜伏期(PWL)。在角叉菜胶对爪垫注射后2.5小时通过口服管饲注射给以药物。在角叉菜胶注射之前、即将药物注射之间和药物注射之后1、2(有时3)小时测量PWL。
角叉菜胶(从海藻提取的多糖)在注射到皮下后导致无菌性炎症。向大鼠爪垫内注射不导致或仅导致轻微的自发性与疼痛有关的行为,但是诱发对外周热或机械刺激物的痛觉过敏(强度大于预期的与疼痛有关的行为反应)。这种痛觉过敏在注射后2至3小时最大。将大鼠用各种止痛药处理会减少以这种方式测量的痛觉过敏,是用于检测大鼠止痛活性的常规试验(Hargreaves K,Dubner R,Brown F,Flores C,Joris J.A new and sensitive method for measuring thermalnociception in cutaneous hyperalgesia.Pain 1988;32:77-88和KayserV,Guilbaud G.Local and remote modifications of nociceptivesensitivity during carrageenan-induced inflammation in the rat.Pain1987;28:99-108)。未治疗大鼠的PWL大约为10秒钟。角叉菜胶注射减少PWL至大约3秒钟达至少4小时,说明对热的痛觉过敏。利用药物治疗前后的PWL差异,测定角叉菜胶热痛觉过敏反应的抑制作用,以反应抑制百分率表示。MEK抑制剂给药剂量依赖性地减少热痛觉过敏(表9)。
表9中,通过口服管饲法(PO)给药,在给药后1小时(1hr)、2小时(2hr)或有时3小时(3hr)测量对反应的抑制作用。抑制作用说明了止痛效果。
表9
MEK抑制剂对大鼠给药减少跖内角叉菜胶的热痛觉过敏
实施例NO. | 剂量(PO) | 抑制%(1hr) | 抑制%(2hr) | 抑制%(3hr) |
9 | 30103 | 103.057.238.1 | 114.480.044.3 | 65.250.826.1 |
34 | 10 | 39.6 | 61.5 | |
41 | 10 | 26.7 | 61.0 | |
55 | 10 | 36.8 | 60 | 22 |
54 | 10 | 49 | 52.9 | 29.6 |
Claims (74)
1、下式化合物
其中
R1是氢或卤素;
R2是氢或氟;
R3是氢或氟;
R4是氢、碘、溴、氯或氟;
R5是氢、卤素或C1-8烷基;
n是1至5的整数;
R6、R7、R8、R9和R10独立地是氢、C1-8烷基、羟基、全卤代(C1-3)烷基、羟基(C1-8)烷基或(C2-7)杂环(C1-5)烷基,其中所述杂环由碳原子和一至四个杂原子组成,所述杂原子选自由N、O和S组成的组;
或者R7和R8独立地连接构成3-10元环;
或者R6和R9独立地连接构成3-10元环,所述环含有另外的杂原子,选自由O、S、NH和N-C1-8烷基组成的组;
W是O或NRa;
R11是氢、C1-8烷基、C2-6链烯基、羟基(C1-8)烷基、(C1-5)烷氧基(C1-5)烷基、苯基或三氟(C1-6)烷基;
其中上述烷基、烷氧基和苯基不被取代或被1至5个取代基取代,取代基独立地选自由羟基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、卤素、氰基、(C1-3)烷氧基、OCORa、CONRaRb、NRaCORb、SO、SO2、SO4和SO2NRaRb组成的组;
Ra和Rb独立地是氢或C1-4烷基;
及其药学上可接受的盐;
其条件是若R11是苯基,n是1,则W不能是O;
进一步的条件是该化合物不是
5-溴-N-(2-二乙氨基-乙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-N-(2-二甲氨基-丙氧基)-3,4-二氟-(4-碘-2-甲基-苯氨基)-苯甲酰胺;或
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2-二甲氨基-乙氧基)-3,4-二氟-苯甲酰胺。
2、权利要求1的化合物,其中卤素是氟、溴或氯。
3、权利要求1的化合物,其中R2是氟。
4、权利要求1的化合物,其中R3是氟。
5、权利要求1的化合物,其中R4是碘。
6、权利要求1的化合物,其中R5是氟、氯或甲基。
7、权利要求1的化合物,其中n是1或2。
8、权利要求1的化合物,其中R6、R7、R8、R9、R10和R11是氢。
9、权利要求1的化合物,其中R6、R7、R8、R9和R10是氢。
10、权利要求1的化合物,其中R6、R7、R9、R10和R11是氢。
11、权利要求1的化合物,其中W是氧。
12、权利要求1的化合物,其中W是NRa,Ra是氢。
13、权利要求1的化合物,其中R11是甲基或苯基。
14、权利要求2的化合物,其中R3是氢。
15、权利要求2的化合物,其中R3是氟。
16、权利要求2的化合物,其中R4是碘。
17、权利要求2的化合物,其中R5是氟、氯或甲基。
18、权利要求2的化合物,其中n是1或2。
19、权利要求2的化合物,其中R6、R7、R8、R9、R10和R11是氢。
20、权利要求2的化合物,其中R6、R7、R8、R9和R10是氢。
21、权利要求2的化合物,其中R6、R7、R9、R10和R11是氢。
22、权利要求2的化合物,其中W是O。
23、权利要求2的化合物,其中W是NRa,Ra是氢。
24、权利要求2的化合物,其中R11是甲基或苯基。
27、权利要求1的化合物,其中该化合物是下式化合物
其中
R5是氟、氯或甲基。
28、权利要求1的化合物,其中该化合物是下式化合物
其中
R5是氟、氯或甲基。
29、权利要求1的化合物,选自下组的化合物:
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
5-氯-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氨基-乙氧基)苯甲酰胺;
N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
5-氯-N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺;和
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺。
30、权利要求1的化合物,选自下组的化合物;
3,4,5-三氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-苯甲酰胺;
4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-苯氨基)-苯甲酰胺;
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
4,5-二氟-N-(2-羟基-乙氧基-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-4-氟-N-(2-羟基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-4,5-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
5-溴-4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-4,5-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-苯氨基)-N-(2-羟基-乙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-乙氧基)-苯甲酰胺;
4-氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-氯-3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-4-氟-N-(3-羟基-丙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-丙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(4-羟基-丁氧基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-氯-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
5-氯-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-4-氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-羟甲基-乙氧基)-苯甲酰胺;
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-苯甲酰胺;
5-氯-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
5-氯-N-((S)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
4-氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-乙烯氧基-乙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-1,1-二甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1,1-二甲基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)苯甲酰胺;
3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基-丙氧基)-苯甲酰胺;
3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(1-羟甲基-环丙基甲氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(-2-羟甲基-环丙基甲氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基-环丙基甲氧基)-苯甲酰胺;
N-(2,3-二羟基-3-甲基-丁氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氨基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氨基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2,2,2-三氟-乙氨基)-乙氧基]-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-4-氟-N-(2-羟基-乙氧基)-N-甲基-苯甲酰胺;
乙酸2-[3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰氨基氧基]-乙基酯;
[3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯基]-(4-羟基-异噁唑烷-2-基)-甲酮;
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4,5-三氟-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-N-(2,3-二羟基-丙氧基)-3,4-二氟-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
N-(2,3-二羟基-丙氧基)-3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4,5-三氟-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-N-(3,4-二羟基-丁氧基)-3,4-二氟-苯甲酰胺;
N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
N-(3,4-二羟基-丁氧基)-3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-N-(3,4-二羟基-丁氧基)-3,4-二氟-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基丙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-丙氧基)苯甲酰胺;
3,4,5-三氟-N-(3-羟基-丙氧基)-2-(4碘-2-甲基苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基丙氧基)-苯甲酰胺;
5-溴-3,4-二氟-N-(3-羟基-丙氧基)-2-(4碘-2-甲基苯氨基)-苯甲酰胺;
3,4-二氟-N-(3-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
2-(2-氨-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基丁氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丁氧基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丁氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-丁氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)N-(2-羟基-丁氧基)苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丁氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟N-(2-羟基-丁氧基)苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-丁氧基)苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基-乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2羟基-1-甲基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-1-甲基-乙氧基)苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-1-甲基乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基-乙氧基)苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-甲氧基乙氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺;
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基乙氧基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-甲氧基乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-甲氧基-乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-3-吗啉-4-基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-吗啉-4-基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-吗啉-4-基-丙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丙氧基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基丙氧基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基丙氧基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基-苯氨基)苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-丙氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-丙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-2-甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基-丙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-2-甲基丙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺;
3,4,5-三氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺;
5-溴-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基-丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-苯氧基丙氧基)-苯甲酰胺;
3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-2-(4-碘-2-甲基苯氨基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺;
3,4,5-三氟-N-(3-羟基-2,2-二甲基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基-丙氧基)-苯甲酰胺;
5-氯-3,4-二氟-N-(3-羟基-2,2-二甲基丙氧基)-2-(4-碘-2-甲基-苯氨基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(3-羟基-2,2-二甲基丙氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺;
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺;
5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-[2-(2-甲氧基-乙氧基)-乙氧基]-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基-乙氧基)乙氧基]-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-[2-(2-甲氧基乙氧基)-乙氧基]-苯甲酰胺;
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(3,3,3-三氟-2-羟基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(3,3,3-三氟-2-羟基-丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟甲基环丙基甲氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
3,4,5-三氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
4,5-二氟-2-(2-氟-4-碘-苯氨基)-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(1-羟甲基环丙基甲氧基)-苯甲酰胺;
2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺;
5-氯-2-(2,4-二氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺;
2-(4-溴-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺;
2-(4-氯-2-氟-苯氨基)-3,4-二氟-N-(2-羟基-3-甲氧基丙氧基)-苯甲酰胺;
3,4,5-三氟-2-(4-碘-2-甲基-苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺;
5-溴-3,4-二氟-2-(4-碘-2-甲基苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基-乙氧基)-苯甲酰胺;
2-(2-氯-4-碘-苯氨基)-3,4,5-三氟-N-(2-苯氨基乙氧基)-苯甲酰胺;
3,4-二氟-2-(4-碘-2-甲基-苯氨基)-N-(2-苯氨基-乙氧基)-苯甲酰胺;
5-溴-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(2-苯氨基乙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((S)-3-羟基-2-甲氨基-丙氧基)-苯甲酰胺;
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-((R)-3-羟基-2-甲氨基丙氧基)-苯甲酰胺;
(S)-5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺;
(R)-5-氯-3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺;
(S)-5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺;
(R)-5-氯-2-(2-氯-4-碘-苯氨基)-3,4-二氟-N-(3-羟基-2-甲氨基-丙氧基)-苯甲酰胺;和
3,4-二氟-2-(2-氟-4-碘-苯氨基)-N-(2-羟基-3-甲氨基丙氧基)-苯甲酰胺。
31、选自下组的化合物:
N-(2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺;和
N-(2,2-二甲基-[1,3]二噁烷-5-基氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺。
32、药物组合物,包含权利要求1的化合物和药学上可接受的载体。
33、权利要求1的化合物在制备用于治疗患者增殖性疾病的药物中的用途。
34、权利要求33的用途,其中该增殖性疾病选自由癌症、再狭窄、牛皮癣和动脉粥样硬化组成的组。
35、权利要求1的化合物在制备用于治疗患者牛皮癣的药物中的用途。
36、权利要求1的化合物在制备用于治疗患者癌症的药物中的用途。
37、权利要求36的用途,其中该癌症是涉及MEK的。
38、权利要求36的用途,其中该癌症是脑、乳腺、肺、卵巢、胰腺、***、肾或结肠直肠癌。
39、权利要求1的化合物在制备用于治疗患者骨关节炎的药物中的用途。
40、权利要求1的化合物在制备用于治疗患者类风湿性关节炎的药物中的用途。
41、权利要求1的化合物在制备用于治疗患者心衰的药物中的用途。
42、权利要求1的化合物在制备用于治疗患者慢性疼痛的药物中的用途。
43、权利要求42的用途,其中该慢性疼痛选自由神经病性疼痛、自发性疼痛、和与慢性酒精中毒、维生素缺乏、***和甲状腺机能减退有关的疼痛组成的组。
44、权利要求42的用途,其中该慢性疼痛是与炎症有关的。
45、权利要求42的用途,其中该慢性疼痛是与关节炎有关的。
46、权利要求42的用途,其中该慢性疼痛是与术后疼痛有关的。
47、权利要求1的化合物在制备用于治疗患者神经病性疼痛的药物中的用途。
48、权利要求47的用途,其中该神经病性疼痛是与选自下组的病症有关的:炎症、术后疼痛、幻肢痛、灼伤痛、痛风、三叉神经痛、急性疱疹与疱疹后疼痛、灼痛、糖尿病性神经病、丛撕脱、神经瘤、脉管炎、病毒感染、挤压伤、收缩伤、组织损伤、肢体切断、术后疼痛、关节炎疼痛、和外周神经***与中枢神经***之间的神经损伤。
49、权利要求1的化合物在制备用于治疗患者癌症的药物中的用途,其中所述药物与放射疗法组合应用。
50、权利要求1的化合物在制备用于治疗患者癌症的药物中的用途,其中所述药物与至少一种化疗剂组合应用。
51、权利要求50的用途,其中该化疗剂是有丝***抑制剂。
52、权利要求51的用途,其中该有丝***抑制剂选自由紫杉醇、多烯紫杉醇、长春新碱、长春碱、长春瑞滨和长春氟宁组成的组。
53、结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:7.1,19.2或32.1。
54、结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:7.1,19.2和32.1。
55、结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:7.1,14.1,15.3,15.8,16.9,18.1,19.2,20.3,21.4,22.3,23.4,24.5,25.5,26.2,26.8,27.8,28.3,29.5,32.1,33.2,33.6,40.0,42.9和44.1。
56、结晶I型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:7.078,14.123,15.280,15.836,16.880,18.082,19.162,20.279,21.360,22.325,23.400,24.522,25.480,26.159,26.801,27.842,28.280,29.475,32.118,33.248,33.645,40.008,42.885和44.095。
57、结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:11.6,12.6或24.9。
58、结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:11.6,12.6,15.6,17.3,17.9,20.3,21.1,22.1,24.9,25.9,26.7,27.8,30.1,30.9,33.8,35.4,38.2,39.3,40.8,41.6,43.6和47.0。
59、结晶II型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:11.582,12.598,15.622,17.302,17.886,20.345,21.140,22.137,24.855,25.885,26.699,27.842,30.059,30.948,33.799,35.399,38.242,39.282,40.755,41.641,43.570和46.958。
60、结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:10.6,13.7,19.0或23.7。
61、结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.6,13.7,14.6,17.3,18.0,18.2,98.0,19.3,20.1,21.0,21.9,22.4,23.7,24.0,24.9,26.3,27.6,28.0,30.1,32.1,32.3,32.9,35.8和37.7。
62、结晶I型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.560,13.720,14.619,17.258,17.958,18.219,18.998,19.258,20.142,21.002,21.940,22.360,23.680,24.043,24.919,26.278,27.603,28.024,30.100,32.142,32.298,32.938,35.841和37.660。
63、结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.5或19.6。
64、结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.5,10.7,16.5,19.6,22.0,22.5,23.6,24.1,25.0,26.2,27.6,29.1,30.5,31.7,33.3和39.0。
65、结晶II型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.482,10.721,16.478,19.563,22.019,22.478,23.621,24.100,24.959,26.181,27.621,29.081,30.476,31.698,33.263和39.020。
66、结晶I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:10.5,13.7,19.0或23.6。
67、结晶I型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:10.548,13.703,17.887,18.958,20.122,21.950,22.321,23.640,24.803,26.244,27.570,28.000,29.566,32.234,32.769,35.804,37.641,41.402,41.956和44.600。
68、结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的至少一个下列2θ值:5.6或19.6。
69、结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.6,10.7,16.5,19.6,20.9,22.0,23.7,24.2,25.0,26.2,27.7,28.0,29.1,31.7,32.8,33.3,34.1,42.0和42.3。
70、结晶II型N-[(S)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺,它的X-射线粉末衍射含有利用CuKα线辐射测量的下列2θ值:5.550,10.763,16.485,19.636,20.922,22.043,23.683,24.153,24.996,26.236,27.680,28.037,29.120,31.718,32.794,33.314,34.085,41.999和42.278。
71、权利要求1的化合物,其中该化合物是N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺。
72、权利要求26的化合物,其中R1是氢,R5是氟。
73、药物组合物,包含权利要求26的化合物和药学上可接受的载体。
74、药物组合物,包含权利要求72的化合物和药学上可接受的载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21937200P | 2000-07-19 | 2000-07-19 | |
US60/219,372 | 2000-07-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1446197A CN1446197A (zh) | 2003-10-01 |
CN1219753C true CN1219753C (zh) | 2005-09-21 |
Family
ID=22819013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018140599A Expired - Lifetime CN1219753C (zh) | 2000-07-19 | 2001-07-12 | 4-碘苯氨基苯氧肟酸的氧合酯 |
Country Status (43)
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104788365A (zh) * | 2014-01-16 | 2015-07-22 | 上海艾力斯医药科技有限公司 | 异烟酰胺衍生物、其制备方法及应用 |
Families Citing this family (212)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EE05450B1 (et) * | 2000-07-19 | 2011-08-15 | Warner-Lambert Company | 4-jodofenlaminobenshdroksaamhapete oksgeenitud estrid, nende kristallvormid ja farmatseutilised kompositsioonid ning kasutamine |
NZ518726A (en) * | 2001-05-09 | 2004-06-25 | Warner Lambert Co | Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor |
US20030008807A1 (en) * | 2001-06-14 | 2003-01-09 | The Regents Of The University Of California | Novel signaling pathway for the production of inflammatory pain and neuropathy |
BR0307060A (pt) | 2002-01-23 | 2004-10-26 | Warner Lambert Co | ésteres hidroxamato do ácido n-(fenil 4-substituìdo)-antranìlico |
DOP2003000556A (es) | 2002-01-23 | 2003-10-31 | Warner Lambert Co | Esteres hidroxamato de acido n-(4-fenil-sustituido)-antranilico. |
US7235537B2 (en) | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
PT3000810T (pt) | 2002-03-13 | 2017-10-25 | Array Biopharma Inc | Derivados de benzimidazole alquilado n3 como inibidores de mek |
EP1496901A2 (en) * | 2002-04-09 | 2005-01-19 | Novartis AG | Compositions comprising mmp7 modulators for the treatment of chronic pain |
MXPA05003431A (es) * | 2002-11-15 | 2005-07-05 | Warner Lambert Co | Quimioterapia de combinacion. |
US7378233B2 (en) | 2003-04-12 | 2008-05-27 | The Johns Hopkins University | BRAF mutation T1796A in thyroid cancers |
US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
EP1674452A4 (en) * | 2003-09-19 | 2007-10-10 | Chugai Pharmaceutical Co Ltd | NOVEL 4-PHENYLAMINO-BENZALDOXIME DERIVATIVE AND ITS USE AS MEK INHIBITOR |
MXPA06004363A (es) * | 2003-10-21 | 2006-06-14 | Warner Lambert Co | Forma polimorfica de la n-[(r)-2, 3-dihidroxipropoxi]-3, 4-difluoro-2 -(2-fluoro-4- yodofenilamino) benzamida. |
US7732616B2 (en) | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
US7772234B2 (en) | 2003-11-19 | 2010-08-10 | Array Biopharma Inc. | Bicyclic inhibitors of MEK and methods of use thereof |
US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
NZ590160A (en) | 2003-11-21 | 2012-07-27 | Array Biopharma Inc | AKT protein kinase inhibitors |
UA89035C2 (ru) | 2003-12-03 | 2009-12-25 | Лео Фарма А/С | Эфиры гидроксамовых кислот и их фармацевтическое применение |
US20050171182A1 (en) * | 2003-12-11 | 2005-08-04 | Roger Briesewitz | Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases |
CA2561516A1 (en) * | 2004-03-30 | 2005-10-13 | Pfizer Products Inc. | Combinations of signal transduction inhibitors |
PL1761528T3 (pl) | 2004-06-11 | 2008-05-30 | Japan Tobacco Inc | Pochodne 5-amino-2,4,7-triokso-3,4,7,8-tetrahydro-2H-pirydo[2,3-D]pirymidyny i związki pokrewne do leczenia raka |
US7378423B2 (en) | 2004-06-11 | 2008-05-27 | Japan Tobacco Inc. | Pyrimidine compound and medical use thereof |
TWI361066B (en) | 2004-07-26 | 2012-04-01 | Chugai Pharmaceutical Co Ltd | 5-substituted-2-phenylamino benzamides as mek inhibitors |
AU2005277587A1 (en) * | 2004-08-18 | 2006-03-02 | Merck Sharp & Dohme Corp. | Mitotic kinesin inhibitors |
DK1802579T3 (da) * | 2004-10-20 | 2014-01-20 | Merck Serono Sa | Derivater af 3-arylaminopyridin |
WO2006061712A2 (en) * | 2004-12-10 | 2006-06-15 | Pfizer Inc. | Use of mek inhibitors in treating abnormal cell growth |
DK1922307T3 (da) | 2005-05-18 | 2012-04-02 | Array Biopharma Inc | Heterocykliske inhibitorer af MEK og fremgangsmåder til anvendelse heraf |
WO2006134469A1 (en) * | 2005-06-14 | 2006-12-21 | Warner-Lambert Company Llc | Methods of preparing mek inhibitor |
US8101799B2 (en) * | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
JP5129143B2 (ja) | 2005-10-07 | 2013-01-23 | エグゼリクシス, インコーポレイテッド | Mekインヒビターおよびその使用方法 |
WO2007042885A2 (en) * | 2005-10-07 | 2007-04-19 | Pfizer Products Inc. | Therapeutic combination comprising methotrexate and a specified inhibitor of mek1 and mek2 |
US8217042B2 (en) | 2005-11-11 | 2012-07-10 | Zentaris Gmbh | Pyridopyrazines and their use as modulators of kinases |
WO2007054556A1 (de) | 2005-11-11 | 2007-05-18 | Æterna Zentaris Gmbh | Neue pyridopyrazine und deren verwendung als modulatoren von kinasen |
EP1790342A1 (de) | 2005-11-11 | 2007-05-30 | Zentaris GmbH | Pyridopyrazin-Derivate und deren Verwendung als Modulatoren der Signaltransduktionswege |
GB0601962D0 (en) | 2006-01-31 | 2006-03-15 | Ucb Sa | Therapeutic agents |
EP2049546B1 (en) | 2006-07-06 | 2010-12-29 | Array Biopharma, Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
WO2008006039A1 (en) | 2006-07-06 | 2008-01-10 | Array Biopharma Inc. | Dihydrothieno pyrimidines as akt protein kinase inhibitors |
ATE523499T1 (de) | 2006-07-06 | 2011-09-15 | Array Biopharma Inc | Cyclopenta [d]-pyrimidine als akt-proteinkinasehemmer |
ZA200901009B (en) * | 2006-08-21 | 2010-05-26 | Genentech Inc | Aza-benzothiophenyl compounds and methods of use |
RU2444524C2 (ru) * | 2006-08-21 | 2012-03-10 | Дженентек, Инк. | Азабензотиофенильные соединения и способы применения |
BRPI0714635A2 (pt) * | 2006-08-21 | 2013-06-18 | Genentech Inc | compostos, composiÇço farmacÊutica, mÉtodo para inibir, o crescimento celular anormal ou tratar uma disfunÇço hiperproliferativa, mÉtodo para tratar uma doenÇa inflamatària e mÉtodo para tratar uma doenÇa autoimune |
EP2069359B1 (en) * | 2006-08-21 | 2014-11-12 | Genentech, Inc. | Aza-benzothiophenyl compounds and methods of use |
WO2008140553A2 (en) | 2006-10-23 | 2008-11-20 | Takeda Pharmaceutical Company Limited | Mapk/erk kinase inhibitors |
PL2101759T3 (pl) | 2006-12-14 | 2019-05-31 | Exelixis Inc | Sposoby stosowania inhibitorów MEK |
JO2985B1 (ar) | 2006-12-20 | 2016-09-05 | Takeda Pharmaceuticals Co | مثبطات كينازmapk/erk |
US8258152B2 (en) | 2007-06-12 | 2012-09-04 | Genentech, Inc. | N-substituted azaindoles and methods of use |
AU2008272830B8 (en) | 2007-07-05 | 2013-12-12 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
AU2008272832B2 (en) | 2007-07-05 | 2014-02-20 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
GB0714384D0 (en) | 2007-07-23 | 2007-09-05 | Ucb Pharma Sa | theraputic agents |
MX2010006800A (es) | 2007-12-19 | 2010-10-05 | Genentech Inc | 5-anilinoimidazopiridinas y metodos de uso de las mismas. |
ATE513832T1 (de) | 2007-12-19 | 2011-07-15 | Genentech Inc | 8-anilinoimidazopyridine und ihre verwendung als antikrebsmittel und/oder entzündungshemmende mittel |
KR20100086503A (ko) | 2007-12-20 | 2010-07-30 | 에프. 호프만-라 로슈 아게 | Mek 키나아제 저해제로서의 치환된 히단토인 |
NZ586575A (en) * | 2007-12-21 | 2012-03-30 | Genentech Inc | Azaindolizines and methods of use |
JP5346345B2 (ja) | 2008-01-09 | 2013-11-20 | アレイ バイオファーマ、インコーポレイテッド | Aktタンパク質キナーゼ阻害剤としての水酸化されたピリミジルシクロペンタン類 |
US8853216B2 (en) | 2008-01-09 | 2014-10-07 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor |
EP2240494B1 (en) | 2008-01-21 | 2016-03-30 | UCB Biopharma SPRL | Thieno-pyridine derivatives as mek inhibitors |
GB0811304D0 (en) | 2008-06-19 | 2008-07-30 | Ucb Pharma Sa | Therapeutic agents |
KR20110028376A (ko) | 2008-07-01 | 2011-03-17 | 제넨테크, 인크. | Mek 키나제 억제제로서의 이소인돌론 유도체 및 사용 방법 |
CN102137847B (zh) | 2008-07-01 | 2015-06-10 | 健泰科生物技术公司 | 作为mek激酶抑制剂的二环杂环 |
PL2307376T3 (pl) | 2008-08-04 | 2016-04-29 | Merck Patent Gmbh | Nowe związki fenyloaminoizonikotynoamidowe |
NZ591820A (en) | 2008-08-27 | 2012-12-21 | Leo Pharma As | Pyridine derivatives as vegfr-2 receptor and protein tyrosine kinase inhibitors |
US8278105B2 (en) * | 2008-09-09 | 2012-10-02 | University Of Southern California | Induction, propagation and isolation of liver progenitor cells |
ES2399384T3 (es) | 2008-11-10 | 2013-04-01 | Bayer Schering Pharma Ag | Sulfonamido fenoxibenzamidas sustituidas |
JP5651125B2 (ja) | 2008-12-10 | 2015-01-07 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | Mek阻害剤に対する耐性を付与するmek突然変異 |
SG10201405568UA (en) | 2009-09-08 | 2014-11-27 | Hoffmann La Roche | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
KR20120099219A (ko) * | 2009-09-23 | 2012-09-07 | 글락소스미스클라인 엘엘씨 | 조합물 |
AU2010314287A1 (en) * | 2009-10-12 | 2012-05-03 | F. Hoffmann-La Roche Ag | Combinations of a PI3K inhibitor and a MEK inhibitor |
JP2013508318A (ja) | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | 置換されたベンゾスルホンアミド誘導体 |
US20120263714A1 (en) | 2009-10-21 | 2012-10-18 | Bayer Intellectual Property Gmbh | Substituted halophenoxybenzamide derivatives |
WO2011047795A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted benzosulphonamides |
EP2519526B1 (en) | 2009-12-31 | 2014-03-26 | Centro Nacional de Investigaciones Oncológicas (CNIO) | Tricyclic compounds for use as kinase inhibitors |
ES2627703T3 (es) | 2010-01-22 | 2017-07-31 | Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii | Inhibidores de PI3·quinasa |
CA2790176A1 (en) | 2010-02-18 | 2011-08-25 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Triazolo [4, 5 - b] pyridin derivatives |
ES2576061T3 (es) | 2010-02-25 | 2016-07-05 | Dana-Farber Cancer Institute, Inc. | Mutaciones de BRAF que confieren resistencia a inhibidores de BRAF |
CA2791247C (en) | 2010-03-09 | 2019-05-14 | Dana-Farber Cancer Institute, Inc. | Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy |
WO2011121317A1 (en) | 2010-04-01 | 2011-10-06 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Imidazo [2,1-b] [1,3,4] thiadiazoles as protein or lipid kinase inhibitors |
WO2011133520A1 (en) | 2010-04-19 | 2011-10-27 | Synta Pharmaceuticals Corp. | Cancer therapy using a combination of a hsp90 inhibitory compounds and a egfr inhibitor |
WO2012052745A1 (en) | 2010-10-21 | 2012-04-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Combinations of pi3k inhibitors with a second anti -tumor agent |
JP2013542214A (ja) | 2010-10-29 | 2013-11-21 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 置換フェノキシピリジン類 |
CN102020651B (zh) | 2010-11-02 | 2012-07-18 | 北京赛林泰医药技术有限公司 | 6-芳基氨基吡啶酮甲酰胺mek抑制剂 |
KR102482184B1 (ko) | 2010-12-22 | 2022-12-28 | 페이트 세러퓨틱스, 인코포레이티드 | 단세포 분류 및 iPSC의 증강된 재프로그래밍을 위한 세포 배양 플랫폼 |
WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
CN102649773A (zh) * | 2011-02-23 | 2012-08-29 | 苏州波锐生物医药科技有限公司 | 氨基芳香烃类化合物及其在制备抗恶性肿瘤药物中的用途 |
CA2831935A1 (en) | 2011-04-01 | 2012-10-04 | Genentech, Inc. | Combinations of akt inhibitor compounds and chemotherapeutic agents, and methods of use |
PL2694073T3 (pl) | 2011-04-01 | 2019-06-28 | Genentech, Inc. | Kombinacje inhibitorów AKT i MEK do leczenia nowotworu |
EP2524918A1 (en) | 2011-05-19 | 2012-11-21 | Centro Nacional de Investigaciones Oncológicas (CNIO) | Imidazopyrazines derivates as kinase inhibitors |
NZ618157A (en) | 2011-05-19 | 2015-07-31 | Fundación Ct Nac De Investigaciones Oncológicas Carlos Iii | Macrocyclic compounds as protein kinase inhibitors |
US20140228418A1 (en) * | 2011-05-23 | 2014-08-14 | Synta Pharmaceuticals Corp. | Combination therapy of hsp90 inhibitory compounds with mek inhibitors |
EP2714037B1 (en) | 2011-05-25 | 2016-07-13 | Université Paris Descartes | Erk inhibitors for use in treating spinal muscular atrophy |
WO2013005041A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Tricyclic heterocyclic compounds as kinase inhibitors |
WO2013004984A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Tricyclic compounds for use as kinase inhibitors |
WO2013005057A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | New compounds |
EP3812387A1 (en) | 2011-07-21 | 2021-04-28 | Sumitomo Dainippon Pharma Oncology, Inc. | Heterocyclic protein kinase inhibitors |
EP2750675A1 (en) | 2011-08-31 | 2014-07-09 | Novartis AG | Synergistic combinations of pi3k- and mek-inhibitors |
WO2013067165A1 (en) | 2011-11-02 | 2013-05-10 | Synta Pharmaceuticals Corp. | Combination therapy of hsp90 inhibitors with platinum-containing agents |
EP2773345A1 (en) | 2011-11-02 | 2014-09-10 | Synta Pharmaceuticals Corp. | Cancer therapy using a combination of hsp90 inhibitors with topoisomerase i inhibitors |
AU2012339679A1 (en) | 2011-11-14 | 2014-06-12 | Synta Pharmaceuticals Corp. | Combination therapy of Hsp90 inhibitors with BRAF inhibitors |
WO2013082511A1 (en) | 2011-12-02 | 2013-06-06 | Genentech, Inc. | Methods for overcoming tumor resistance to vegf antagonists |
CN102532089B (zh) * | 2011-12-22 | 2014-05-14 | 凯莱英医药集团(天津)股份有限公司 | 一种制备手性甘油醇缩丙酮的方法 |
BR112014016870A2 (pt) | 2012-01-09 | 2017-06-27 | Huesken Dieter | composições orgânicas para tratar doenças relacionadas com beta-catenina |
CN103204827B (zh) | 2012-01-17 | 2014-12-03 | 上海科州药物研发有限公司 | 作为蛋白激酶抑制剂的苯并噻二唑化合物及其制备方法和用途 |
WO2013169858A1 (en) | 2012-05-08 | 2013-11-14 | The Broad Institute, Inc. | Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy |
US20150267258A1 (en) | 2012-05-31 | 2015-09-24 | Bayer Pharma Aktiengesellschaft | Biomarkers for determining effective response of treatments of hepatocellular carcinoma (hcc) patients |
TR201807861T4 (tr) | 2012-10-12 | 2018-06-21 | Exelixis Inc | Kanser tedavisinde kullanım için bileşikler yapmak için yeni işlem. |
JP6243918B2 (ja) | 2012-10-16 | 2017-12-06 | トレロ ファーマシューティカルズ, インコーポレイテッド | Pkm2調節因子およびそれらの使用方法 |
EP2920144A4 (en) * | 2012-11-15 | 2016-06-29 | Univ Holy Ghost Duquesne | MEK INHIBITORS IN THE FORM OF CARBOXYLIC ACID ESTER PRODRUGS |
AU2013352379B2 (en) | 2012-11-29 | 2018-09-06 | Novartis Ag | Pharmaceutical combinations |
EP2752191A1 (en) | 2013-01-07 | 2014-07-09 | Sanofi | Compositions and methods using hdm2 antagonist and mek inhibitor |
US10139415B2 (en) | 2013-02-27 | 2018-11-27 | Daiichi Sankyo Company, Limited | Method for predicting responsiveness to compound inhibiting MAPK signal transduction pathway |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
CN105358156A (zh) * | 2013-03-13 | 2016-02-24 | 密执安大学评议会 | 双重mek/pi3k抑制剂和使用其的治疗方法 |
ES2740299T3 (es) | 2013-03-14 | 2020-02-05 | Msd Int Gmbh | Métodos para preparar inhibidores de SGLT2 |
CA2905993C (en) | 2013-03-14 | 2022-12-06 | Tolero Pharmaceuticals, Inc. | Substituted 4-amino-pyrimidinyl-2-amino-phenyl derivatives and pharmaceutical compositions thereof for use as jak2 and alk2 inhibitors |
MA38396B1 (fr) | 2013-03-15 | 2019-05-31 | Novartis Ag | Anticorps medicamenteux conjugues et leurs compositions pharmaceutiques pour traiter un cancer positif a ckit |
EP3043822A1 (en) | 2013-09-11 | 2016-07-20 | The J. David Gladstone Institutes, A Testamentary Trust Established under The Will of J. David Gladstone | Compositions for preparing cardiomyocytes |
EP3043790B1 (en) * | 2013-09-11 | 2021-05-26 | The Administrators of the Tulane Educational Fund | Novel anthranilic amides and the use thereof |
DK3068393T5 (da) | 2013-11-11 | 2022-08-22 | Amgen Inc | Kombinationsterapi som inkluderer en mdm2-inhibitor og et eller flere yderligere farmaceutisk aktive midler til behandlingen af kræftformer |
KR102340553B1 (ko) | 2014-03-04 | 2021-12-21 | 페이트 세러퓨틱스, 인코포레이티드 | 개선된 재프로그래밍 방법 및 세포 배양 플랫폼 |
US10023879B2 (en) | 2014-06-04 | 2018-07-17 | Fate Therapeutics, Inc. | Minimal volume reprogramming of mononuclear cells |
WO2016020791A1 (en) | 2014-08-05 | 2016-02-11 | Novartis Ag | Ckit antibody drug conjugates |
PE20170903A1 (es) | 2014-08-12 | 2017-07-12 | Novartis Ag | Conjugados de farmacos con anticuerpos anti-cdh6 |
CN105384754B (zh) * | 2014-09-02 | 2018-04-20 | 上海科州药物研发有限公司 | 作为蛋白激酶抑制剂的杂环类化合物及其制备方法和用途 |
WO2016040892A1 (en) | 2014-09-13 | 2016-03-17 | Novartis Ag | Combination therapies |
AU2015327868A1 (en) | 2014-10-03 | 2017-04-20 | Novartis Ag | Combination therapies |
EP3204516B1 (en) | 2014-10-06 | 2023-04-26 | Dana-Farber Cancer Institute, Inc. | Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response |
AU2015347015B2 (en) | 2014-11-14 | 2019-02-14 | Novartis Ag | Antibody drug conjugates |
WO2016100882A1 (en) | 2014-12-19 | 2016-06-23 | Novartis Ag | Combination therapies |
PE20171307A1 (es) | 2014-12-23 | 2017-09-05 | Novartis Ag | Compuestos de triazolopirimidina y usos de los mismos |
CA2974381A1 (en) | 2015-01-26 | 2016-08-04 | Fate Therapeutics, Inc. | Methods and compositions for inducing hematopoietic cell differentiation |
US10189813B2 (en) | 2015-03-25 | 2019-01-29 | Novartis Ag | Formylated N-heterocyclic derivatives as FGFR4 inhibitors |
MA41866A (fr) | 2015-03-31 | 2018-02-06 | Massachusetts Gen Hospital | Molécules à auto-assemblage pour l'administration ciblée de médicaments |
CN104906081A (zh) * | 2015-05-25 | 2015-09-16 | 上海中医药大学附属曙光医院 | 一种化合物在制备治疗骨关节炎药物中的应用 |
EP3310813A1 (en) | 2015-06-17 | 2018-04-25 | Novartis AG | Antibody drug conjugates |
US20190060309A1 (en) | 2015-08-28 | 2019-02-28 | Novartis Ag | Mdm2 inhibitors and combinations thereof |
AU2016338680B2 (en) | 2015-10-16 | 2022-11-17 | Fate Therapeutics, Inc. | Platform for the induction and maintenance of ground state pluripotency |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
WO2017078807A1 (en) | 2015-11-04 | 2017-05-11 | Fate Therapeutics, Inc. | Methods and compositions for inducing hematopoietic cell differentiation |
JP6928604B2 (ja) | 2015-11-04 | 2021-09-01 | フェイト セラピューティクス,インコーポレイテッド | 万能性細胞のゲノム改変 |
CN105646438A (zh) * | 2015-12-22 | 2016-06-08 | 天津大学 | 一种缩酮类糖醇基小分子凝胶因子及其制备方法和应用 |
CA3010236A1 (en) | 2016-01-20 | 2017-07-27 | Fate Therapeutics, Inc. | Compositions and methods for immune cell modulation in adoptive immunotherapies |
EP3405568A4 (en) | 2016-01-20 | 2019-12-04 | Fate Therapeutics, Inc. | COMPOUNDS AND METHODS FOR IMMUNOCELL MODULATION IN ADOPTIVE IMMUNOTHERAPIES |
US11883404B2 (en) | 2016-03-04 | 2024-01-30 | Taiho Pharmaceuticals Co., Ltd. | Preparation and composition for treatment of malignant tumors |
JP2019522049A (ja) | 2016-06-20 | 2019-08-08 | ノバルティス アーゲー | トリアゾロピリジン化合物及びその使用 |
JP2019524872A (ja) | 2016-06-20 | 2019-09-05 | ノバルティス アーゲー | 癌の治療に有用なイミダゾピリミジン化合物 |
EP3472168B1 (en) | 2016-06-20 | 2024-01-10 | Novartis AG | Crystalline forms of triazolopyrimidine compound |
AU2017291838B2 (en) | 2016-07-06 | 2021-01-28 | The Regents Of The University Of Michigan | Multifunctional inhibitors of MEK/PI3K and mTOR/MEK/PI3K biological pathways and therapeutic methods using the same |
WO2018092064A1 (en) | 2016-11-18 | 2018-05-24 | Novartis Ag | Combinations of mdm2 inhibitors and bcl-xl inhibitors |
US11932870B2 (en) | 2016-12-05 | 2024-03-19 | Fate Therapeutics, Inc. | Compositions and methods for immune cell modulation in adoptive immunotherapies |
JP7341060B2 (ja) | 2017-02-10 | 2023-09-08 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | Mapk経路の活性化に関連付けられる癌の処置のための方法及び医薬組成物 |
US11179413B2 (en) | 2017-03-06 | 2021-11-23 | Novartis Ag | Methods of treatment of cancer with reduced UBB expression |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
KR20240032157A (ko) | 2017-05-02 | 2024-03-08 | 노파르티스 아게 | 병용 요법 |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
AU2018274216A1 (en) | 2017-05-24 | 2019-12-12 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer |
US20200362058A1 (en) | 2017-05-24 | 2020-11-19 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use |
WO2018215937A1 (en) | 2017-05-24 | 2018-11-29 | Novartis Ag | Interleukin-7 antibody cytokine engrafted proteins and methods of use in the treatment of cancer |
TW201922291A (zh) | 2017-11-16 | 2019-06-16 | 瑞士商諾華公司 | 組合療法 |
KR102473372B1 (ko) | 2018-03-19 | 2022-12-05 | 다이호야쿠힌고교 가부시키가이샤 | 알킬황산나트륨을 포함하는 의약 조성물 |
US11013741B1 (en) | 2018-04-05 | 2021-05-25 | Sumitomo Dainippon Pharma Oncology, Inc. | AXL kinase inhibitors and use of the same |
MA52501A (fr) | 2018-05-04 | 2021-03-10 | Amgen Inc | Inhibiteurs de kras g12c et leurs procédés d'utilisation |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
CA3103385A1 (en) | 2018-07-10 | 2020-01-16 | Novartis Ag | 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases |
WO2020021465A1 (en) | 2018-07-25 | 2020-01-30 | Advanced Accelerator Applications (Italy) S.R.L. | Method of treatment of neuroendocrine tumors |
KR20240033296A (ko) | 2018-07-25 | 2024-03-12 | 어드밴스드 엑셀러레이터 어플리케이션즈 | 안정한 농축 방사성 핵종 복합체 용액 |
CN112512597A (zh) | 2018-07-26 | 2021-03-16 | 大日本住友制药肿瘤公司 | 用于治疗与acvr1表达异常相关的疾病的方法以及用于此的acvr1抑制剂 |
FI3837256T3 (fi) | 2018-08-17 | 2023-05-15 | Novartis Ag | Ureayhdisteitä ja koostumuksia smarca2/brm-atpaasiestäjinä |
CN112867512A (zh) | 2018-09-25 | 2021-05-28 | 意大利国际先进加速器应用有限公司 | 联合疗法 |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
CN113271945A (zh) | 2018-12-20 | 2021-08-17 | 诺华股份有限公司 | 包含3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物的给药方案和药物组合 |
KR20210146290A (ko) | 2019-02-12 | 2021-12-03 | 스미토모 다이니폰 파마 온콜로지, 인크. | 헤테로시클릭 단백질 키나제 억제제를 포함하는 제제 |
AU2020222346B2 (en) | 2019-02-15 | 2021-12-09 | Novartis Ag | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
MX2021009763A (es) | 2019-02-15 | 2021-09-08 | Novartis Ag | Derivados de 3-(1-oxo-5-(piperidin-4-il)isoindolin-2-il)piperidina -2,6-diona y usos de los mismos. |
US11712433B2 (en) | 2019-03-22 | 2023-08-01 | Sumitomo Pharma Oncology, Inc. | Compositions comprising PKM2 modulators and methods of treatment using the same |
US11236091B2 (en) | 2019-05-21 | 2022-02-01 | Amgen Inc. | Solid state forms |
CN114302878A (zh) | 2019-07-03 | 2022-04-08 | 大日本住友制药肿瘤公司 | 酪氨酸激酶非受体1(tnk1)抑制剂及其用途 |
WO2021043724A1 (en) | 2019-09-02 | 2021-03-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pyrvinium for the treatment of a ras pathway mutated acute myeloid leukemia |
KR20220116257A (ko) | 2019-12-20 | 2022-08-22 | 노파르티스 아게 | 골수섬유증 및 골수이형성 증후군을 치료하기 위한, 데시타빈 또는 항 pd-1 항체 스파르탈리주맙을 포함하거나 또는 포함하지 않는, 항 tim-3 항체 mbg453 및 항 tgf-베타 항체 nis793의 조합물 |
EP4134081A1 (en) | 2020-04-10 | 2023-02-15 | Taiho Pharmaceutical Co., Ltd. | Cancer therapy using 3,5-disubstituted benzene alkynyl compound and mek inhibitor |
AU2021288224A1 (en) | 2020-06-11 | 2023-01-05 | Novartis Ag | ZBTB32 inhibitors and uses thereof |
KR20230027056A (ko) | 2020-06-23 | 2023-02-27 | 노파르티스 아게 | 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 |
EP4188549A1 (en) | 2020-08-03 | 2023-06-07 | Novartis AG | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
AR123185A1 (es) | 2020-08-10 | 2022-11-09 | Novartis Ag | Compuestos y composiciones para inhibir ezh2 |
WO2022043557A1 (en) | 2020-08-31 | 2022-03-03 | Advanced Accelerator Applications International Sa | Method of treating psma-expressing cancers |
EP4204020A1 (en) | 2020-08-31 | 2023-07-05 | Advanced Accelerator Applications International S.A. | Method of treating psma-expressing cancers |
WO2022043556A1 (en) | 2020-08-31 | 2022-03-03 | Novartis Ag | Stable radiopharmaceutical composition |
TW202237119A (zh) | 2020-12-10 | 2022-10-01 | 美商住友製藥腫瘤公司 | Alk﹘5抑制劑和彼之用途 |
AU2022218128A1 (en) | 2021-02-02 | 2023-08-17 | Les Laboratoires Servier | Selective bcl-xl protac compounds and methods of use |
US11066358B1 (en) | 2021-02-17 | 2021-07-20 | Warner-Lambert Company Llc | Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof |
US11084780B1 (en) | 2021-02-17 | 2021-08-10 | Springworks Therapeutics, Inc. | Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof |
JP2024509759A (ja) | 2021-02-17 | 2024-03-05 | スプリングワークス、セラピューティクス、インコーポレイテッド | Mek阻害剤n-((r)-2,3-ジヒドロキシプロポキシ)-3,4-ジフルオロ-2-(2-フルオロ-4-ヨード-フェニルアミノ)-ベンズアミドの結晶性固体及びその使用 |
JP2024507822A (ja) | 2021-02-17 | 2024-02-21 | ワーナー-ランバート カンパニー リミテッド ライアビリティー カンパニー | N-((r)-2,3-ジヒドロキシプロポキシ)-3,4-ジフルオロ-2-(2-フルオロ-4-ヨードフェニルアミノ)-ベンズアミドの本質的に純粋な形態ivの組成物及びその使用 |
IL305079A (en) | 2021-02-17 | 2023-10-01 | Springworks Therapeutics Inc | Dispersible formulations of N-((R)-3,2-dihydroxypropoxy)-4,3-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and their uses |
US11571402B2 (en) | 2021-02-17 | 2023-02-07 | Springworks Therapeutics, Inc. | Dispersible formulations of N-((R)-2,3-dihydroxypropoly)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof |
WO2022195551A1 (en) | 2021-03-18 | 2022-09-22 | Novartis Ag | Biomarkers for cancer and methods of use thereof |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
TW202309022A (zh) | 2021-04-13 | 2023-03-01 | 美商努法倫特公司 | 用於治療具egfr突變之癌症之胺基取代雜環 |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
CN114524753B (zh) * | 2022-02-24 | 2024-03-26 | 安徽大学 | 一种多取代异羟肟酸衍生物的合成方法 |
TW202342018A (zh) | 2022-03-04 | 2023-11-01 | 美商奇奈特生物製藥公司 | Mek激酶抑制劑 |
WO2023178266A2 (en) | 2022-03-17 | 2023-09-21 | SpringWorks Therapeutics Inc. | Fluorinated phenylamino compounds and pharmaceutical compositions |
WO2023209611A1 (en) | 2022-04-26 | 2023-11-02 | Beigene Switzerland Gmbh | Methods of treating cancer with a b-raf inhibitor, in particular lifirafenib |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
WO2023223205A1 (en) | 2022-05-17 | 2023-11-23 | Teva Pharmaceuticals International Gmbh | Solid state forms of mirdametinib and process for preparation thereof |
WO2023225336A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Met bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
WO2023225320A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
WO2024023666A1 (en) | 2022-07-26 | 2024-02-01 | Novartis Ag | Crystalline forms of an akr1c3 dependent kars inhibitor |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4368207A (en) * | 1977-05-31 | 1983-01-11 | Block Drug Company Inc. | Higher alcohol toxicants effective against insects |
US5155110A (en) * | 1987-10-27 | 1992-10-13 | Warner-Lambert Company | Fenamic acid hydroxamate derivatives having cyclooxygenase and 5-lipoxygenase inhibition |
US5783202A (en) * | 1995-03-14 | 1998-07-21 | Soltec Research Pty. Ltd. | Pediculicidal mousse composition for killing head lice |
US6251943B1 (en) | 1997-02-28 | 2001-06-26 | Warner-Lambert Company | Method of treating or preventing septic shock by administering a MEK inhibitor |
PT993439E (pt) | 1997-07-01 | 2004-12-31 | Warner Lambert Co | Derivados de acido 4-bromo ou 4-iodofenilaminobenzidroxamico e sua utilizacao como inibidores de mek |
ES2274572T3 (es) | 1997-07-01 | 2007-05-16 | Warner-Lambert Company Llc | Derivados de acido 2-(4-bromo- o 4-yodo-fenilamino) benzoico y su uso como inhibidor de mek. |
EP1133467B1 (en) | 1998-12-04 | 2004-09-15 | Neurosearch A/S | Ion channel modulating agents |
JP2002532414A (ja) | 1998-12-15 | 2002-10-02 | ワーナー−ランバート・カンパニー | 移植片拒絶反応を防止するためのmek阻害剤の使用 |
JP2002532415A (ja) | 1998-12-16 | 2002-10-02 | ワーナー−ランバート・カンパニー | Mek阻害剤による関節炎の治療 |
NZ512859A (en) | 1998-12-22 | 2004-06-25 | Warner Lambert Co | Combination chemotherapy |
US6054493A (en) | 1998-12-30 | 2000-04-25 | The Lubrizol Corporation | Emulsion compositions |
JP2002534380A (ja) | 1999-01-07 | 2002-10-15 | ワーナー−ランバート・カンパニー | Mek阻害剤による喘息の治療 |
WO2000040237A1 (en) | 1999-01-07 | 2000-07-13 | Warner-Lambert Company | Antiviral method using mek inhibitors |
JP2001055376A (ja) | 1999-01-13 | 2001-02-27 | Warner Lambert Co | ジアリールアミン |
ES2247859T3 (es) | 1999-01-13 | 2006-03-01 | Warner-Lambert Company Llc | Benzoheterociclos y su uso como inhibidores de mek. |
CA2374052A1 (en) | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
AU2735201A (en) | 1999-12-28 | 2001-07-09 | Pharmacopeia, Inc. | Pyrimidine and triazine kinase inhibitors |
EE05450B1 (et) * | 2000-07-19 | 2011-08-15 | Warner-Lambert Company | 4-jodofenlaminobenshdroksaamhapete oksgeenitud estrid, nende kristallvormid ja farmatseutilised kompositsioonid ning kasutamine |
-
2001
- 2001-07-12 EE EEP200300030A patent/EE05450B1/xx unknown
- 2001-07-12 KR KR1020037000810A patent/KR100773621B1/ko active IP Right Grant
- 2001-07-12 GE GE5067A patent/GEP20053496B/en unknown
- 2001-07-12 JP JP2002512119A patent/JP3811775B2/ja not_active Expired - Lifetime
- 2001-07-12 AU AU7349801A patent/AU7349801A/xx active Pending
- 2001-07-12 OA OA1200300002A patent/OA12333A/en unknown
- 2001-07-12 AU AU2001273498A patent/AU2001273498B2/en not_active Expired
- 2001-07-12 PL PL365775A patent/PL203387B1/pl unknown
- 2001-07-12 CZ CZ20030069A patent/CZ303815B6/cs not_active IP Right Cessation
- 2001-07-12 WO PCT/US2001/022331 patent/WO2002006213A2/en active IP Right Grant
- 2001-07-12 EA EA200300065A patent/EA005818B1/ru not_active IP Right Cessation
- 2001-07-12 EP EP01952778.7A patent/EP1301472B1/en not_active Expired - Lifetime
- 2001-07-12 AP APAP/P/2003/002742A patent/AP2003002742A0/en unknown
- 2001-07-12 CA CA002416685A patent/CA2416685C/en not_active Expired - Lifetime
- 2001-07-12 YU YU2503A patent/YU2503A/sh unknown
- 2001-07-12 DK DK01952778.7T patent/DK1301472T3/da active
- 2001-07-12 IL IL15381701A patent/IL153817A0/xx unknown
- 2001-07-12 HU HU0302781A patent/HU230251B1/hu unknown
- 2001-07-12 US US10/333,399 patent/US6960614B2/en not_active Expired - Lifetime
- 2001-07-12 PT PT1952778T patent/PT1301472E/pt unknown
- 2001-07-12 SK SK42-2003A patent/SK288317B6/sk not_active IP Right Cessation
- 2001-07-12 ES ES01952778.7T patent/ES2461854T3/es not_active Expired - Lifetime
- 2001-07-12 CN CNB018140599A patent/CN1219753C/zh not_active Expired - Lifetime
- 2001-07-12 NZ NZ524120A patent/NZ524120A/en not_active IP Right Cessation
- 2001-07-12 AP APAP/P/2001/002217A patent/AP2001002217A0/en unknown
- 2001-07-12 DZ DZ013401A patent/DZ3401A1/fr active
- 2001-07-12 BR BR0112584-2 patent/BRPI0112584B8/pt not_active IP Right Cessation
- 2001-07-12 SI SI200131033T patent/SI1301472T1/sl unknown
- 2001-07-17 TN TNTNSN01108A patent/TNSN01108A1/en unknown
- 2001-07-17 MY MYPI20013387 patent/MY151458A/en unknown
- 2001-07-17 AR ARP010103402A patent/AR033542A1/es active IP Right Grant
- 2001-07-18 GT GT200100141A patent/GT200100141A/es unknown
- 2001-07-18 PE PE2001000725A patent/PE20020664A1/es not_active Application Discontinuation
- 2001-07-18 PA PA20018522601A patent/PA8522601A1/es unknown
- 2001-07-18 SV SV2001000563A patent/SV2002000563A/es not_active Application Discontinuation
- 2001-07-19 TW TW090117693A patent/TWI311551B/zh not_active IP Right Cessation
- 2001-12-07 UA UA2003021455A patent/UA76425C2/uk unknown
-
2002
- 2002-12-31 IS IS6666A patent/IS6666A/is unknown
-
2003
- 2003-01-14 EC EC2003004430A patent/ECSP034430A/es unknown
- 2003-01-15 MA MA26999A patent/MA26930A1/fr unknown
- 2003-01-17 NO NO20030249A patent/NO328436B1/no not_active IP Right Cessation
- 2003-02-06 HR HR20030083A patent/HRP20030083A2/hr not_active Application Discontinuation
- 2003-02-17 BG BG107564A patent/BG66386B1/bg unknown
- 2003-05-13 ZA ZA200300348A patent/ZA200300348B/en unknown
- 2003-11-13 HK HK03108249A patent/HK1055943A1/xx not_active IP Right Cessation
-
2005
- 2005-04-07 US US11/102,307 patent/US7411001B2/en active Active
-
2014
- 2014-08-25 AR ARP140103181A patent/AR097445A2/es unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104788365A (zh) * | 2014-01-16 | 2015-07-22 | 上海艾力斯医药科技有限公司 | 异烟酰胺衍生物、其制备方法及应用 |
CN104788365B (zh) * | 2014-01-16 | 2018-08-10 | 上海艾力斯医药科技有限公司 | 异烟酰胺衍生物、其制备方法及应用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1219753C (zh) | 4-碘苯氨基苯氧肟酸的氧合酯 | |
CN1161331C (zh) | 肼衍生物 | |
CN1273444C (zh) | 二肽腈 | |
CN1178927C (zh) | 组胺h3受体配体 | |
CN1166658C (zh) | 作为环加氧酶-2-抑制剂的4,5二芳基-3(2h)-呋喃酮衍生物 | |
CN1196671C (zh) | 单和双取代的3-丙基-γ-氨基丁酸 | |
CN1852891A (zh) | 具有高镇痛活性的香草素拮抗剂4-(甲磺酰基氨基)苯基类似物及含此类似物的药用组合物 | |
CN1515548A (zh) | 用作甲状腺受体配体的草氨酸及衍生物 | |
CN1348442A (zh) | 新的磺胺化合物及其应用 | |
CN1900067A (zh) | 三环化合物及其制备和用途 | |
CN1094052A (zh) | 含杂环碳酸衍生物 | |
CN101031541A (zh) | 4-氨基甲基苄脒衍生物及其作为因子Ⅷa抑制剂的用途 | |
CN1910144A (zh) | 用于疾病治疗的磺胺衍生物 | |
CN1171394A (zh) | 新的脲衍生物及其制法和医药用途 | |
CN1438991A (zh) | 作为中性内肽酶的抑制剂的环戊基-取代的戊二酰胺衍生物 | |
CN1680338A (zh) | 抑制细胞附着的抗炎和免疫抑制的化合物 | |
CN1942432A (zh) | 作为β-2-激动剂的苯乙醇胺衍生物 | |
CN1348441A (zh) | N-取代的芳基磺酰基氨基异羟肟酸 | |
CN1093082A (zh) | N,n-双取代芳基环烷基胺及其盐,含有该化合物的药物组合物及其应用以及其制备方法 | |
CN1805915A (zh) | 作为药物活性剂的茚衍生物 | |
CN1060466A (zh) | 苯、吡啶和嘧啶的衍生物 | |
CN1098404A (zh) | 用作治疗爱滋病的人免疫缺陷病毒蛋白酶抑制剂 | |
CN1088199A (zh) | N-取代的苯胺 | |
CN1310709A (zh) | N,n-取代环胺衍生物 | |
CN1056602C (zh) | 用作磷脂酶a2抑制剂的酯类和酰胺类化合物 |
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 | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20050921 |