CN116265453A - 作为ar抑制剂的化合物及其应用 - Google Patents
作为ar抑制剂的化合物及其应用 Download PDFInfo
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- CN116265453A CN116265453A CN202111549319.6A CN202111549319A CN116265453A CN 116265453 A CN116265453 A CN 116265453A CN 202111549319 A CN202111549319 A CN 202111549319A CN 116265453 A CN116265453 A CN 116265453A
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- China
- Prior art keywords
- alkyl
- hydroxy
- alkoxy
- pharmaceutically acceptable
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 119
- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 239000000651 prodrug Substances 0.000 claims abstract description 37
- 229940002612 prodrug Drugs 0.000 claims abstract description 37
- 239000012453 solvate Substances 0.000 claims abstract description 37
- 239000013078 crystal Substances 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- -1 alkylamido Chemical group 0.000 claims description 103
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 9
- 239000011574 phosphorus Substances 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000004973 liquid crystal related substance Substances 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 235000013311 vegetables Nutrition 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims 5
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 238000002360 preparation method Methods 0.000 abstract description 63
- 239000000203 mixture Substances 0.000 abstract description 26
- 238000006243 chemical reaction Methods 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 44
- 102100032187 Androgen receptor Human genes 0.000 description 32
- 108010080146 androgen receptors Proteins 0.000 description 31
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 238000005406 washing Methods 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 13
- 239000002609 medium Substances 0.000 description 13
- 125000006012 2-chloroethoxy group Chemical group 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- CUSQXAPAQNXLMS-UHFFFAOYSA-N 3-methylsulfonylazetidine Chemical compound CS(=O)(=O)C1CNC1 CUSQXAPAQNXLMS-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 206010060862 Prostate cancer Diseases 0.000 description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- AVRSCASDNQJKGR-UHFFFAOYSA-N 3-chloro-2-(2-chloroethoxy)-5-[2-(4-hydroxyphenyl)propan-2-yl]benzonitrile Chemical compound ClC=1C(=C(C#N)C=C(C=1)C(C)(C)C1=CC=C(C=C1)O)OCCCl AVRSCASDNQJKGR-UHFFFAOYSA-N 0.000 description 5
- 239000003098 androgen Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 4
- ABXBBEBCOITZEX-UHFFFAOYSA-N 2-methylsulfonylethyl methanesulfonate Chemical compound CS(=O)(=O)CCOS(C)(=O)=O ABXBBEBCOITZEX-UHFFFAOYSA-N 0.000 description 4
- NWWNAYPTNGTTOU-UHFFFAOYSA-N 3-chloro-2-(2-chloroethoxy)-5-[2-[4-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propan-2-yl]benzonitrile Chemical compound ClC=1C(=C(C#N)C=C(C=1)C(C)(C)C1=CC=C(C=C1)OCC1=NC(=NC=C1)Cl)OCCCl NWWNAYPTNGTTOU-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 108020001756 ligand binding domains Proteins 0.000 description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- JTHZCTTVKRVCDZ-UHFFFAOYSA-N 4-[2-[3,5-dichloro-4-(2-chloroethoxy)phenyl]propan-2-yl]phenol Chemical compound ClC=1C=C(C=C(C=1OCCCl)Cl)C(C)(C)C1=CC=C(C=C1)O JTHZCTTVKRVCDZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 3
- 229960000853 abiraterone Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960004671 enzalutamide Drugs 0.000 description 3
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UYDYZODXUHSBIB-SNVBAGLBSA-N (4R)-4-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]-1,3-oxazolidin-2-one Chemical compound OC[C@H]1N(C(OC1)=O)CC1=CC=C(C=C1)OC UYDYZODXUHSBIB-SNVBAGLBSA-N 0.000 description 2
- FNZXXGGFJFIORC-GSVOUGTGSA-N (4S)-4-(fluoromethyl)-1,3-oxazolidin-2-one Chemical compound FC[C@H]1NC(OC1)=O FNZXXGGFJFIORC-GSVOUGTGSA-N 0.000 description 2
- MLEAOLLWGBVUDJ-SNVBAGLBSA-N (4S)-4-(fluoromethyl)-3-[(4-methoxyphenyl)methyl]-1,3-oxazolidin-2-one Chemical compound FC[C@H]1N(C(OC1)=O)CC1=CC=C(C=C1)OC MLEAOLLWGBVUDJ-SNVBAGLBSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 2
- HNHVCSCFJSKSQK-UHFFFAOYSA-N 2-chloro-4-(chloromethyl)pyrimidine Chemical compound ClCC1=CC=NC(Cl)=N1 HNHVCSCFJSKSQK-UHFFFAOYSA-N 0.000 description 2
- NPWRCDBZSNWPLR-UHFFFAOYSA-N 2-chloro-4-[[4-[2-[3,5-dichloro-4-(2-chloroethoxy)phenyl]propan-2-yl]phenoxy]methyl]pyrimidine Chemical compound ClC1=NC=CC(=N1)COC1=CC=C(C=C1)C(C)(C)C1=CC(=C(C(=C1)Cl)OCCCl)Cl NPWRCDBZSNWPLR-UHFFFAOYSA-N 0.000 description 2
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CSOZENNOLPWYJD-UHFFFAOYSA-N CC(C)(C(C=C1Cl)=CC(C#N)=C1OCCCl)O Chemical compound CC(C)(C(C=C1Cl)=CC(C#N)=C1OCCCl)O CSOZENNOLPWYJD-UHFFFAOYSA-N 0.000 description 2
- AZOSXUXVQBBKBC-UHFFFAOYSA-N COC(C(C=C1C#N)=CC(Cl)=C1OCCCl)=O Chemical compound COC(C(C=C1C#N)=CC(Cl)=C1OCCCl)=O AZOSXUXVQBBKBC-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 101000746263 Conus leopardus Conotoxin Lp5.1 Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
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- 239000005557 antagonist Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005138 cryopreservation Methods 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
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- 210000004211 gastric acid Anatomy 0.000 description 2
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- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- YMGQPFUVBBSGQQ-UHFFFAOYSA-N methyl 3-chloro-4-hydroxy-5-iodobenzoate Chemical compound COC(=O)C1=CC(Cl)=C(O)C(I)=C1 YMGQPFUVBBSGQQ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 2
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- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
本发明属于医药化学领域,涉及一类作为AR抑制剂的化合物及其应用,具体地,本发明提供式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗AR介导的疾病的用途。
Description
技术领域
本发明属于医药化学领域,具体涉及作为AR抑制剂的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗AR介导的疾病的用途。
背景技术
雄激素剥夺疗法(ADT)一直是***癌治疗的主要手段。虽然ADT能够延缓***癌的进展,但随着产生去势抵抗性***癌(CRPC),这种治疗方式最终会变得无效。在过去几年中,随着阿比特龙和恩杂鲁胺等新一代激素类药物的问世,对CRPC的治疗有了更新的选择。然而,绝大多数CRPC患者表现出对这些药物的原发耐药性(对治疗无反应的患者)或获得性耐药(最初对治疗有反应但随后复发的患者)。接受阿比特龙或恩杂鲁胺治疗的患者中约有四分之一对这些药物表现出耐药性。此外,几乎所有的CRPC患者,包括最初从激素治疗中受益的那部分患者,都会发生获得性耐药。***癌进行去势治疗(GnRH激动剂或拮抗剂以及前期的AR拮抗剂一线药物)后,疾病会对该治疗敏感一段时间,随后产生耐药。之后使用新一代的AR抑制剂剂(如Enzalutamide,Abiraterone),又产生良好的治疗效果,但作用一段时间后,也出现耐药。
雄激素受体(AR)属于核受体超家族,该超家族成员众多,但在脊椎动物中只存在5种,即***受体,***受体,雄激素受体,糖皮质激素受体和盐皮质激素受体。AR包含919个氨基酸,位于人类染色体(q11-12)DNA序列编码。雄激素受体(AR)包含以下主要三个部分:雄激素非依赖型N末端结构域(NTD),DNA-结合结构域(DBD)和雄激素依赖型配体结合结构域(LBD)。如***和二氢***等雄激素与AR LBD结合,导致构象变化和翻译后修饰,二聚化,核易位,并最终与靶基因DNA的调节区(雄激素反应元件)结合。
相比于现有AR抑制剂疗法均依赖于对LBD区域的结合,AR-NTD也是药物研发的方向。NTD区域保留了AR转录活性的关键区域,其具有内在激活功能区域(Activationfunction-1,AF-1),对AR激活至关重要,并且该区域的缺失将导致AR转录活性的失活。AF-1包含两个转录激活单元(Transcription activation unit,Tau)Tau-1和Tau-5。其中Tau-1主要是负责wtAR的反式激活能力,而Tau-5组成型活化AR的反式激活能力。AR-NTD对雄激素不存在下激活AR起到重要的作用。
AR抑制剂在***等相关疾病方面有着明确的机制,有很大潜力可以成为肿瘤治疗领域新的治疗手段,因此,需要开发更有效的AR抑制剂以满足临床需求。
发明内容
本发明的一个目的是提供通式(I)所示的一类具有AR抑制活性的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,
其中,
R1和R2各自独立地选自氢、烷基、羟基、卤素、氰基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基和硝基;
R3选自其中环A选自芳基和杂芳基;R4选自烷基磷氧基和3-10元杂环;所述的3-10元杂环可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、烷基磷氧基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基和氧代基团的基团取代;环B为4-7元含氮杂芳环,R5选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、烷基磷氧基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基和氧代基团的基团取代。
本发明的另一个目的是提供制备本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药的方法。
本发明的再一个目的是提供包含本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体的组合物,以及包含本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和另一种或多种药物的组合物。
本发明的还一个目的是提供本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药治疗AR介导的疾病的方法,以及本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药在制备用于治疗AR介导的疾病的药物中的应用。
针对上述发明目的,本发明提供以下技术方案:
第一方面,本发明提供通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,
其中,
R1和R2各自独立地选自烷基、羟基、卤素、氰基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基和硝基;优选地,R1和R2各自独立地选自C1-6烷基、羟基、卤素、氰基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、羧基和硝基;
R3选自其中环A选自芳基和杂芳基;R4选自烷基磷氧基和3-10元杂环;所述的3-10元杂环可被一个或多个选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、烷基磷氧基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基和氧代基团的基团取代;环B为4-7元含氮杂芳环,R5选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、烷基磷氧基、烷基酰基、烷基磺酰基、氨基酰基、烷基氨基酰基和氧代基团的基团取代。
在一些优选的实施方案中,本发明的化合物为通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中:
R3为环A选自C6-12芳基、5-12元杂芳基,R4选自烷基磷氧基和3-10元杂环,所述的3-10元杂环可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代;
进一步优选地,环A选自苯基、嘧啶基、吡啶基、吡嗪基、呋喃基、噻吩基、吡唑基、咪唑基和噁唑基,R4选自烷基磷氧基和3-10元杂环;所述的3-10元杂环可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代;
更进一步优选地,环A选自苯基、嘧啶基、吡啶基、吡嗪基、呋喃基、噻吩基、吡唑基、咪唑基和噁唑基,R4选自 R6选自素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代,n为0、1、2或3。
在一些实施方案中,根据本发明的通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中R1和R2各自独立地选自氢、甲基、卤素、氰基、-CF3和–CONH2。
在一些实施方案中,本发明提供通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中通式(I)具有以下通式(Ia)的结构,
其中,R1、R2和R4具有以上通式(I)所述的定义。
在一些实施方案中,根据本发明的式(Ia)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中:
R4选自 R6选自素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代,n为0、1、2或3。
在一些实施方案中,根据本发明的式(Ia)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中:
在一些优选的实施方案中,本发明的化合物为通式(I)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中:
R3为其中环B为4-7元含氮杂芳环,R5选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代;
进一步优选地,选自/>R5选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代。
本发明提供以下具体化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药:
另一方面,本发明提供本发明的通式(I)的化合物的制备方法,包括使式1的化合物通过一系列反应制得式(I)的步骤:
其中,R1、R2、R3具有通式(I)所述的定义,X选自卤素、羟基,式1的化合物和市售化合物或可采用本领域技术人员惯用的其它技术手段进行合成。
第三方面,本发明提供药物组合物,其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药。
在一些实施方案中,本发明提供本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药及包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药的药物组合物,所述化合物或药物组合物用于治疗AR介导的疾病。
在一些实施方案中,本发明提供药物组合物,其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。
可以将本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药与可药用载体、稀释剂或赋形剂混合制备成药物制剂,以适合于经口或胃肠外给药。给药方法包括,但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用,例如通过输注或推注,通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型,具体而言,包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备,且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面,本发明提供本发明式(I)、(Ia)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,或包含其的药物组合物用于治疗AR介导的疾病的方法以及在制备治疗AR介导的疾病的药物中的用途。
在一些优选的实施方案中,本发明提供本发明式(I)、(Ia)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,或包含其的药物组合物用于治疗AR介导的疾病的方法以及在制备治疗AR介导的疾病的药物中的用途,其中所述的AR介导的疾病包括但不限于:***癌、乳腺癌、卵巢癌、膀胱癌、胰腺癌、肝细胞癌、子宫内膜癌、唾液腺癌、脱发、痤疮、多毛症、***、多囊卵巢疾病、性早熟、脊髓和延髓肌肉萎缩(例如,肯尼迪氏病)和年龄相关性黄斑变性。
在一些实施方案中,本发明所述的AR介导的疾病为***癌,所述***癌可以是去势抵抗性***癌。
术语定义
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说,氢的同位素包括氕、氚和氘,碳的同位素包括12C、13C和14C,氧的同位素包括16O和18O等。
本发明的“异构体”是指原子组成及连接方式相同,而其三维空间排列不同的分子,包括但不限于非对映体,对映异构体,顺反异构体,和它们的混合物,如外消旋混合物。很多有机化合物都以光学活性形式存在,即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时,前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀D、L或(+)、(-)用来命名化合物平面偏振光旋转的符号,(-)或L是指化合物是左旋的,前缀(+)或D是指化合物是右旋的。这些立体异构体的化学结构是相同的,但其立体结构不一样。特定的立体异构体可以是对映体,异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体,这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物,缺乏光学活性。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
本发明的“卤素”是指氟、氯、溴、碘。本发明的“卤代”是指被氟、氯、溴或碘取代。
本发明的“烷基”指直链或支链的饱和脂肪烃基团,优选含1至6个碳原子的直链或支链基团,进一步优选含有1至3个碳原子的直链或支链基团,非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上。
本发明的“羰基”、“酰基”均指-C(O)-。
本发明的“磺酰基”是指-S(O)2-。
本发明的“磺酰胺基”是指-S(O)2NH-。
本发明的“卤代烷基”是指至少被一个卤素取代的烷基。
本发明的“羟基烷基”是指至少被一个羟基取代的烷基。
本发明的“Ms-”是指甲基磺酰基。
本发明的“烷氧基”是指-O-烷基。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、正丙氧基、异丙氧基、异丁氧基、仲丁氧基等。烷氧基可以是任选取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上。
本发明的“芳基”是指可以包含单环或稠合多环的芳香体系,优选包含单环或稠合双环的芳香体系,其含有6个至12个碳原子,优选含有约6至约10个碳原子。合适的芳基包括但不限于苯基、萘基、蒽基、芴基、茚满基。芳基可以是任选取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上。
本发明的“杂芳基”是指至少有一个碳原子被杂原子替代的芳基,优选由5-12个原子构成(5-12元杂芳基),进一步优选由5-10个原子组成(5-10元杂芳基),所述的杂原子为O、S、N。所述杂芳基包括但不限于咪唑基、吡咯基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、***基、四唑基、吲哚基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、异吲哚基、苯并吡唑基、苯并咪唑基、苯并呋喃基、苯并吡喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并异噁唑基、苯并异噻唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、喹喔啉基、苯并噁嗪基、苯并噻嗪基、咪唑并吡啶基、嘧啶并吡唑基、嘧啶并咪唑基等。杂芳基可以是任选取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上。
本发明的“药学上可接受的盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
本发明的“溶剂化物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水,则溶剂化物通常被称作水合物,例如半水合物、一水合物、二水合物、三水合物或其替代量等。
具有化学式(I)、(Ia)的化合物的体内作用可以部分地由在给予具有化学式(I)、(Ia)的化合物之后在人体或动物体内形成的一种或多种代谢物来发挥。如上所述,具有化学式(I)、(Ia)的化合物的体内作用也可以经由前体化合物(“前药”)代谢来发挥。本发明的“前药”是指在生物体中的生理条件下,由于与酶、胃酸等反应而转化成本发明化合物的化合物,即通过酶的氧化、还原、水解等转化成本发明化合物的化合物和/或通过胃酸等的水解反应等转化成本发明化合物的化合物等。
本发明的“结晶”是指其内部结构是在三维上规律地重复构成原子(或其集团)而形成的固体,有别于不具有这种规律的内部结构的无定形固体。
本发明的“药物组合物”是指包含任何一种本发明所述的化合物,包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式,和一种或多种可药用载体和/或另一种或多种药物的混合物。药用组合物的目的是促进化合物对生物体的给药。所述组合物通常用于制备治疗和/或预防由一种或多种激酶介导的疾病的药物。
本发明的“可药用载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体,包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括,但不限于糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、以及纤维素和乙酸纤维素;麦芽、明胶等。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
具体实施方式
下面结合实施例对本发明作进一步详细阐述,但本发明不限于这些实施例。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲磺酰基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:3-氯-4-羟基-5-碘苯甲酸甲酯的制备
将3-氯-4-羟基苯甲酸甲酯(30g,160mmol)溶于300mL二氯甲烷中,氩气保护下,0℃下加入N-碘代丁二酰亚胺(36g,160mmol),室温反应16小时。反应完全后,200mL二氯甲烷萃取,合并有机相水洗,饱和食盐水洗一遍,无水硫酸钠干燥有机相,减压浓缩得标题化合物。ESI-MS m/z:312.9[M+H]+。
步骤2:3-氯-4-(2-氯乙氧基)-5-碘苯甲酸甲酯的制备
将3-氯-4-羟基-5-碘苯甲酸甲酯(38g,121.6mmol)溶于380ml N,N-二甲基甲酰胺中,加入碳酸铯(79.2g,243.2mmol)和1-溴-2-氯乙烷(19.1g,133.8mmol),70℃下反应过夜。反应完全后,滤除不溶固体,220mL乙酸乙酯萃取,水洗有机相,饱和食盐水洗,无水硫酸钠干燥有机相,减压浓缩,柱层析,得标题化合物,白色固体。ESI-MS m/z:375.0[M+H]+。
步骤3:3-氯-4-(2-氯乙氧基)-5-氰基苯甲酸甲酯的制备
将3-氯-4-(2-氯乙氧基)-5-碘苯甲酸甲酯(6.3g,16.8mmol)溶于35mL N-甲基吡咯烷酮中,加入氰化亚铜(1.79g,20.0mmol),氩气保护,160℃反应3小时。反应完全后,滤除不溶固体,100mL乙酸乙酯萃取,水洗有机相,饱和食盐水洗,无水硫酸钠干燥有机相,减压浓缩,柱层析,得标题化合物。ESI-MS m/z:274.3[M+H]+。
步骤4:3-氯-2-(2-氯乙氧基)-5-(2-羟基丙烷-2-基)苯甲腈的制备
将3-氯-4-(2-氯乙氧基)-5-氰基苯甲酸甲酯(2.9g,10.6mmol),溶于30mL四氢呋喃中,0℃下滴加甲基溴化镁(3M,14mL,52mmol),氩气保护,常温反应3小时。反应完全后,氯化铵水溶液淬灭,100mL乙酸乙酯萃取,水洗有机相,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:274.3[M+H]+。
步骤5:3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-羟基丙烷-2-基)苯甲腈(1.2g,4.4mmol)溶于20mL四氯化碳中,加入苯酚(0.46g,5.3mmol),0℃下滴加三氟化硼***(1.3g,8.8mmol),氩气保护,0℃下反应1小时,反应完全后,80mL二氯甲烷萃取两遍,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:350.1[M+H]+。
步骤6:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈(0.1g,0.29mmol)和碳酸铯(0.19g,0.57mmol)溶于10mL N,N-二甲基甲酰胺中,加入2-氯-4-(氯甲基)嘧啶(55.9mg,0.35mmol),氩气保护,常温反应16小时。反应完全后,100mL乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:476.1[M+H]+。
步骤7:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲磺酰基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(142.0mg,0.3mmol)和3-(甲磺酰基)氮杂环丁胺(51.5mg,0.3mmol)溶于15mL乙醇中,加入三乙胺(121.4mg,1.2mmol),氩气保护,100℃下反应6小时。反应完全后,60mL乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:575.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.41(d,J=4.5Hz,1H),7.63(s,1H),7.57(s,1H),7.18(d,J=8.3Hz,2H),6.95(d,J=8.3Hz,2H),6.85(d,J=4.4Hz,1H),5.01(s,2H),4.41(s,3H),4.34(t,J=8.6Hz,2H),4.28–4.15(m,2H),3.95(s,2H),3.06(s,3H),1.63(s,6H).
实施例2:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为3-(三氟甲基)氮杂环丁醇盐酸盐,得标题产物。ESI-MS m/z:581.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.41(d,J=4.9Hz,1H),7.62(s,1H),7.57(s,1H),7.38(s,1H),7.18(d,J=8.5Hz,2H),6.95(d,J=8.5Hz,2H),6.86(d,J=4.8Hz,1H),5.02(s,2H),4.46–4.36(m,2H),4.27(d,J=10.1Hz,2H),4.06(d,J=10.1Hz,2H),3.99–3.89(m,2H),1.63(s,6H).
实施例3:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(二甲基磷酰基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将实施例1步骤6产物3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(60mg,0.13mmol)和二甲基氧化膦(39.3mg,0.51mmol),三乙胺(21mg,0.21mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(14mg,0.03mmol),三(二亚苄基丙酮)二钯(12mg,0.013mmol)溶于10mL二氧六环中,氩气保护,90℃下反应6小时。反应完全后,60mL乙酸乙酯,水洗,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物,白色固体粉末。ESI-MS m/z:518.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.99(d,J=5.1Hz,1H),7.71(s,1H),7.63(d,J=1.6Hz,1H),7.57(s,1H),7.20(d,J=8.6Hz,2H),7.00(d,J=8.6Hz,2H),5.28(s,2H),4.44–4.38(m,2H),3.98–3.91(m,2H),1.77(s,3H),1.74(s,3H),1.63(s,6H).
实施例4:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(4-(甲基磺酰基)哌啶-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为4-甲磺酰基-哌啶,得标题化合物。ESI-MS m/z:603.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.38(d,J=4.6Hz,1H),7.63(s,1H),7.57(s,1H),7.18(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),6.72(d,J=4.5Hz,1H),5.00(s,2H),4.41(d,J=4.6Hz,2H),4.04–3.88(m,2H),2.93(d,J=16.3Hz,5H),2.09(d,J=12.0Hz,2H),2.04–1.91(m,1H),1.63(s,6H),1.51(dd,J=21.8,11.8Hz,4H).
实施例5:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(1,1-二氧化硫代吗啉)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将3-氯-2-2-氯乙氧基-5-2-(4-(2-氯嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(50mg,0.105mmol)和硫吗啉1,1-二氧化物(42.5mg,0.32mmol),碳酸铯(68.4mg,0.21mmol),双二苯基膦-9,9-二甲基氧杂蒽(6mg,0.011mmol),三(二亚苄基丙酮)二钯(9mg,0.011mmol)溶于10mL二氧六环中,氩气保护,90℃下反应6小时。反应完全后,60mL乙酸乙酯萃取两遍,水洗两遍,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物,白色固体粉末。ESI-MS m/z:575.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.45(d,J=4.9Hz,1H),7.63(d,J=1.7Hz,1H),7.57(s,1H),7.18(d,J=8.6Hz,2H),6.95(d,J=8.7Hz,2H),6.84(d,J=4.8Hz,1H),5.03(s,2H),4.47–4.37(m,2H),4.21(s,4H),4.00–3.91(m,2H),3.15(s,4H),1.63(s,6H).
实施例6:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基))丙-2-基)苯甲腈的制备
步骤1:2-(甲基磺酰基)乙基甲磺酸盐的合成
将2-(甲基磺酰基)乙-1-醇(1g,8.1mmol)加入到二氯甲烷中(25mL),加入N,N-二异丙基乙胺(1.56g,12.1mmol)。在冰水下滴加甲磺酰氯(0.97g,8.5mmol),反应过夜。萃取,浓缩得到标题化合物,直接用于下步反应。
步骤2:3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-羧酸叔丁酯的合成
将60%的钠氢(0.12g,3.0mmol)加入到无水N,N-二甲基甲酰胺(15ml)中,0℃下加入3-羟基氮杂环丁烷-1-羧酸叔丁酯(0.4g,2.3mmol),搅拌30min,再加入2-(甲基磺酰基)乙基甲磺酸盐(0.5g,2.5mmol),室温下过夜。反应完毕后。将反应液倒入冰水中,乙酸乙酯萃取,分液,合并有机相,无水硫酸钠干燥,抽滤,滤液浓缩,柱层析纯化,得到标题化合物。ESI-MS m/z:280.1[M+H]+。
步骤3:3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷盐酸盐
将3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-羧酸叔丁酯(0.2g,0.93mmol)加入到二氯甲烷(5ml)中,加入盐酸-二氧六环(1mL,4M),室温下搅拌2小时,TLC显示反应完毕。浓缩,得到标题化合物。ESI-MS m/z:180.1[M+H]+。
步骤4:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基))丙-2-基)苄甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷盐酸盐,得标题化合物。ESI-MS m/z:619.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.35(d,J=4.9Hz,1H),7.63(s,1H),7.57(s,1H),7.18(d,J=8.6Hz,2H),6.94(d,J=8.6Hz,2H),6.77(d,J=4.8Hz,1H),4.98(s,2H),4.47(s,1H),4.43–4.38(m,2H),4.30–4.21(m,2H),3.99–3.93(m,2H),3.89(dd,J=9.4,2.7Hz,2H),3.78(t,J=5.5Hz,2H),3.43(t,J=5.3Hz,2H),3.01(s,3H),1.63(s,6H).
实施例7:(S)-3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(4-(氟甲基)-2-氧恶唑烷-3-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:(R)-4-(羟甲基)-3-(4-甲氧基苄基)恶唑烷-2-酮的制备
将4-甲氧苄基异氰酸酯(1.36g,18.4mmol)加入到二氯甲烷中(25mL),加入(R)-缩水甘油(3g,18.4mmol)。再加入三乙胺(3.35g,33.1mmol),40℃下反应过夜。LC-MS跟踪监测反应,反应完毕后,二氯甲烷萃取,分液,合并有机相,用无水硫酸钠干燥,抽滤,滤液浓缩,柱层析纯化,得到标题化合物。ESI-MS m/z:238.1[M+H]+。
步骤2:(S)-4-(氟甲基)-3-(4-甲氧基苄基)恶唑烷-2-酮的制备
将(R)-4-(羟甲基)-3-(4-甲氧基苄基)恶唑烷-2-酮(0.43g,1.8mmol)加入到二氯甲烷中(10mL),在冰水下加入二乙胺基三氟化硫(0.58g,3.6mmol)。常温下反应3小时。LC-MS显示反应完全,将反应液倒入冰水中,二氯甲烷萃取,分液,合并有机相,用无水硫酸钠干燥,抽滤,滤液浓缩,柱层析纯化,得到标题化合物。ESI-MS m/z:240.1[M+H]+。
步骤3:(S)-4-(氟甲基)恶唑烷-2-酮的制备
将(S)-4-(氟甲基)-3-(4-甲氧基苄基)恶唑烷-2-酮(0.23g,0.96mmol)加入到三氟乙酸中(5mL),65℃下加热反应过夜。反应完全后,浓缩得标题化合物。ESI-MS m/z:120.1[M+H]+。
步骤4:(S)-3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(4-(氟甲基)-2-氧恶唑烷-3-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
制备方法同实施例5的制备方法,不同的是将硫吗啉1,1-二氧化物替换为(S)-4-(氟甲基)-恶唑烷-2-酮,得标题产物。ESI-MS m/z:559.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.75(d,J=5.0Hz,1H),7.64(s,1H),7.57(s,1H),7.34(d,J=4.9Hz,1H),7.19(d,J=8.5Hz,2H),6.98(d,J=8.6Hz,2H),5.18(s,2H),4.44(d,J=4.8Hz,2H),4.42–4.39(m,2H),4.12–4.08(m,2H),4.04–3.99(m,1H),3.98–3.92(m,2H),1.63(s,6H).
实施例8:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-((2-(甲基磺酰基)乙基)氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-羟基氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为3-羟基氮杂环丁烷,得标题产物。ESI-MS m/z:513.2[M+H]+。
步骤2:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-氧杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-羟基氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(0.12g,0.24mmol),加入戴斯-马丁氧化剂(148.9mg,0.35mmol),碳酸氢钠(29.5mg,0.35mmol),加入30mL二氯甲烷,常温下过夜。反应完全后,过滤,浓缩,柱层析,得标题化合物。ESI-MS m/z:511.2[M+H]+。
步骤3:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-((2-(甲基磺酰基)乙基)氨基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-氧杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(52mg,0.11mmol)加入到100mL单口瓶中,加入10mL甲醇,加入钛酸四异丙酯(115.9mg,0.41mmol),三乙胺(41.3mg,0.41mmol),搅拌过夜。再加入乙酸(30.63mg,0.510mmol)及氰基硼氢化钠(44.9mg,0.72mmol)反应过夜。反应完全后,减压除去甲醇,乙酸乙酯萃取两遍,水洗两遍,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:618.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.34(d,J=4.9Hz,1H),7.63(d,J=1.6Hz,1H),7.57(s,1H),7.18(d,J=8.6Hz,2H),6.94(d,J=8.6Hz,2H),6.74(d,J=4.8Hz,1H),4.97(s,2H),4.41(t,J=4.9Hz,2H),4.19(t,J=6.8Hz,2H),4.00–3.88(m,2H),3.75(d,J=7.4Hz,3H),3.23(t,J=6.5Hz,2H),3.15–3.06(m,1H),3.02(s,3H),2.94(t,J=6.6Hz,2H),1.63(s,6H).
实施例9:5-(2-(4-((2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈的制备
制备方法同实施例1的制备方法,将3-(甲磺酰基)氮杂环丁胺换为2-氧杂-6-氮杂-螺[3,3]庚烷,得标题产物。ESI-MS m/z:539.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.34(d,J=4.9Hz,1H),7.63(d,J=1.7Hz,1H),7.57(s,1H),7.17(d,J=8.6Hz,2H),6.93(d,J=8.7Hz,2H),6.75(d,J=4.9Hz,1H),4.97(s,2H),4.72(s,4H),4.45–4.37(m,2H),4.20(s,4H),3.99–3.92(m,2H),1.62(s,6H).
实施例10:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(6-(甲基磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:4-((4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)-2,6-二氮螺环[3.3]庚烷-2-甲酸叔丁酯的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯,得标题产物。ESI-MS m/z:638.2[M+H]+。
步骤2:5-(2-(4-((2-(2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(6-(甲基磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(130mg,0.21mmol),溶于3mL二氯甲烷中,加入三氟乙酸1.5ml,保持室温反应1h。LC-MS监测反应完全后,直接浓缩,得标题化合物,白色固体。ESI-MS m/z:538.2[M+H]+。
步骤3:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(6-(甲基磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶-4-基))甲氧基)苯基)丙-2-基)苯甲腈的制备
将5-(2-(4-((2-(2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶-4-基)甲氧基)苯基)丙-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈(118mg,0.22mmol),溶于4.5mL二氯甲烷中,加入三乙胺(44.4mg,0.44mmol),冷却至0℃,氩气保护,缓慢滴加甲璜酰氯(27.6mg,0.24mmol),加毕后室温反应3h。LC-MS监测反应完全后,加入30ml水淬灭,二氯甲烷萃取萃取三遍,水洗两遍,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:616.2[M+H]+。
1H NMR(400MHz,CDCl3)δ8.33(d,J=4.7Hz,1H),7.44(s,1H),7.31(s,1H),7.10(d,J=8.4Hz,2H),6.90–6.84(m,3H),4.97(s,2H),4.42(t,J=6.0Hz,2H),4.28(s,4H),4.13(s,4H),3.87(t,J=6.0Hz,2H),2.89(s,3H),1.64(s,6H).
实施例11:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-甲基-3-(2-(甲磺酰基)乙氧基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈的制备
步骤1:2-(甲基磺酰基)乙基甲磺酸盐的制备
将2-(甲基磺酰基)乙-1-醇(1g,8.1mmol)加入到二氯甲烷中(25mL),加入N,N-二异丙基乙胺(1.56g,12.1mmol)。在冰水下滴加甲磺酰氯(0.97g,8.5mmol),过夜反应。LC-MS跟踪监测反应,反应完毕后,萃取,浓缩得到标题化合物。
步骤2:3-甲基-3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-羧酸叔丁酯
将60%的钠氢(0.138g,3.5mmol)加入到无水N,N-二甲基甲酰胺中(15ml),在冰水下加入3-羟基-3-甲基氮杂环丁烷-1-羧酸叔丁酯(0.5g,2.7mmol),搅拌30min,再加入2-(甲基磺酰基)乙基甲磺酸盐(0.59g,2.9mmol),室温下过夜。反应完全后。将反应液倒入冰水中,乙酸乙酯萃取,分液,合并有机相,无水硫酸钠干燥,抽滤,滤液浓缩,柱层析纯化得到标题化合物。ESI-MS m/z:294.1[M+H]+.
步骤3:3-甲基-3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷的制备
将3-甲基-3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷-1-羧酸叔丁酯(0.15g,0.50mmol)加入到二氯甲烷中(5mL),加入盐酸-二氧六环(1mL,4M),室温下搅拌2h,反应完全后。浓缩,得到标题化合物,直接用于下步反应。ESI-MS m/z:194.1[M+H]+。
步骤4:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-甲基-3-(2-(甲磺酰基)乙氧基)氮杂环丁烷-1-基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为3-甲基-3-(2-(甲基磺酰基)乙氧基)氮杂环丁烷盐酸盐,得标题产物。ESI-MS m/z:633.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.36(d,J=4.9Hz,1H),7.63(s,1H),7.57(s,1H),7.18(d,J=8.5Hz,2H),6.95(d,J=8.5Hz,2H),6.78(d,J=4.7Hz,1H),4.99(s,2H),4.42(t,J=4.8Hz,2H),4.03(d,J=9.2Hz,2H),3.99–3.93(m,2H),3.89(d,J=9.2Hz,2H),3.78(t,J=5.2Hz,2H),3.40(s,2H),3.00(s,3H),1.63(s,6H),1.51(s,3H).
实施例12:3-氯-2-(2-氯乙氧基(-5-(2-(4-((2-(2,2-二氧基-2-噻-6-氮杂螺[3.3]庚烷-6-基)嘧啶-4-基)甲氧基)苯基)丙烷-2-基)苯甲腈的制备
6.5mL乙醇溶解3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙-2-基)苯甲腈(160.6mg,0.34mmol)于反应瓶中,随后加入2-噻-6-氮杂螺环[3.3]庚烷2,2-二氧基(59.5mg,0.41mmol)和三乙胺(136.4mg,1.35mmol),保持100℃回流反应过夜。LC-MS监测反应完全后,直接浓缩,柱层析,得标题化合物。ESI-MS m/z:587.1[M+H]+。
1H NMR(400MHz,CDCl3)δ8.36(d,J=4.1Hz,1H),7.44(s,1H),7.31(d,J=1.6Hz,1H),7.10(d,J=8.6Hz,2H),6.91(d,J=4.8Hz,1H),6.88(d,J=8.6Hz,2H),4.98(s,2H),4.45–4.35(m,10H),3.87(t,J=6.1Hz,2H),1.64(s,6H).
实施例13:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(6-(甲基磺酰基)-2-氮杂螺[3.3]庚烷-2-基)嘧啶-4-基)甲氧基))苯基)丙基-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,不同的是将3-(甲磺酰基)氮杂环丁胺换为6-(甲磺酰基)-2-氮杂螺[3.3]庚烷,得标题产物。ESI+MS m/z:615.2[M+H]+。
1H NMR(400MHz,CDCl3)δ8.24(d,J=4.7Hz,1H),7.37(s,1H),7.25(s,1H),7.02(d,J=8.5Hz,2H),6.81(d,J=8.6Hz,2H),6.75(d,J=4.6Hz,1H),4.90(s,2H),4.34(t,J=6.1Hz,2H),4.13(d,J=16.9Hz,4H),3.80(t,J=6.1Hz,2H),3.68–3.61(m,1H),2.74(d,J=14.6Hz,5H),2.61–2.52(m,2H),1.56(s,6H).
实施例14:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲基磺酰基)氮杂环丁烷-1-基)嘧啶-5-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙基-2-基)苯甲腈的制备
将实施例1中步骤5产物3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈(0.1g,0.29mmol)、碳酸铯(0.19g,0.57mmol)溶于10mL N,N-二甲基甲酰胺中,加入2-氯-5-(氯甲基)嘧啶(55.9mg,0.34mmol),氩气保护,常温下反应16小时。LC-MS监测反应完全后,乙酸乙酯萃取两遍,水洗两遍,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:476.1[M+H]+。
步骤2:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲基磺酰基)氮杂环丁烷-1-基)嘧啶-5-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
制备方法同实施例1的制备方法,将以3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯嘧啶-4-基)甲氧基)苯基)丙基-2-基)苯甲腈、3-(甲磺酰基)氮杂环丁胺为原料,可得标题产物,白色固体粉末。ESI-MS m/z:575.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.50(s,2H),7.62(s,1H),7.56(d,J=1.6Hz,1H),7.17(d,J=8.6Hz,2H),6.95(d,J=8.6Hz,2H),4.94(s,2H),4.45–4.39(m,3H),4.34(t,J=8.6Hz,2H),4.27–4.19(m,2H),3.95(t,J=4.9Hz,2H),3.06(s,3H),1.63(s,6H).
实施例15:3-氯-2-(2-氯乙氧基)-5-(2-(4-(3-(二氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)苯基)丙-2-基)苯甲腈的制备
步骤1:4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙-2-基)苯基三氟甲磺酸酯的制备
将3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈(0.5g,1.4mmol)和N,N-二异丙基乙胺(0.56g,4.3mmol)溶于10mL二氯甲烷中,0℃下加入三氟甲磺酸酐(0.61g,2.2mmol),常温下过夜反应。LC-MS监测反应完成后,用乙酸乙酯萃取两遍,水洗两遍,饱和食盐水洗一遍,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MSm/z:482.1[M+H]+。
步骤2:3-氯-2-(2-氯乙氧基)-5-(2-(4-(3-(二氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)苯基)丙-2-基)苯甲腈的制备
将3-(2-氟甲基)-5,6,7,8-四氢-[1,2,4]***[4,3-a]吡嗪盐酸盐(0.20g,0.42mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.071g,0.13mmol),三(二亚苄基丙酮)二钯(0.076g,0.83mmol)和碳酸铯(0.65g,2.0mmol)溶于40mL二氧六环中,加入4-(2-(3-氯-4-(2-氯乙氧基)-5-氰基苯基)丙-2-基)苯基三氟甲磺酸酯(0.22g,1.25mmol),氩气保护,常温下反应16小时。LC-MS监测反应完全后,乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:505.9[M+H]+。
1H NMR(400MHz,DMSO-d6)δ7.60(d,J=24.1Hz,2H),7.37(s,1H),7.16(d,J=8.5Hz,2H),7.05(d,J=8.6Hz,2H),4.61(s,2H),4.45–4.38(m,2H),4.22(s,2H),3.99–3.92(m,2H),3.75(s,2H),1.62(s,6H).
实施例16:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲基磺酰基)氮杂环丁烷-1-基)恶唑-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯恶唑-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
将(2-氯恶唑-4-基)甲基甲磺酸酯(420mg,1.99mmol)溶于6.5mL N,N-二甲基甲酰胺中,加入碳酸铯(650mg,2.0mmol)和3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙-2-基)苯甲腈(200mg,0.57mmol),保持反应过夜。LC-MS监测反应完全,80mL乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:465.1[M+H]+。
步骤2:3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-(3-(甲基磺酰基)氮杂环丁烷-1-基)恶唑-4-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
以3-氯-2-(2-氯乙氧基)-5-(2-(4-((2-氯恶唑-4-基)甲氧基)苯基)丙-2-基)苯甲腈、3-(甲磺酰基)氮杂环丁胺为原料,按照实施例1中步骤7合成,得标题产物,白色固体粉末。ESI-MS m/z:564.1[M+H]+。
1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.32(s,1H),7.30(s,1H),7.09(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),4.90(s,2H),4.52(s,4H),4.41(t,J=6.1Hz,2H),4.13(s,1H),3.87(t,J=6.1Hz,2H),2.96(s,3H),1.64(s,6H).
实施例17:3-氯-2-(2-氯乙氧基)-5-(2-(4-((5-(二甲基磷酰基)噻唑-2-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
步骤1:5-(2-(4-((5-溴噻唑-2-基)甲氧基)苯基)丙-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈的制备
10mL N,N-二甲基甲酰胺溶解3-氯-2-(2-氯乙氧基)-5-(2-(4-羟基苯基)丙烷-2-基)苯甲腈(0.18g,0.52mmol)和碳酸铯(0.67g,2.1mmol)于反应瓶中,加入5-溴-2-(氯甲基)噻唑(0.2g,0.94mmol),氩气保护,常温反应16小时。LC-MS监测反应完全后,乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:525.0[M+H]+
步骤2:3-氯-2-(2-氯乙氧基)-5-(2-(4-((5-(二甲基磷酰基)噻唑-2-基)甲氧基)苯基)丙-2-基)苯甲腈的制备
称取5-(2-(4-((5-溴噻唑-2-基)甲氧基)苯基)丙-2-基)-3-氯-2-(2-氯乙氧基)苯甲腈(0.22g,0.42mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.049g,0.084mmol),三(二亚苄基丙酮)二钯(0.077g,0.84mmol)和三乙胺(0.085g,0.84mmol)于反应瓶,15mL二氧六环溶解,加入5-溴-2-(氯甲基)噻唑(0.2g,0.94mmol),氩气保护,常温下反应16小时。LC-MS监测反应完成后,乙酸乙酯萃取,水洗,饱和食盐水洗,收集有机相,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:523.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J=3.4Hz,1H),7.63(s,1H),7.57(s,1H),7.21(d,J=8.5Hz,2H),7.02(d,J=8.5Hz,2H),5.48(s,2H),4.50–4.38(m,2H),4.00–3.91(m,2H),1.78(d,J=13.9Hz,6H),1.64(s,6H).
实施例18:1-(4-((4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)-3-(三氟甲基)氮杂环丁基-3-醇的制备
步骤1:1-(3,5-二氯-4-(2-氯乙氧基)苯基)乙烷-1-酮的制备
将1-(3,5-二氯-4-羟基苯基)乙烷-1-酮(20g,90.4mmol)、1-溴-2-氯乙烷(52g,362mmol)、碳酸铯(73.8g,226mmol)溶于二氯甲烷(100mL)中,在氩气保护下,70℃加热搅拌1h。TLC监测反应完全,反应体系冷却至室温,乙酸乙酯萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥有机相。浓缩纯化得标题化合物。ESI-MS m/z:267.2[M+H]+.
步骤2:2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙醇的制备
50mL四氢呋喃溶解1-(3,5-二氯-4-(2-氯乙氧基)苯基)乙烷-1-酮(9.3g,197mmol)于反应瓶中,0℃下,滴加甲基溴化镁(65.6ml,197mmol)的四氢呋喃(30mL)溶液,滴完后保持此温继续反应1h,TLC监测反应完全。饱和氯化铵溶液淬灭反应,乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥后浓缩,柱层析得标题化合物。ESI-MS m/z:283.0[M+H]+。
步骤3:4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙烷-2-基)苯酚的制备
将2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙醇(6.8g,24mmol)、苯酚(2.71g,28.8mmol)溶于四氯化碳(75.75mL)中,0℃下,滴加三氟化硼***(5.92mL,48mmol),氩气保护,滴完后保持此温继续反应1h。反应完全后,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:359.1[M+H]+。
步骤4:2-氯-4-((4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯氧基)甲基)嘧啶的制备
将4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙烷-2-基)苯酚(300mg,0.84mmol)、2-氯-4-(氯甲基)嘧啶(326mg,1.00mmol)溶于二氯甲烷(10mL)中,在氩气保护下,室温搅拌6h。反应完全后,乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析,得标题化合物。ESI-MS m/z:484.8[M+H]+
步骤5:1-(4-((4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙烷-2-基)苯氧基)甲基)嘧啶-2-基)-3-(三氟甲基)氮杂环丁醇的制备
将2-氯-4-((4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯氧基)甲基)嘧啶(50mg,0.10mmol)、3-(三氟甲基)氮杂环丁醇(18.3mg,0.10mmol)、三乙胺(31mg,0.31mmol)溶于乙醇(5mL)中,在氩气保护下,100℃加热搅拌6h,反应完全。浓缩除去乙醇,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析得标题化合物。ESI-MS m/z:590.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.42(d,J=4.9Hz,1H),7.40(s,1H),7.24(s,2H),7.18(d,J=8.7Hz,2H),6.95(d,J=8.6Hz,2H),6.86(d,J=4.9Hz,1H),5.02(s,2H),4.27(d,J=10.2Hz,2H),4.24–4.17(m,2H),4.05(d,J=10.1Hz,2H),3.97–3.88(m,2H),1.60(s,6H).
实施例19:7-(4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯基)-3-(二氟甲基)-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪的制备
步骤1:4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯基三氟甲磺酸酯的制备
以实施例18步骤3的产物4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙烷-2-基)苯酚为原料,按照实施例15步骤1的操作,得标题化合物。ESI-MS m/z:491.0[M+H]+。
步骤2:7-(4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯基)-3-(二氟甲基)-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪的制备
以4-(2-(3,5-二氯-4-(2-氯乙氧基)苯基)丙-2-基)苯基三氟甲磺酸酯、3-(2-氟甲基)-5,6,7,8-四氢-[1,2,4]***[4,3-a]吡嗪盐酸盐为原料,按照实施例15步骤2进行操作即可得标题化合物。ESI-MS m/z:514.8[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.25(s,2H),7.16(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H),4.61(s,2H),4.21(d,J=5.0Hz,4H),3.94(t,J=4.9Hz,2H),3.75(s,2H),1.60(s,6H).
按照本发明实施例中的合成方法,利用不同市售原料合成实施例20-25的化合物,这些化合物的表征参数如表1所示:
表1
比较例1
参照WO2020/081999中化合物A109公开的方法(Example 22)制备下式代表的化合物(化合物A),并通过氢谱和质谱鉴定,
实验例1:化合物体外细胞活性评价
一、实验材料
人***癌细胞株22RV1购于江苏凯基生物技术股份有限公司。
CTG增殖抑制检测试剂盒购于Promega公司。
二、实验方法
1.药物配制
根据分子量、纯度以及送样质量,将化合物以DMSO配制成20mM浓度的储存液,用时稀释至所需工作浓度。
2.细胞的复苏
从液氮罐中取出22RV1细胞冻存管置于37℃水浴锅中,轻轻摇动使其尽快解冻。解冻后取出冻存管,用酒精棉球消毒后旋开盖子,吸出细胞液注入离心管,并加入1mL含血清的完全培养基,混匀后置于离心机中,1000rpm,离心5min。之后弃上清液,加入完全培养基反复吹打至细胞完全吹散、重悬。以适宜浓度接种于培养皿中。置37℃,5%CO2、95%潮湿空气的CO2培养箱中培养。
3.细胞的培养和传代
细胞生长至约80-90%融合,吸弃原有22RV1完全培养基(1640培养基+10%FBS+1%青链霉素+1%丙酮酸钠),加入1mL的PBS将残余培养基洗净后吸弃,加入1mL胰蛋白酶消化液,消化1-2min,镜下观察细胞伪足回缩变圆但细胞还未成片脱落,此时吸弃胰酶并用2mL完全培养基终止消化,轻轻吹打并收集细胞悬液,1000rpm,离心5min。去除上清,用完全培养基重悬细胞,按所需密度接种于培养皿中,置于37℃、5%CO2、95%潮湿空气的CO2培养箱中培养,视细胞生长情况每2-3天换一次培养液或进行传代。
4.细胞铺板及加药处理
(1)Day 0:22RV1细胞传代后以1×103个细胞/孔的密度重悬于22RV1完全培养基中,接种于96孔培养板内:96孔板最外面一圈36个孔以200μL PBS填充,以防边缘培养基蒸发较快导致内部板孔的培养条件差异过大;内部60个孔以排枪进行细胞铺板,放入5%CO2培养箱内37℃培养24h。
(2)Day 1:24h后,在原有旧培养基(100μL)基础上,加入100μL稀释有不同浓度(2×)药物的培养基。依据参考文献,待测化合物终浓度以100μM为起始最高浓度,按1:2比例依次稀释8个浓度梯度(单位μM):33.3、11.1、3.7037、1.2345、0.4115、0.1371、0.0457、0.0152μM。每个浓度组设置两个复孔。加药后继续放入培养箱培养。
(3)Day 7:药物处理7d后吸弃孔内培养基,尽量吸干,加入150μL已加入CTG的完全培养基(CTG:培养基=1:1),室温孵育12min后,检测化学发光信号,震荡,Read进样检测条件为500ms。
三、数据处理及分析
(1)根据酶标仪导出的A.U.值,计算每个孔相对于溶剂对照孔的抑制率:
Inhibition(%)=100-(A.U.实验孔–A.U.空白孔)/(A.U.溶剂对照孔–A.U.空白孔)×100
(2)根据不同药物浓度及其所对应的抑制率,使用GraghPad 5.0软件进行IC50曲线绘制,分析数据,得出最终IC50值,撰写报告。具体数据如下见表2:
表2
实验结果表明,本发明的化合物对22RV1人***癌细胞株均表现明显的的增值抑制活性,非常有希望成为治疗AR介导的***癌的优效药物。
尽管以上已经对本发明作了详细描述,但是本领域技术人员理解,在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述,而应归属于权利要求书。
Claims (10)
1.一种通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,
其中,
R1和R2各自独立地选自烷基、羟基、卤素、氰基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基和硝基;
3.根据权利要求1或2所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中R4选自烷基磷氧基和3-10元杂环,所述的3-10元杂环可被一个或多个选自卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、烯基、炔基、C1-6烷基磷氧基、C1-6烷基酰基、C1-6烷基磺酰基、氨基酰基、C1-6烷基氨基酰基和氧代基团的基团取代。
9.一种药物组合物,其包含权利要求1至8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。
10.权利要求1-8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药或权利要求9所述的药物组合物在制备用于治疗AR介导的疾病的药物中的应用。
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