CN110305045A - 一种酰胺类化合物及其在治疗癌症中的用途 - Google Patents
一种酰胺类化合物及其在治疗癌症中的用途 Download PDFInfo
- Publication number
- CN110305045A CN110305045A CN201910209987.0A CN201910209987A CN110305045A CN 110305045 A CN110305045 A CN 110305045A CN 201910209987 A CN201910209987 A CN 201910209987A CN 110305045 A CN110305045 A CN 110305045A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- cancer
- chloro
- unsubstituted
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 amides compound Chemical class 0.000 title claims abstract description 72
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 61
- 201000011510 cancer Diseases 0.000 title claims abstract description 58
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 35
- 229940002612 prodrug Drugs 0.000 claims abstract description 35
- 239000000651 prodrug Substances 0.000 claims abstract description 35
- 239000002207 metabolite Substances 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 33
- 239000013078 crystal Substances 0.000 claims abstract description 32
- 230000000155 isotopic effect Effects 0.000 claims abstract description 30
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 28
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 37
- 229910052805 deuterium Inorganic materials 0.000 claims description 37
- 229910052722 tritium Inorganic materials 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 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 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000001537 neural effect Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 102000001307 androgen receptors Human genes 0.000 claims description 4
- 108010080146 androgen receptors Proteins 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 230000004060 metabolic process Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 210000005075 mammary gland Anatomy 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 230000035755 proliferation Effects 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 239000003560 cancer drug Substances 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 64
- 239000002585 base Substances 0.000 description 51
- 238000005406 washing Methods 0.000 description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 46
- 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 40
- 238000004809 thin layer chromatography Methods 0.000 description 40
- 239000004698 Polyethylene Substances 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 28
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- 229940095102 methyl benzoate Drugs 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 17
- 229960004365 benzoic acid Drugs 0.000 description 17
- 239000005711 Benzoic acid Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 14
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 14
- 238000012544 monitoring process Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- NEURYOYRKPFLKH-UHFFFAOYSA-N 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=C(N=C=O)C(Cl)=C1 NEURYOYRKPFLKH-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 238000003809 water extraction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- PFWWSGFPICCWGU-UHFFFAOYSA-N cyclopropanesulfonyl chloride Chemical compound ClS(=O)(=O)C1CC1 PFWWSGFPICCWGU-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 238000005360 mashing Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 238000009413 insulation Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000013517 stratification Methods 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000007445 Chromatographic isolation Methods 0.000 description 4
- IJPSQYHSLATOPD-UHFFFAOYSA-N NC(=O)Oc1ccc(F)cc1Cl Chemical compound NC(=O)Oc1ccc(F)cc1Cl IJPSQYHSLATOPD-UHFFFAOYSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000011097 chromatography purification Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000004907 gland Anatomy 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- IPGPMDGVMCYODH-UHFFFAOYSA-N n-chloro-4-(trifluoromethyl)aniline Chemical compound FC(F)(F)C1=CC=C(NCl)C=C1 IPGPMDGVMCYODH-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- BQTXBXPJGJLPHX-UHFFFAOYSA-N (2-bromo-4-fluorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(F)C=C1Br BQTXBXPJGJLPHX-UHFFFAOYSA-N 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical class CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- SMRVATNCPGDZHP-UHFFFAOYSA-N N-bromo-4-(trifluoromethyl)aniline Chemical compound BrNC1=CC=C(C=C1)C(F)(F)F SMRVATNCPGDZHP-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
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- QQEXMHVHLWKOQT-UHFFFAOYSA-N benzene;formamide Chemical compound NC=O.C1=CC=CC=C1 QQEXMHVHLWKOQT-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 2
- 239000012930 cell culture fluid Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- MJWVCJUSRGLHFO-UHFFFAOYSA-N cyclohexanesulfonyl chloride Chemical compound ClS(=O)(=O)C1CCCCC1 MJWVCJUSRGLHFO-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 2
- BTBWTXDJYUHSBO-UHFFFAOYSA-N n-chlorocyclopropanesulfonamide Chemical compound ClNS(=O)(=O)C1CC1 BTBWTXDJYUHSBO-UHFFFAOYSA-N 0.000 description 2
- UJTWKCITGOFPOL-UHFFFAOYSA-N n-fluoro-4-(trifluoromethyl)aniline Chemical compound FNC1=CC=C(C(F)(F)F)C=C1 UJTWKCITGOFPOL-UHFFFAOYSA-N 0.000 description 2
- 150000002921 oxetanes Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GIWQSPITLQVMSG-UHFFFAOYSA-N 1,2-dimethylimidazole Chemical class CC1=NC=CN1C GIWQSPITLQVMSG-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- KTHTXLUIEAIGCD-UHFFFAOYSA-N 2-amino-3,5-dichlorobenzoic acid Chemical compound NC1=C(Cl)C=C(Cl)C=C1C(O)=O KTHTXLUIEAIGCD-UHFFFAOYSA-N 0.000 description 1
- LWUAMROXVQLJKA-UHFFFAOYSA-N 2-amino-3-chlorobenzoic acid Chemical compound NC1=C(Cl)C=CC=C1C(O)=O LWUAMROXVQLJKA-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- LWOKLXMNGXXORN-UHFFFAOYSA-N 2-chloro-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1Cl LWOKLXMNGXXORN-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- FICAQKBMCKEFDI-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole Chemical compound CC=1C=C(C)ON=1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 description 1
- GZLPFEYTAAXJCP-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-sulfonyl chloride Chemical compound CC1=NOC(C)=C1S(Cl)(=O)=O GZLPFEYTAAXJCP-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- JRDMGVGCATYZPW-UHFFFAOYSA-N 4-chloro-2-fluorobenzonitrile Chemical compound FC1=CC(Cl)=CC=C1C#N JRDMGVGCATYZPW-UHFFFAOYSA-N 0.000 description 1
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VCHSXYHBMFKRBK-UHFFFAOYSA-N 4771-47-5 Chemical compound OC(=O)C1=CC=CC(Cl)=C1[N+]([O-])=O VCHSXYHBMFKRBK-UHFFFAOYSA-N 0.000 description 1
- SORSTNOXGOXWAO-UHFFFAOYSA-N 5-chlorothiophene-2-sulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)S1 SORSTNOXGOXWAO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006131 Brain neoplasm malignant Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 208000001154 Dermoid Cyst Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101100519431 Homo sapiens PDZD2 gene Proteins 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 1
- 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 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102100025646 PDZ domain-containing protein 2 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- WNEYAIJFUGWKBT-UHFFFAOYSA-M S(=O)(=O)=[Cl+].[F-] Chemical compound S(=O)(=O)=[Cl+].[F-] WNEYAIJFUGWKBT-UHFFFAOYSA-M 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- PSDYQSWHANEKRV-UHFFFAOYSA-N [S]N Chemical compound [S]N PSDYQSWHANEKRV-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- SBGGMONTNMIBTI-UHFFFAOYSA-N azetidine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1CNC1 SBGGMONTNMIBTI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect 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
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 208000015322 bone marrow disease Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- MDQDBTCGQGXTBP-UHFFFAOYSA-N bromomethyl benzoate Chemical compound BrCOC(=O)C1=CC=CC=C1 MDQDBTCGQGXTBP-UHFFFAOYSA-N 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- BOXZXICVMMSYPE-UHFFFAOYSA-N chloromethyl benzoate Chemical compound ClCOC(=O)C1=CC=CC=C1 BOXZXICVMMSYPE-UHFFFAOYSA-N 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- CMKBCTPCXZNQKX-UHFFFAOYSA-N cyclohexanethiol Chemical compound SC1CCCCC1 CMKBCTPCXZNQKX-UHFFFAOYSA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical group CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 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
- 239000008103 glucose Substances 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 229940049920 malate Drugs 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
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- FODZNORQIATQIP-UHFFFAOYSA-N methyl 2-amino-3,5-dichlorobenzoate Chemical class COC(=O)C1=CC(Cl)=CC(Cl)=C1N FODZNORQIATQIP-UHFFFAOYSA-N 0.000 description 1
- ZQPNEFLGTOZVIC-UHFFFAOYSA-N methyl 2-chloro-3-methylbenzoate Chemical class COC(=O)C1=CC=CC(C)=C1Cl ZQPNEFLGTOZVIC-UHFFFAOYSA-N 0.000 description 1
- CPXCDEMFNPKOEF-UHFFFAOYSA-N methyl 3-methylbenzoate Chemical class COC(=O)C1=CC=CC(C)=C1 CPXCDEMFNPKOEF-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- KXIBCCFSAMRWIC-UHFFFAOYSA-N morpholine-4-sulfonyl chloride Chemical compound ClS(=O)(=O)N1CCOCC1 KXIBCCFSAMRWIC-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/10—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- 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
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- 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
- C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
本发明公开了一种酰胺类化合物及其在治疗癌症中的用途,属于药物化学领域,本发明公开了式Ⅰ所示的酰胺类化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在治疗癌症中的用途。实验结果表明,本发明化合物能够抑制前列腺癌细胞的增殖,尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时,本发明化合物还能够显著抑制多种癌细胞的增殖。此外,本发明化合物具有良好的药代动力学。对癌症,尤其是前列腺癌具有潜在的治疗作用,为临床上筛选和/或制备癌症药物提供了一种新的选择。
Description
技术领域
本发明属于医药领域,涉及一种酰胺类化合物及其在治疗癌症中的用途,尤其是在治疗前列腺癌中的用途。
背景技术
癌症是人类面临的最危险的疾病之一。在多数情况下癌症最终会导致病人的死亡。尽管现代医学为治疗癌症做了很大的努力,但癌症目前仍然是一个有待解决的问题。前列腺癌是老年男性常见的恶性肿瘤之一。在世界范围内,前列腺癌发病率在男性所有恶性肿瘤中位居第二。在美国,前列腺癌发病率在所有男性恶性肿瘤中居第一位,死亡率居第二位。在我国,近年来其发病率亦已跃居泌尿生殖系恶性肿瘤的第三位。前列腺癌的发病临床早期症状少,大部分患者确诊时已到晚期,失去手术根治时机。行前列腺癌根治术的患者,有27%~53%在术后10年内局部复发或远处转移。内分泌治疗是目前晚期前列腺癌的主要治疗方法,但经过中位时间14~30个月后,几乎所有前列腺癌患者最终均转为雄激素非依赖前列腺癌(androgen-independent prostate cancer,AIPC),进而发展为激素难治性前列腺癌(hormone-refractory prostate cancer,HRPC)。此类前列腺癌统称为去势抵抗性前列腺癌(castrate-resistant prostate cancer,CRPC)。去势抵抗性前列腺癌患者生存质量差,中位生存期12~20个月。随着前列腺癌发病率、死亡率的上升,如何有效治疗去势抵抗性前列腺癌患已成为现代医学研究的热点。
目前去势抵抗性前列腺癌的治疗手段主要是以多西紫杉醇、米托蒽醌、泼尼松等药物联合化学治疗,副作用明显,且尚无最佳治疗方案。新型抗肿瘤药物目前处于不断开发研究阶段。因此,寻找一种高效、安全、副作用少的抗肿瘤药物的研究具有广阔市场前景。
发明内容
为了解决上述问题,本发明提供了一种酰胺类化合物及其在治疗癌症中的用途。
本发明提供了式Ⅰ所示的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物:
式中,
R1~R9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO2Ra、取代或未取代的C1~C12烷基、取代或未取代的C1~C12烷氧基、环烷基、芳基;
其中,Ra选自C1~C12烷基;所述取代基为氘、氚、卤素、C1~C12烷基、芳基;
R10选自氢、C1~C12烷基;
R11选自OR、SR’、NR12R13;
R、R’、R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C12烷基、取代或未取代的3~8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、所述取代基为氘、氚、卤素、氰基、C1~C12烷基、C1~C12烷氧基;
R15选自取代或未取代的C1~C12烷基,取代或未取代的3~8元环烷基;
R16、R17各自独立地选自氢、取代或未取代的C1~C12烷基、取代或未取代的3~8元环烷基;或者,R16、R17相连形成取代或未取代的3~8元环。
进一步地,R1~R9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO2Ra、取代或未取代的C1~C8烷基、取代或未取代的C1~C8烷氧基、环烷基、芳基;
其中,Ra选自C1~C8烷基;
所述取代基为氘、氚、卤素、C1~C8烷基、芳基;
R10选自氢、C1~C8烷基。
进一步地,R1~R9各自独立地选自氢、氘、氚、卤素、取代或未取代的C1~C4烷基、取代或未取代的C1~C4烷氧基;
所述取代基为氘、氚、卤素、C1~C4烷基;
R10选自氢、C1~C4烷基。
进一步地,R1~R9各自独立地选自氢、氘、氚、卤素、取代或未取代的C1~C2烷基;
所述取代基为氘、氚、卤素;
R10选自氢。
进一步地,R11选自OR、SR’、NR12R13;
R、R’、R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C8烷基、取代或未取代的3~8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、
所述取代基为氘、氚、卤素、氰基、C1~C8烷基、C1~C8烷氧基;
R15选自C1~C8烷基;
R16、R17各自独立地选自氢、C1~C8烷基;或者,R16、R17相连形成3~8元环。
进一步地,所述化合物Ⅰ如式Ⅱ所示:
其中,
R1~R9各自独立地选自氢、氘、氚、F、Cl、Br、CF3、CH3;
R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C4烷基、取代或未取代的3~6元环烷基、取代或未取代的3~6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、
所述取代基为氘、氚、卤素、氰基、C1~C2烷基;
R15选自C1~C4烷基;
R16、R17各自独立地选自氢、C1~C6烷基;或者,R16、R17相连形成3~6元环。进一步地,
R1、R3、R6各自独立地选自氢、氘、氚。
进一步地,所述化合物Ⅱ如式ⅢA所示:
式中,
R14’选自取代或未取代的C1~C4烷基;所述取代基为氘、氚、卤素。
进一步地,所述化合物ⅢA如式ⅢA-1所示:
式中,
R14’选自C1~C3烷基、CF3。
进一步地,所述化合物ⅢA-1为下述结构式之一:
进一步地,所述化合物Ⅱ如式ⅢB所示:
式中,
A环选自取代或未取代的3~6元环烷基、取代或未取代的3~6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代基选自氘、氚、卤素、氰基、C1~C2烷基。
进一步地,所述化合物ⅢB如式ⅢB-1所示:
式中,
R2、R3、R5、R7、R8、R9各自独立地选自F、Cl、Br、CF3、CH3;
A环选自3~6元环烷基、取代或未取代的4~6元杂环基、取代或未取代的苯基、取代或未取代的杂芳基;
所述取代基选自Cl、氰基、甲基。
进一步地,A环为环丙烷。
进一步地,所述化合物ⅢB-1为下述结构式之一:
进一步地,所述化合物Ⅱ如式ⅢC所示:
式中,
R15选自C1~C4烷基。
进一步地,所述化合物ⅢC如式ⅢC-1所示:
式中,
R15选自C1~C4烷基。
进一步地,所述化合物ⅢC-1为下述结构式之一:
进一步地,所述化合物Ⅱ如式ⅢD所示:
式中,
R16、R17各自独立地选自氢、C1~C2烷基;
或者,R16、R17相连形成4~6元环。
进一步地,所述化合物ⅢD如式ⅢD-1所示:
式中,
R16、R17各自独立地选自氢、甲基;
或者,R16、R17相连形成5~6元杂环基。
进一步地,所述化合物ⅢD-1为下述结构式之一:
进一步地,所述化合物Ⅱ如式ⅢE所示:
式中,
R14”选自C1~C4烷基、3~6元环烷基、3~6元杂环基、芳基。进一步地,所述化合物ⅢE如式ⅢE-1所示:
式中,
R14”选自C1~C3烷基、3~5元环烷基、5~6元杂环基、苯基。
进一步地,所述化合物ⅢE-1为下述结构式之一:
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。
进一步地,所述癌症为乳腺癌、脑癌、前列腺癌,肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
进一步地,所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。
进一步地,所述癌细胞是下述癌症的癌细胞:乳腺癌、脑癌、前列腺癌,肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
进一步地,所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明中所述化合物的结构均是指能够稳定存在的结构。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
“氘”是指氢(H)的同位素,也被称为重氢,元素符号一般为D或2H。
“氚”是指氢(H)的同位素,元素符号一般为T或3H。
“卤素”为氟、氯、溴或碘。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C4烷基是指包含1~4个碳原子的烷基。C1~C4烷基是指含有一个至四个碳原子的直链或支链的烃链。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基,例如,甲基-CH3,乙基-CH3CH2等。
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基,例如亚甲基-CH2-,亚乙基-CH2CH2-等。“C1-4亚烷基”是指含有一个至四个碳原子的直链或支链的烃链。
“取代或未取代的C1-4烷基”是指C1-4烷基可以是被取代的,也可以没有取代基的。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。含有至少一个选自N、O或S的环杂原子,其余环原子是C,另外具有完全共轭的π电子系统。例如呋喃基、吡咯基、喹啉基、噻吩基、吡啶基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、噻吩并吡啶基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
本发明所述“取代或未取代的杂芳基”可以是
“环烷基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“C3-8环烷基”指碳原子数为3~8的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个选自O、S或取代的氮原子的环烷基,其余环原子为碳,例如,“C3-8杂环基”指碳原子数和杂原子数共为3~8的杂环基。杂环基可以是非取代的,也可以被一个或多个取代基取代。具体的,本发明中“5~6元杂环基”可以是等
“本发明化合物”指式(I)所示的化合物。该术语还包括式(I)化合物的各种晶型、立体异构体、同位素体、互变异构体、立体化学异构体、药学上可接受的盐、溶剂合物、前体药物、代谢产物。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,例如:顺反异构体、对映异构体、构象异构体等。
“药学上可接受的”是指当给药至动物例如哺乳动物(例如人类)时生理学上可耐受且通常不会产生过敏或类似的不良反应(例如头晕等)的添加剂或组合物。药物载体和赋形剂可以包括但不限于稀释剂,例如乳糖、葡萄糖、甘露糖和/或甘油;润滑剂;聚乙二醇;粘合剂,例如硅酸铝镁、淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;并且,如果需要的话,还包括崩解剂,例如淀粉、琼脂、海藻酸或其盐如海藻酸钠;和/或吸附剂、着色剂、防腐剂、稳定剂、矫味剂和甜味剂。
“盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、氢氟酸盐、硫酸盐、硝酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、酒石酸盐、天冬氨酸盐或三氟乙酸盐。
“式(I)所示的化合物的溶剂合物”,溶剂如乙醇、水等,其中,可含有不同量的水,如一水合物、半水合物、一个半水合物、二水合物或者三水合物。
“前体药物”是通式Ⅰ化合物的衍生物,其在可能具有较弱的活性或甚至没有活性,但在生理条件下(例如通过代谢、溶剂分解或另外的方式)转化为本发明的活性成分,从而发挥其药理作用的化合物。例如,含有羧基的化合物可形成生理上可水解的酯,其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药,这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时,可使用肠胃外给药。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
癌症包括但不限于下列癌症:乳腺癌、卵巢癌、前列腺癌、子宫颈癌、食道癌、睾丸癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、神经母细胞瘤、大细胞癌、腺癌、腺瘤、滤泡癌、表皮样癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
本发明所述“室温”为25±5℃。
本发明所述“过夜”为12±1小时。
通用合成方法:
通用合成方法A:
通用合成方法B:
本发明提供了一种结构新颖的酰胺类化合物及其在治疗癌症中的用途。实验结果表明,本发明化合物能够抑制前列腺癌细胞的增殖,尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时,本发明化合物还能够显著抑制多种癌细胞的增殖。此外,本发明化合物具有良好的药代动力学。对癌症,尤其是前列腺癌具有潜在的治疗作用,为临床上筛选和/或制备癌症药物提供了一种新的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1:5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(1)
第一步:5-氯-N-(2-氯-4-三氟甲基苯基)-2-硝基苯甲酰胺(1-1)
氮气保护下,将5-氯-2-硝基苯甲酸(5.0g,24.8mmol),三乙胺(5.0g,24.8mmol)和3-氯-4-氨基三氟甲苯(4.6g,23.6mmol)加入到50mL二甲苯中,加热到110℃,缓慢滴加三氯化磷(3.4g,24.8mmol)。110℃下,搅拌2h。冷却至室温,真空旋干。加入100mL水,固体抽滤,滤饼用水洗涤,再用少量乙酸乙酯打浆,固体再抽滤,干燥,得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-硝基苯甲酰胺(8.2g,21.6mmol)。收率:87.2%。MS(ESI)m/e396.0(M+18)+。1H NMR(400MHz,CDCl3)δ8.63(d,J=8.5Hz,1H),8.16(d,J=8.4Hz,1H),7.99(s,1H),7.71(s,1H),7.69-7.57(m,3H)。
第二步:5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(1)
将5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-硝基苯甲酰胺(5.0g,13.2mmol)溶于50mL醋酸,铁粉(3.7g,65.9mmol)。加热到80℃,搅拌1h。冷却至室温。反应液倒入冰水中,大量固体析出。固体抽滤,滤饼用水洗涤,干燥,得到白色固体2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(4.1g,11.7mmol)。收率:89.0%。MS(ESI)m/e 349.0(M+H)+。1H NMR(400MHz,CDCl3)δ8.60(d,J=8.7Hz,1H),8.39(s,1H),7.70(s,1H),7.58(d,J=8.7Hz,1H),7.48(d,J=2.0Hz,1H),7.25(d,J=1.8Hz,1H),6.70(d,J=8.8Hz,1H),5.59(s,2H)。
实施例2:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(甲磺酰胺基)苯甲酰胺(2)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)和3mL吡啶,缓慢滴加甲基磺酰氯(65.6mg,0.57mmol)。加热到40℃,搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(甲基磺酰胺基)苯甲酰胺(60.0mg,0.14mmol)。收率:49.0%。MS(ESI)m/e427.0(M+H)+。
实施例3:5-氯-N-(2-氯-4-三氟甲基苯基)-2-丙酰胺基苯甲酰胺(3)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),丙酰氯(1.2eq,23mg),二氯甲烷1ml和TEA(2eq,40mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,旋干,用冰二氯甲烷打浆,过滤,得白色固体10mg,产率13%
MS m/z(ESI):210.2。
实施例4:5-氯-N-(2-氯-4-三氟甲基苯基)-2-丙磺酰胺基苯甲酰胺(4)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),丙磺酰氯(1.2eq,43mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得类白色固体7mg,产率6%。
MS m/z(ESI):455.0(M+H)+。1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.58(d,J=8.7Hz,1H),8.48(s,1H),7.81(d,J=9.0Hz,1H),7.74(d,J=1.5Hz,1H),7.66(d,J=2.3Hz,1H),7.63(dd,J=8.7,1.2Hz,1H),7.54(dd,J=9.0,2.3Hz,1H),3.17–3.10(m,2H),1.93–1.81(m,2H),1.02(t,J=7.5Hz,3H).
实施例5:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(异丙磺酰胺基)苯甲酰胺(5)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加异丙磺酰氯(147.3mg,1.15mmol)。室温搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(5.0mg,0.01mmol)。收率:3.8%。MS(ESI)m/e455.0(M+H)+。
实施例6:5-氯-N-(2-氯-4-三氟甲基苯基)-2-环丙磺酰胺基苯甲酰胺(6)
方法一:25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.5mmol,174mg),环丙磺酰氯(1.2eq,85mg),二氯甲烷3ml和TEA(2eq,100mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得类白色固体23mg,产率10%MS m/z(ESI):453.0(M+H)+
1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),10.19(s,1H),8.17–7.87(m,3H),7.82(d,J=8.4Hz,1H),7.70(dd,J=8.8,2.4Hz,1H),7.61(d,J=8.8Hz,1H),2.82–2.68(m,1H),0.94(ddd,J=16.2,9.7,7.0Hz,4H).
方法二:氮气保护下,将5-氯-2-环丙基磺酰胺基苯甲酸(500.0mg,1.81mmol)和3-氯-4-氨基三氟甲苯(461.0mg,2.36mmol)加入到10mL二甲苯中,加热到140℃,缓慢滴加三氯化磷(124.0mg,0.91mmol)。140℃下,搅拌2h。冷却至室温,有白色固体析出。固体抽滤,滤饼少量甲醇打浆。固体再抽滤,干燥,得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(环丙磺酰胺基)苯甲酰胺(450.0mg,0.99mmol)。收率:54.7%。MS(ESI)m/e453.0(M+H)+。1HNMR(400MHz,CDCl3)δ9.89(s,1H),8.59(d,J=8.6Hz,1H),8.48(s,1H),7.83(d,J=8.9Hz,1H),7.74(d,J=1.6Hz,1H),7.66(d,J=2.4Hz,1H),7.63(dd,J=8.7,1.7Hz,1H),7.54(dd,J=8.9,2.4Hz,1H),2.52(tt,J=8.0,4.8Hz,1H),1.28–1.20(m,2H),1.01–0.92(m,2H)。
实施例7:5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(7)
第一步:将2-氨基-5-溴-苯甲酸(1g,4.63mmol)溶于15ml甲醇,加入H2SO4(2ml),体系在油浴中回流反应过夜。减压浓缩,柱层析分离纯化(PE/EA=1:1),得产品2-氨基-5-溴-苯甲酸甲酯873mg,收率:81.9%。
第二步:将2-氨基-5-溴-苯甲酸甲酯(194mg,0.84mmol)溶于2ml二氯甲烷,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(2mL)以及环丙基磺酰氯(237mg,1.68mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入5ml 0.5N HCl剧烈搅拌,静置分层,水相用10ml二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=5:1),得产品5-溴-2-(环丙基磺酰胺基)-苯甲酸甲酯95mg,收率:33.7%。
第三步:将5-溴-2-(环丙基磺酰胺基)-苯甲酸甲酯(50mg,0.15mmol)溶于3ml甲醇,并加入1ml饱和LiOH溶液,室温搅拌反应过夜,TLC监测反应(PE/EA=5:1),至原料消失。旋蒸除去大部分溶剂,用1N HCl调节体系的pH值约2-3左右,加入乙酸乙酯剧烈搅拌,后静置分层,有机相分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得5-溴-2-(环丙基磺酰胺基)-苯甲酸35mg,收率:73.1%。
第四步:将5-溴-2-(环丙基磺酰胺基)-苯甲酸(35mg,0.11mmol)溶于3ml二甲苯,加入2-氯-4-三氟甲基-苯胺(22mg,0.11mmol)后,加热至140℃,随即加入三氯化磷(9mg,0.07mmol),保温反应6h。旋蒸除去溶剂,薄层层析分离纯化(PE/EA=1:1),得目标产品5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(7)17mg,收率:31.3%。MS(M+2):499.0。1HNMR(400Hz,DMSO-d6):δ10.653(1H,s),10.205(1H,s),8.116(1H,d,J=2.4Hz),8.036-8.009(2H,m),7.822-7.802(2H,m),7.552(1H,d,J=8.8Hz),2.781-2.718(1H,m),0.993-0.893(4H,m).
实施例8:5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)
第一步:2-氨基-5-溴-4-氟苯甲酸(8-1)
将2-氨基-4-氟苯甲酸(620mg,4.0mmol)溶于5ml DMF中,加入NBS(712mg,4.0mmol),室温反应过夜,TLC监控反应直至原料2-氨基-4-氟苯甲酸反应完全(PE:EA=2:1),加入10ml EA,加入10ml水,搅拌萃取,有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到产品2-氨基-5-溴-4-氟苯甲酸(8-1)400mg,收率:42.8%。
第二步:2-氨基-5-溴-4-氟苯甲酸甲酯(8-2)
将上一步产品2-氨基-5-溴-4-氟苯甲酸(400mg,1.71mmol)溶于15ml甲醇,加入H2SO4(1ml),反应70℃回流过夜,减压浓缩,薄层层析纯化(PE:EA=2:1),得到产品2-氨基-5-溴-4-氟苯甲酸甲酯(8-2)141mg,收率:33.3%。
第三步:5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(8-3)
将2-氨基-5-溴-4-氟苯甲酸甲酯(141mg,0.57mmol)溶于5ml甲苯,加入吡啶(898mg,11.36mmol),加入环丙基磺酰氯(795mg,5.68mmol),100℃反应过夜,TLC监控反应进程,反应完成,冷却至室温,加入水5ml,搅拌,静置分液,水层用5ml EA萃取,合并有机层,饱和食盐水洗涤,干燥,减压浓缩,薄层层析纯化(PE:EA=2:1),得到产品5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(8-3)100mg,收率:49.1%。
第四步:5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(8-4)
将5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(100mg,0.28mmol)溶于5ml甲醇/5ml水中,加入LiOH(140mg,5.83mmol)固体,加热搅拌升温至70℃反应0.5h,TLC监控反应(PE:EA=5:1),直至原料5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯反应完全,用浓盐酸调节反应体系pH=3~4,有固体析出,过滤,得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(8-4)125mg(湿品),收率:132.1%。
第五步:5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)
将5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸(125mg,0.37mmol)溶于5ml二甲苯中,加入2-氯-4-三氟甲基-苯胺(86mg,0.44mmol),加热搅拌升温至120℃,加入三氯化磷(19mg,0.14mmol),反应过夜,TLC监控反应进程,反应完全,65℃减压浓缩至干,薄层层析纯化(PE:EA=2:1),得到目标产品5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)32mg,收率:16.8%。1H NMR(400MHz,DMSO-d6)δ14.28(s,1H),8.75(d,J=4Hz,1H),8.20(d,J=12Hz,1H),7.84(s,1H),7.68(d,J=8Hz,1H),7.58(d,J=12Hz,1H),1.23(s,1H),0.83(m,2H),0.73(dd,2H)。
实施例9、10:5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(9),N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(10)
第一步:将2-氨基-4-氟苯甲酸(310mg,2.0mmol)溶于5mlDMF,加入NCS(266mg,2.0mmol),50℃加热反应8h,TLC监控反应直至原料反应完全(PE/EA=1:1),加入10mlEa,加入10ml水,搅拌萃取,有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到产品2-氨基-5-氯-4-氟苯甲酸350mg,收率:92.4%。
第二步:将上一步产品2-氨基-5-氯-4-氟苯甲酸(350mg,1.85mmol)溶于5ml甲醇,加入H2SO4(1ml),反应70℃回流过夜,减压浓缩,薄层柱层析纯化(PE/Ea=1:1),得到产品2-氨基-5-氯-4-氟苯甲酸甲酯135mg,收率:35.9%。
第三步:将2-氨基-5-氯-4-氟苯甲酸甲酯(135mg,0.66mmol)溶于5ml甲苯,加入吡啶(1.05g,13.2mmol),加入环丙基磺酰氯(930.4mg,6.6mmol),120℃反应过夜,冷却至室温,加入5ml0.5N HCl洗涤,分层,水层用5ml EA萃取,合并有机层,饱和食盐水洗涤,干燥,减压浓缩,薄层柱层析纯化(PE/Ea=5:1),得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯65mg,收率:31.9%。
第四步:将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(65mg,0.21mmol)溶于3ml四氢呋喃,加入1ml LiOH饱和水溶液,室温反应2h,TLC监控反应(PE/Ea=5:1),直至原料反应完全,用1N HCl调节Ph=5.0,加入Ea萃取,有机层用饱和水溶液洗涤,无水硫酸钠干燥,减压浓缩,得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸60mg,收率:96.7%。
第五步:将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(60mg,0.20mmol)溶于3ml二甲苯,加入2-氯-4-三氟甲基-苯胺(39.95mg,0.20mmol),加热至140℃,加入三氯化磷(9.82mg,0.07mmol),保温反应4h,65℃减压浓缩干,薄层柱层析纯化(PE/Ea=2:1),得到目标产品5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(9)12mg,收率:12.5%。MS(M+1):471。1H NMR(400MHz,DMSO)δ10.53(s,2H),8.19(d,J=7.5Hz,1H),7.99(s,2H),7.79(d,J=8.0Hz,1H),7.58(d,J=11.5Hz,1H),2.87(s,1H),0.95(s,4H).
同时得到副产品N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(10)11mg,MS(M+1):437,1H NMR(400MHz,DMSO)δ10.65(s,2H),8.07(dd,J=23.2,16.6Hz,3H),7.80(d,J=8.2Hz,1H),7.40(dd,J=11.0,2.3Hz,1H),7.20(s,1H),2.88(s,1H),0.97(s,4H).
实施例11:3,5-二氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)苯胺(11)
将3,5-氯-2-(环丙基磺酰胺基)-苯甲酸(124.06mg,0.4mmol)溶于5mL二甲苯,加入2-氯-4-三氟甲基-苯胺(78.23mg,0.4mmol),体系加热至140℃,加入三氯化磷(19.23mg,0.14mmol),保温反应6h,旋蒸除去溶剂,薄层层析纯化(PE/EA=1:1),得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺119mg,收率:61%。MS(M+1):487。
1HNMR(400Hz,DMSO-d6):δ10.20(1H,s),9.79(1H,s),8.20-8.18(1H,d,J=8.8Hz),7.97-7.96(2H,m),7.81-7.78(1H,m),7.71-7.70(1H,d,J=2.4Hz),2.67-2.65(1H,m),0.92-0.90(2H,m),0.84-0.82(1H,m)。
实施例12:3,5-二氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)苯胺(12)
第一步:化合物12-1的合成:
将2-氨基-3,5-二氯-苯甲酸(1g,4.85mmol)溶于15mL甲醇,加入H2SO4(2mL),体系在油浴中回流反应过夜。减压浓缩,柱层析分离纯化(PE/EA=1:1),得产品2-氨基-3,5-二氯-苯甲酸甲酯845mg,收率:78.97%。
第二步:化合物12-2的合成:
将2-氨基-3,5-二氯-苯甲酸甲酯(440.1mg,2mmol)溶于4mL二氯甲烷,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(4mL)以及环丙基磺酰氯(562.32mg,4mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入10mL0.5N HCl剧烈搅拌,静置分层,水相用10mL二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=4:1),得产品3,5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯246.38mg,收率:38%。
第三步:化合物12-3的合成:
将3,5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯(194.51mg,0.6mmol)溶于3mL甲醇,并加入5mL饱和2N LiOH溶液,室温搅拌反应过夜,TLC监测反应(PE/EA=4:1),至原料消失。旋蒸除去大部分溶剂,用1N HCl调节体系的pH值约2-3左右,加入乙酸乙酯剧烈搅拌,后静置分层,有机相分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得3,5-氯-2-(环丙基磺酰胺基)-苯甲酸135.85mg,收率:73%。
第四步:化合物12的合成:
将3,5-氯-2-(环丙基磺酰胺基)-苯甲酸(124.06mg,0.4mmol)溶于5mL二甲苯,加入2-氯-5-氟-4-三氟甲基-苯胺(85.42mg,0.4mmol),体系加热至140℃,加入三氯化磷(19.23mg,0.14mmol),保温反应6h,旋蒸除去溶剂,薄层层析纯化(PE/EA=1:1),得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺116.92mg,收率:58%。MS(M+1):505。1HNMR(400Hz,DMSO-d6):δ10.29(1H,s),9.87(1H,s),8.20-8.17(1H,d,J=12Hz),8.02-7.98(1H,m),7.72-7.71(1H,d,J=2.4Hz),2.67-2.64(1H,m),0.92-0.84(1H,m),0.83-0.81(1H,m)。
实施例13:5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(13)
第一步:将2-氨基-5-氯-苯甲酸(1g,5.83mmol)溶于15ml甲醇,加入H2SO4(2ml),体系在油浴中回流反应过夜。减压浓缩,柱层析分离纯化(PE/EA=1:1),得产品2-氨基-5-氯-苯甲酸甲酯780mg,收率:72.1%。
第二步:将2-氨基-5-氯-苯甲酸甲酯(300mg,1.62mmol)溶于2mL二氯甲烷,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(2mL)以及环丙基磺酰氯(454mg,3.24mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入5ml 0.5N HCl剧烈搅拌,静置分层,水相用10ml二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=5:1),得产品5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯250mg,收率:53.4%。
第三步:将5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯(100mg,0.35mmol)溶于6ml甲醇,并加入2ml饱和LiOH溶液,室温搅拌反应过夜,TLC监测反应(PE/EA=5:1),至原料消失。旋蒸除去大部分溶剂,用1N HCl调节体系的pH值约2-3左右,加入乙酸乙酯剧烈搅拌,后静置分层,有机相分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得5-氯-2-(环丙基磺酰胺基)-苯甲酸83mg,收率:87.2%。
第四步:将5-氯-2-(环丙基磺酰胺基)-苯甲酸(50mg,0.18mmol)溶于5ml二甲苯,加入2-溴-4-三氟甲基-苯胺(44mg,0.18mmol),体系加热至140℃,加入三氯化磷(15mg,0.11mmol),保温反应6h,旋蒸除去溶剂,薄层层析纯化(PE/EA=1:1),得到目标产品5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺41mg,收率:45.4%。MS(M+2):499.0
1HNMR(400Hz,DMSO-d6):δ10.637(1H,s),10.236(1H,s),8.137(1H,s),8.015(1H,d,J=2.4Hz),7.953(1H,d,J=8.0Hz),7.869-7.844(1H,dd,J1=8.6Hz,J2=1.4Hz),7.719-7.691(1H,dd,J1=8.8Hz,J2=2.4Hz),7.624(1H,d,J=8.8Hz),2.789-2.726(1H,m),0.998-0.895(4H,m).
实施例14:5-氯-N-(2-氯-5-氟-4-三氟甲基)-2-(环丙磺酰胺基)-3-氟苯甲酰胺(14)
第一步:5-氯-2-(环丙磺酰胺基)苯甲酸甲酯
氮气保护下,将5-氯-2-氨基苯甲酸甲脂(600.0mg,3.23mmol)加入到14mL甲苯和7mL吡啶中,缓慢滴加环丙磺酰氯(2.27g,16.13mmol)。加热110℃,搅拌过夜。冷却至室温,加入乙酸乙酯和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(600.0mg,2.1mmol)。收率:76.9%。MS(ESI)m/e290.2(M+H)+。
第二步:.5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸甲酯
氮气保护下,将5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(100.0mg,0.35mmol)和选择性氟试剂(1.2g,3.50mmol)加入4mL乙酸中。加热95℃,搅拌过夜。冷却至室温,加入乙酸乙酯和水萃取,有机层用饱和碳酸氢钠洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸甲酯(40.0mg,0.11mmol)。收率:37.6%。MS(ESI)m/e308.0(M+H)+。
第三步:5-氯-2-(环丙基磺酰胺)-3-氟苯甲酸
将5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(100.0mg,0.35mmol)(1.2g,3.50mmol)溶于2mL甲醇中,加入2mL2N氢氧化锂。室温搅拌过夜。加入冰水,用2N稀盐酸调节pH至5~6,有白色固体析出。固体抽滤,滤饼干燥,得到白色固体5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸(30.0mg,0.05mmol)。收率:78.6%。
第四步:5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸
氮气保护下,将5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸(100.0mg,0.10mmol)和2-氯-5-氟-4-(三氟甲基)苯胺(26.2mg,0.12mmol)加入到2mL二甲苯中,加热到140℃,缓慢滴加三氯化磷(18.0mg,0.13mmol)。140℃下,搅拌2h。冷却至室温,有白色固体析出。固体抽滤,滤饼少量甲醇打浆。固体再抽滤,干燥,得到白色固体5-氯-N-(2-氯-4-氰基-5-氟苯基)-2-(环丙磺酰胺基)-3-氟苯甲酰胺(15.0mg,0.03mmol)。收率:30.0%。MS(ESI)m/e489.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.59–10.30(m,1H),9.93(s,1H),8.23(d,J=12.8Hz,1H),8.03(d,J=7.3Hz,1H),7.84(dd,J=9.4,2.3Hz,1H),7.65(d,J=1.4Hz,1H),2.64(ddd,J=12.5,7.8,4.7Hz,1H),0.94–0.87(m,2H),0.85–0.76(m,2H)。
实施例15:5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(15)
第一步:将2-氨基-4-氟苯甲酸(466mg,3.0mmol)溶于5mlDMF,加入NCS(399mg,3.0mmol),60℃加热反应6h,TLC监控反应直至原料反应完全(PE/Ea=1:1),加入10mlEa,加入10ml水,搅拌萃取,有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到产品2-氨基-5-氯-4-氟苯甲酸500mg,收率:87.8%。
第二步:将上一步产品2-氨基-5-氯-4-氟苯甲酸(500mg,mmol)溶于5ml甲醇,加入H2SO4(1ml),反应70℃回流过夜,减压浓缩,薄层柱层析纯化(PE/Ea=1:1),得到产品2-氨基-5-氯-4-氟苯甲酸甲酯405mg,收率:75.4%。
第三步:将2-氨基-5-氯-4-氟苯甲酸甲酯(91mg,0.45mmol)溶于1ml二氯甲烷,加入吡啶(1ml),加入环丙基磺酰氯(126mg,0.9mmol),室温反应过夜,加入5ml0.5N HCl洗涤,分层,水层用5mlEa萃取,合并有机层,饱和食盐水洗涤,干燥,减压浓缩,薄层柱层析纯化(PE/Ea=5:1),得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯45mg,收率:32.7%。
第四步:将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(45mg,0.15mmol)溶于3ml四氢呋喃,加入1ml LiOH饱和水溶液,室温反应2h,TLC监控反应(PE/Ea=5:1),直至原料反应完全,用1N HCl调节Ph=5.0,加入Ea萃取,有机层用饱和水溶液洗涤,无水硫酸钠干燥,减压浓缩,得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸40mg,收率:93.1%。
第五步:将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(40mg,0.14mmol)溶于3ml二甲苯,加入2-溴-4-三氟甲基-苯胺(33mg,0.14mmol),加热至140℃,加入三氯化磷(7mg,0.05mmol),保温反应4h,65℃减压浓缩干,薄层柱层析纯化(PE/Ea=2:1),得到目标产品5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(15)10mg,收率:14.2%。MS(M+1):514.9.1H NMR(400MHz,DMSO)δ10.61(s,2H),8.22(d,J=7.4Hz,1H),8.13(s,1H),7.85(d,J=7.9Hz,2H),7.58(d,J=11.3Hz,1H),2.90(s,1H),0.93(dd,J=18.3,10.9Hz,4H).
实施例16:5-氯-N-(2-氯-4-三氟甲基-5-氟苯基)-2-环丙磺酰胺基苯甲酰胺(16)
25ml圆底烧瓶中,放入5-氯-2-环丙磺酰胺基苯甲酸(0.4mmol,110mg),2-氯-4-三氟甲基-5氟苯胺(1.2eq,102mg)和2ml二甲苯,室温搅拌下滴加三氯化磷(0.3eq,16mg),滴加完毕后升温至140℃搅拌过夜。搅拌下冷却至室温,pre-TLC纯化,得类白色固体20mg,产率10%MS m/z(ESI):471.0(M+H)+。1H NMR(400MHz,CDCl3)δ9.81(s,1H),8.56(s,1H),8.49(d,J=12.1Hz,1H),7.82(d,J=8.9Hz,1H),7.70(d,J=6.8Hz,1H),7.65(d,J=2.2Hz,1H),7.55(dd,J=8.9,2.2Hz,1H),2.59–2.48(m,1H),1.30–1.22(m,2H),1.04–0.97(m,2H).
实施例17:5-氯-2-(环丙基磺酰胺基)-N-(2-氟-4-(三氟甲基)苯基)苯甲酰胺(17)
用类似于实施例15的方法制备得到。MS m/z(ESI):437(M+H)+.
实施例18:5-氯-N-(4-氯-2-氟苯基)-2-(环丙基磺酰胺基)苯甲酰胺(18)
用类似于实施例15的方法制备得到。MS m/z(ESI):403(M+H)+.
实施例19:5-氯-2-(环丙基磺酰胺基)-N-(2,5-二氟-4-(三氟甲基)苯基)苯甲酰胺(19)
用类似于实施例15的方法制备得到。MS m/z(ESI):455(M+H)+.
实施例20:5-氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-3-甲基-苯胺(20)
第一步:化合物20-2的合成:
将2-氨基-5-氯-3-甲基-苯甲酸(1g,5.39mmol)溶于15mL甲醇,加入H2SO4(2mL),体系在油浴中回流反应过夜。减压浓缩,柱层析分离纯化(PE/EA=1:1),得产品2-氨基-5-氯-3-甲基-苯甲酸甲酯852mg(20-2)。
第二步:化合物20-3的合成:
将2-氨基-5-氯-3-甲基-苯甲酸甲酯(399.28mg,2mmol)溶于4mL二氯甲烷,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(4mL)以及环丙基磺酰氯(562.32mg,4mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入10mL 0.5N HCl剧烈搅拌,静置分层,水相用10mL二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=4:1),得产品5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸甲酯212.63mg(20-4),收率:35%。
第三步:化合物20-4的合成:
将5-氯-2-(环丙基磺酰胺基)-3-甲基苯甲酸甲酯(182.26mg,0.6mmol)溶于3mL甲醇,并加入5mL饱和2N LiOH溶液,室温搅拌反应过夜,TLC监测反应(PE/EA=4:1),至原料消失。旋蒸除去大部分溶剂,用1N HCl调节体系的pH值约2-3左右,加入乙酸乙酯剧烈搅拌,后静置分层,有机相分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸130.38mg,收率:75%。
第四步:化合物20-5的合成:
将5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸(115.90mg,0.4mmol)溶于5mL二甲苯,加入2-氯-5-氟-4-三氟甲基-苯胺(85.42mg,0.4mmol),体系加热至140℃,加入三氯化磷(19.23mg,0.14mmol),保温反应6h,旋蒸除去溶剂,薄层层析纯化(PE/EA=1:1),得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺120.35mg,收率:62%。MS(M+1):485.0。1HNMR(400Hz,DMSO-d6):δ10.25(1H,s),9.51(1H,s),8.20-8.17(1H,d,J=12Hz),8.01-7.97(1H,m),7.50-7.54(2H,m),2.62-2.60(1H,m),2.49(3H,s),0.90-0.88(2H,m),0.82-0.79(2H,m)。
实施例21:5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(氧杂环丁烷-3-磺酰氨基)苯胺(21)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)苯胺(104.74mg,0.3mmol)溶于5mL二甲苯,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(4mL)以及加入氧杂环丁烷-3-磺酰氯(62.64mg,0.4mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入10mL 0.5N HCl剧烈搅拌,静置分层,水相用10mL二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=4:1),得产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(氧杂环丁烷-3-磺酰氨基)苯胺59.13mg,收率:42%。MS m/z(ESI):469(M+H)+。1HNMR(400Hz,DMSO-d6):δ14.47–14.08(m,1H),8.91–8.64(m,1H),8.53–8.22(m,1H),7.93(d,J=17.7Hz,2H),7.67(d,J=38.6Hz,2H),7.50–7.13(m,1H),4.68(s,4H),4.52–4.29(m,1H)。
实施例22:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环戊磺酰胺基)苯甲酰胺(22)
用类似于实施例23的方法得到。MS m/z(ESI):481(M+H)+.
实施例23:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己磺酰胺基)苯甲酰胺(23)
第一步:环己基磺酰氯的合成
NCS(4.6g,34.4mmol)加入到50mL乙腈中,冰水浴下,加入6.5mL2N稀盐酸,搅拌2分钟,将环己硫醇(1.0g,8.6mmol)加入到反应液中,室温搅拌2h。加入乙酸乙酯和水萃取,有机层用饱和食盐水洗涤2次,干燥,旋干。得到无色液体环己基磺酰氯(1.1g,6.0mmol)。收率:70.0%。
第二步:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己基磺酰胺)苯甲酰胺的合成
氮气保护下,将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加二甲胺基磺酰氯(261.0mg,1.43mmol)。室温搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己基磺酰胺)苯甲酰胺(28.2mg,0.08mmol)。收率:28.2%。MS(ESI)m/e495.0(M+H)+。
实施例24:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(三氟甲基磺酰胺基)苯甲酰胺(24)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),三氟甲基磺酰氯(2eq,68mg),二氯甲烷1ml和TEA(5eq,100mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,正己烷打浆,过滤,得类白色固体10mg,产率10%。MS m/z(ESI):481.0(M+H)+。1H NMR(400MHz,CDCl3)δ7.89(d,J=2.4Hz,1H),7.87(d,J=8.4Hz,1H),7.79(s,1H),7.62(d,J=8.0Hz,1H),7.36(dd,J=8.6,2.3Hz,1H),6.75(d,J=8.6Hz,1H)
实施例25:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(氨基磺酰胺基)苯甲酰胺(25)
N-叔丁氧羰基-氨基磺酰氯的二氯甲烷溶液在冰浴下,加入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg)和TEA(2eq,50mg),自然升至室温,搅拌过夜,TLC显示原料消失,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化后,溶于二氯甲烷/三氟乙酸(1:1)中,室温搅拌0.5h脱去Boc保护基,旋干反应液,溶于乙酸乙酯中,饱和碳酸钠溶液洗,饱和食盐水洗,干燥,旋干得类白色固体25mg,产率23%。MS m/z(ESI):428.0(M+H)+
1H NMR(400MHz,DMSO-d6)δ14.77(s,1H),8.76(d,J=8.7Hz,1H),7.93(d,J=2.9Hz,1H),7.81(d,J=1.7Hz,1H),7.64(dd,J=8.8,2.0Hz,1H),7.54(d,J=9.1Hz,1H),7.17(dd,J=9.1,2.9Hz,1H),5.48(s,2H).
实施例26:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-((N-甲胺磺酰基)胺基)苯甲酰胺(26)
氮气保护下,将甲胺磺酸(250.0mg,2.25mmol)加入到10mL甲苯中,加入五氯化磷(468.5g,2.25mmol)。加热110℃,搅拌2h。冷却至室温,溶剂浓缩干。加入二氯甲烷,抽滤,滤液旋干,得到粗品甲胺磺酰氯(250mg,1.93mmol)。氮气保护下,将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加粗品甲胺磺酰氯(250mg,1.93mmol)。室温搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(N-甲胺磺酰胺基)苯甲酰胺(60.0mg,0.14mmol)。收率:47.4%。MS(ESI)m/e442.0(M+H)+。
实施例27:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-((N,N-二甲基磺酰基)氨基)苯甲酰胺(27)
氮气保护下,将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加二甲胺基磺酰氯(350.0mg,2.44mmol)。室温搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-三氟甲基)苯基)-(2-吗啉-4-磺酰胺)苯甲酰胺(40.0mg,0.01mmol)。收率:30.6%。MS(ESI)m/e 456.0(M+H)+。
实施例28:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(吡咯烷-1-磺酰胺基)苯甲酰胺(28)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),吡咯烷-1-磺酰氯(3eq,102mg)和吡啶1ml,室温搅拌过夜,反应液以乙酸乙酯稀释,稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得类白色固体5mg,产率5%
MS m/z(ESI):482.0(M+H)+。1H NMR(400MHz,DMSO)δ10.80(s,1H),10.33(s,1H),8.06-6.90(m,6H),2.99-2.90(m,4H),1.90-1.82(m,4H).
实施例29:5-氯-N-(2-氯-4-三氟甲基)苯基)-(2-吗啉-4-磺酰胺基)苯甲酰胺(29)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加吗啉-4-磺酰氯(265.8mg,1.43mmol)。室温搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(50.0mg,0.01mmol)。收率:35.0%。MS(ESI)m/e498.0(M+H)+。
实施例30:乙基(4-氯-2-((2-氯-4-(三氟甲基)苯基)氨基甲酰基)苯基)氨基磺酸酯(30)
用类似于实施例26的方法得到。MS m/z(ESI):457(M+H)+。
实施例31:异丙基(4-氯-2-((2-氯-4-(三氟甲基)苯基)氨基甲酰基)苯基)氨基磺酸酯(31)
用类似于实施例26的方法得到。MS m/z(ESI):471(M+H)+。
实施例32:5-氯-N-(2-氯-4-三氟甲基苯基)-2-苯磺酰胺基苯甲酰胺(32)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),苯磺酰氯(1.2eq,53mg),二氯甲烷2ml和DMAP(1.5eq,45mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,旋干,少量冰二氯甲烷打浆,过滤,得白色固体24mg,产率20%。MS m/z(ESI):489.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.80–10.44(m,2H),8.01(d,J=1.0Hz,1H),7.97(d,J=8.4Hz,1H),7.92(d,J=2.4Hz,1H),7.82(dd,J=8.4,1.3Hz,1H),7.77–7.71(m,2H),7.66(t,J=7.4Hz,1H),7.62–7.51(m,3H),7.31(d,J=8.8Hz,1H).
实施例33:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(33)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,分批加入对甲基苯磺酰氯(65.6mg,0.57mmol)。加热到60℃,搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(50.0mg,0.10mmol)。收率:34.5%。MS(ESI)m/e503.0(M+H)+。
实施例34:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(4-氰基苯磺酰胺基)苯甲酰胺(34)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.22mmol,77mg),4-氰基苯磺酰氯(0.9eq,40mg),二氯甲烷1ml和吡啶(3eq,49mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得淡黄色固体40mg,产率40%。MS m/z(ESI):514.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.60(s,2H),8.16–7.92(m,4H),7.88(d,J=8.4Hz,3H),7.79(d,J=7.7Hz,1H),7.53(d,J=5.6Hz,1H),7.28(d,J=8.6Hz,1H).
实施例35:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(吡啶-3-磺酰胺基)苯甲酰胺(35)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),吡啶-3-磺酰氯(1.2eq,54mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,旋干,少量冰二氯甲烷打浆,过滤,得黄色固体13mg,产率11%。MS m/z(ESI):490.0(M+H)+。1H NMR(400MHz,DMSO)δ10.69(s,1H),8.86(d,J=1.7Hz,1H),8.81(dd,J=4.8,1.4Hz,1H),8.11(ddd,J=8.1,2.3,1.6Hz,1H),8.04(d,J=8.3Hz,1H),7.99(d,J=1.3Hz,1H),7.87(d,J=2.5Hz,1H),7.81(dd,J=8.7,1.5Hz,1H),7.62–7.56(m,2H),7.30(d,J=8.7Hz,1H).
实施例36:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(噻吩-2-磺酰胺基)苯甲酰胺(36)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),噻吩-2-磺酰氯(1.2eq,55mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得类白色固体7mg,产率6%。MS m/z(ESI):495.0(M+H)+。1H NMR(400MHz,CDCl3)δ9.99(s,1H),8.53(d,J=8.7Hz,1H),8.18(s,1H),7.83–7.77(m,1H),7.72(d,J=1.5Hz,1H),7.62(dd,J=8.7,1.3Hz,1H),7.54(dt,J=6.0,2.9Hz,2H),7.48(ddd,J=6.2,4.4,1.2Hz,2H),6.93(dd,J=4.9,3.8Hz,1H).
实施例37:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(5-氯噻吩-2-磺酰胺基)苯甲酰胺(37)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),5-氯噻吩-2-磺酰氯(1.2eq,65mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得类白色固体7mg,产率5%。MS m/z(ESI):528.9(M+H)+。1H NMR(400MHz,CDCl3)δ8.54(d,J=8.6Hz,1H),7.75(d,J=8.8Hz,1H),7.72(d,J=1.5Hz,1H),7.62(dd,J=11.6,1.9Hz,2H),7.53(dd,J=8.8,2.3Hz,1H),7.25(s,1H),6.76(d,J=4.0Hz,1H).
实施例38:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(3,5-二甲基异恶唑-4-磺酰胺基)苯甲酰胺(38)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),3,5-二甲基异恶唑-4-磺酰氯(1.2eq,59mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,浓缩,pre-TLC纯化,得淡黄色固体13mg,产率10%。MS m/z(ESI):508.0(M+H)+。1H NMR(400MHz,DMSO)δ10.61(s,2H),8.05(s,1H),8.00(s,1H),7.92(d,J=2.4Hz,1H),7.83(d,J=8.4Hz,1H),7.66(d,J=7.7Hz,1H),7.35(d,J=8.7Hz,1H),2.40(s,3H),2.15(s,3H).
实施例39:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(1-甲基-1H-咪唑-4-磺酰胺基)苯甲酰胺(39)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),1-甲基-1H-咪唑-4-磺酰氯(1.2eq,54mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜,反应液稀盐酸洗,饱和食盐水洗,干燥,旋干,少量冰二氯甲烷打浆,过滤,得白色固体25mg,产率20%。MS m/z(ESI):493.0(M+H)+。1H NMR(400MHz,DMSO)δ10.70(s,1H),10.62(s,1H),8.06–7.74(m,6H),7.60(dd,J=34.7,20.2Hz,2H),3.65(s,3H).
实施例40:5-氯-N-(2-氯-4-三氟甲基苯基)-(1,2-二甲基-1H-咪唑-4-磺酰胺基)苯甲酰胺(40)
25ml圆底烧瓶中,放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.5mmol,174mg),1,2-二甲基-1H-咪唑-4-磺酰氯(1.2eq,117mg),二氯甲烷3ml和TEA(2eq,100mg),室温搅拌过夜,反应液浓缩,溶于乙酸乙酯中,稀盐酸洗,饱和食盐水洗,取EA层和EA层的沉淀,过滤,得白色固体67mg,产率27%。MS m/z(ESI):507.0(M+H)+。1H NMR(400MHz,DMSO)δ10.98–10.18(m,2H),8.06–7.96(m,3H),7.88–7.81(m,2H),7.62(d,J=10.2Hz,1H),7.56(d,J=8.8Hz,1H),3.56(s,3H),2.22(d,J=16.0Hz,3H).
实施例41:2-乙酰氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(41)
用类似于实施例42的方法得到。MS m/z(ESI):391(M+H)+。
实施例42:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(乙磺酰胺基)苯甲酰胺(42)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶,滴加乙酰氯(147.3mg,1.15mmol)。加热到40℃,搅拌过夜。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(40.0mg,0.91mmol)。收率:31.6%。MS(ESI)m/e441.0(M+H)+。1H NMR(400MHz,DMSO)δ10.51(s,2H),8.15(d,J=8.8Hz,1H),8.01(s,1H),7.97(d,J=8.3Hz,1H),7.90(d,J=2.3Hz,1H),7.82(d,J=8.5Hz,1H),7.65(dd,J=8.9,2.4Hz,1H),2.36(q,J=7.5Hz,2H),1.07(t,J=7.5Hz,3H).
实施例43:5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(正丁酰胺基)-苯甲酰胺(43)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(80mg,0.23mmol)溶于2ml二氯甲烷,加入1ml吡啶,加入正丁酰氯(50.0mg,0.46mmol),室温搅拌过夜,TLC监测反应(PE/Ea=5:1),反应完全,减压浓缩,加入0.5N HCl调节pH=5.0,加入5mlEa萃取,有机层水洗,饱和食盐水洗涤,干燥,减压浓缩,薄层柱层析纯化(PE/Ea=5:1),得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(正丁酰胺基)-苯甲酰胺15mg。收率:15.6%。MS:224.1,1HNMR(400MHz,CDCl3)δ10.53(s,1H),8.69(d,J=9.0Hz,1H),8.55(d,J=8.7Hz,1H),8.42(s,1H),7.74(d,J=1.7Hz,1H),7.64–7.60(m,2H),7.53(dd,J=9.0,2.4Hz,1H),2.44–2.35(m,2H),1.82–1.72(m,2H),1.05–0.96(m,3H).
实施例44:5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(异丁酰胺基)-苯甲酰胺(44)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(100mg,0.29mmol)溶于2ml二氯甲烷,加入1ml吡啶,加入异丁酰氯(61.1mg,0.57mmol),45℃反应5h,TLC监测反应(PE/Ea=5:1),反应完全,减压浓缩,加入0.5N HCl调节pH=5.0,加入5mlEa萃取,有机层水洗,饱和食盐水洗涤,干燥,减压浓缩,薄层柱层析纯化(PE/Ea=2:1),得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(异丁酰胺基)-苯甲酰胺20mg。收率:16.4%。MS:224.2,1HNMR(400MHz,CDCl3)δ10.64(s,1H),8.70(d,J=9.0Hz,1H),8.57(d,J=8.6Hz,1H),8.42(s,1H),7.74(d,J=1.5Hz,1H),7.63(d,J=2.3Hz,2H),7.53(dd,J=8.9,2.2Hz,1H),2.60(s,1H),1.30–1.26(m,6H).
实施例45:5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙甲酰胺基)-苯甲酰胺(45)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(107mg,0.3mmol),溶于1ml二氯甲烷,加入1ml吡啶,加入环丙基甲酰氯(48mg,0.45mmol),45℃反应过夜,TLC监测反应(PE/Ea=5:1),反应完全,减压浓缩,加入0.5N HCl调节pH=5.0,加入5mlEa萃取,有机层水洗,饱和食盐水洗涤,干燥,减压浓缩,加入1mlEa打浆,过滤,得到20mg白色固体产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙甲酰胺基)-苯甲酰胺。MS:222;1H NMR(400MHz,DMSO)δ10.70(s,1H),10.46(s,1H),8.06(d,J=8.9Hz,1H),8.00(d,J=8.3Hz,2H),7.85(d,J=2.5Hz,1H),7.80(dd,J=8.5,1.5Hz,1H),7.62(dd,J=8.9,2.5Hz,1H),1.75(tt,J=6.9,5.4Hz,1H),0.90–0.73(m,4H).收率:15.6%。
实施例46:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(环丁甲酰胺基)-苯甲酰胺(46)
用类似于实施例45的方法得到。MS m/z(ESI):431(M+H)+。
实施例47:5-氯-N-(2-氯-4-三氟甲基苯基)-2-(环戊甲酰胺基)-苯甲酰胺(47)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(104.74mg,0.3mmol)溶于5mL二甲苯,待澄清后将体系移置于冰水浴中继续降温冷却搅拌,随后加入吡啶(4mL)以及加入环戊基甲酰氯(53.04mg,0.4mmol),完毕体系在油浴中升温加热搅拌反应过夜。翌日,冷却至室温,向体系中加入10mL 0.5N HCl剧烈搅拌,静置分层,水相用10mL二氯甲烷萃取,合并有机相,分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,薄层层析分离纯化(PE/EA=4:1),得产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环戊基甲酰胺基)苯胺85mg,收率:63.6%。1HNMR(400Hz,DMSO-d6):δ10.57(1H,s),10.52(1H,s),8.18-8.16(1H,d,J=8.8Hz),8.0(1H,d,J=1.6Hz),7.95-7.90(2H,m),7.82-7.79(1H,m),7.65-7.62(1H,m),2.79-2.53(1H,m),1.85-1.51(8H,m).
实施例48:5-氯-N-(2-氯-4-三氟甲基-5-氟苯基)-2-环丙磺酰胺基苯甲酰胺(48)
25ml圆底烧瓶中,放入2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(0.2mmol,70mg),苯甲酸(1.2eq,30mg)和1ml二甲苯,室温搅拌下滴加三氯化磷(0.3eq,8mg),滴加完毕后升温至140℃搅拌过夜。搅拌下冷却至室温,pre-TLC纯化,得类白色固体10mg,产率11%
MS m/z(ESI):258.0。1H NMR(400MHz,DMSO)δ11.67(s,1H),10.74(s,1H),8.50(d,J=8.5Hz,1H),8.16–7.47(m,10H).
实施例49:5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(四氢呋喃甲酰胺基)-苯甲酰胺(49)
将2-四氢呋喃甲酸(232mg,2.0mmol)溶于2ml二氯亚砜,95℃回流3h,减压浓缩,加入5ml二氯甲烷,减压浓缩,再次加入5ml二氯甲烷,加入2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(175mg,0.5mmol),室温反应过夜,TLC监测,原料大部分反应完全,减压浓缩,加入0.5N HCl调节pH=5.0,加入5mlEa萃取,有机层水洗,饱和食盐水洗涤,干燥,减压浓缩,加入2ml混合溶液(正己烷/Ea=10:1)打浆,过滤,得到30mg白色固体产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(四氢呋喃甲酰胺基)-苯甲酰胺,收率:13.4%。MS:252.2,1HNMR(400MHz,CDCl3)δ11.27(s,1H),8.69(d,J=9.0Hz,1H),8.64(d,J=8.7Hz,1H),8.40(s,1H),7.72(s,1H),7.63(dd,J=9.0,5.7Hz,2H),7.54(dd,J=9.0,2.3Hz,1H),4.50(dd,J=8.5,5.3Hz,1H),4.17(dd,J=14.1,7.1Hz,1H),4.00(dd,J=15.1,7.1Hz,1H),2.36(dd,J=12.8,8.1Hz,1H),2.17(dd,J=13.0,7.3Hz,1H),2.04–1.83(m,2H).
实施例50:5-氯-N-(2-氯-4-三氟甲基-苯基)-3-(四氢呋喃甲酰胺基)-苯甲酰胺(50)
用类似于实施例49的方法得到。MS m/z(ESI):447(M+H)+。
实施例51:N-(4-氯-2-((2-氯-4-(三氟甲基)苯基)胺甲酰基)苯基)四氢吡喃-4-甲酰胺(51)
氮气保护下,将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)和三乙胺(87.0mg,0.86mmol)溶于3mL二氯甲烷,滴加四氢吡喃-4-甲酰氯(64.0mg,0.43mmol)。室温搅拌2h。加入二氯甲烷和水萃取,有机层用1N稀盐酸洗涤,再用饱和食盐水洗涤,干燥,旋干,硅胶柱层析纯化。得到白色固体N-(4-氯-2-((2-氯-4-(三氟甲基)苯基)胺甲酰基)苯基)四氢吡喃-4-甲酰胺(80.0mg,0.17mmol)。收率:60.5%。MS(ESI)m/e461.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),10.57(s,1H),8.21(d,J=8.9Hz,1H),8.00(d,J=1.5Hz,1H),7.92(t,J=5.5Hz,2H),7.81(dd,J=8.5,1.6Hz,1H),7.65(dd,J=8.9,2.5Hz,1H),3.92–3.82(m,2H),3.35(dd,J=11.7,2.3Hz,2H),2.65–2.53(m,1H),1.72(dd,J=12.8,2.0Hz,2H),1.67–1.53(m,2H)。
以下通过实验例证明本发明的有益效果。
实验例1本发明化合物抑制癌细胞增殖
实验目的:测定化合物对癌细胞增殖的抑制作用
1.实验材料及仪器:
RIPM1640培养基(Hyclone Cat#308090.01)
胎牛血清(FBS)(Gibco Cat#10099-141)
青-链霉素Pen Strep(Hyclone Cat#SV30010)
22RV1细胞(中国科学院细胞库TCHu100)
CCK8试剂盒(Signalway Antibody Cat#CP002)
酶标仪(Thermo Multiskan MK3型)
细胞培养液:RIPM1640培养基,10%FBS,1%Pen Strep。
2.实验步骤:
22RV1细胞用细胞培养液传代培养后,接种于96孔板,每孔80μl,每孔细胞数为2万,放在37℃,5%CO2培养箱中培养过夜。
将药物用二甲基亚砜(DMSO)配置成30mM的储存液。临用前再用DMSO稀释3倍,再按3倍梯度稀释,得到9个浓度梯度,再用培养液将各浓度的化合物稀释200倍(以此保证培养体系中DMSO浓度为0.1%),每个浓度做2个孔重复。取20μl稀释好的化合物加到细胞培养孔,轻轻振荡混匀。另外设置3个只加细胞的阴性对照孔和3个只加培养液的空白对照孔(6孔各加20μl培养液稀释200倍的DMSO),氯硝柳氨为参照化合物。
3.结果检测:
培养48小时后,每孔滴加10μl CCK-8溶液,放37℃,5%CO2培养箱继续培养2.5小时。
用多功能酶标仪在450nm处测吸光度(OD值)。
数据用软件GraphPad Prism5中Dose-response-inhibition方程分析,得出IC50值,结果见表1:
表1本发明化合物对22RV1癌细胞增殖的抑制作用
应用类似的检测方法我们发现本发明的化合物对其他癌细胞系,包括卵巢癌细胞系SKOV-3,也有显著的抑制增殖活性:
表2.本发明化合物对其他癌细胞增殖的抑制作用
上述实验结果表明,本发明的化合物能够显著抑制多个癌细胞系,尤其是能够显著抑制前列腺癌细胞22RV1、乳腺癌细胞、卵巢癌细胞、肝癌细胞的增殖。本发明的化合物有潜力应用于各种癌症,特别是前列腺癌、乳腺癌、卵巢癌和肝癌的治疗。
试验例2:本发明化合物的小鼠药代动力学
1)实验材料及仪器:
LC-20AD高效液相色谱系统(日本SHIMADZU(岛津)公司)
API4000三重四极杆质谱仪,(美国Applied Biosystem公司)
PhenixWinnolin药动学软件(Version 6.3,美国Certara公司)
高速冷冻离心机(Thermo Fisher Scientific)
分析天平(赛多利斯,SECURA225D-1CN)
实验动物:ICR小鼠(成都达硕实验动物有限公司)
DMA(Sigma)
CMC-Na(成都科龙化工)
肝素(成都科龙化工)
2)实验方法及结果
精密称取化合物6加入相应的溶媒至终体积10ml,超声涡旋混匀。配置成浓度为0.5mg/ml的溶液。取配制的终溶液0.2ml,于-20℃保存,用于浓度测定。健康成年ICR小鼠9只(20-30g),禁食过夜(自由饮水)后,灌胃给药,给药体积0.2ml/10g;于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml,4℃离心5min分离血浆,于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。口服生物利用度由PO给药测得的药物暴露量和IV给药测得的药物暴露量计算得到。
表3.本发明化合物的药代动力学参数
化合物6做了小鼠PK实验。本发明的化合物显示出达到较高的暴露量(AUC),相比于类似发明参照化合物有更长的半衰期和更佳的口服生物利用度,在药代动力学上有显著提高。
综上,本发明提供了一种结构新颖的酰胺类化合物及其在治疗癌症中的用途。实验结果表明,本发明化合物能够抑制前列腺癌细胞的增殖,尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时,本发明化合物还能够显著抑制多种癌细胞的增殖。此外,本发明化合物具有良好的药代动力学。对癌症,尤其是前列腺癌具有潜在的治疗作用,为临床上筛选和/或制备癌症药物提供了一种新的选择。
Claims (30)
1.式Ⅰ所示的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物:
式中,
R1~R9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO2Ra、取代或未取代的C1~C12烷基、取代或未取代的C1~C12烷氧基、环烷基、芳基;
其中,Ra选自C1~C12烷基;所述取代基为氘、氚、卤素、C1~C12烷基、芳基;
R10选自氢、C1~C12烷基;
R11选自OR、SR’、NR12R13;
R、R’、R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C12烷基、取代或未取代的3~8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、所述取代基为氘、氚、卤素、氰基、C1~C12烷基、C1~C12烷氧基;
R15选自取代或未取代的C1~C12烷基,取代或未取代的3~8元环烷基;
R16、R17各自独立地选自氢、取代或未取代的C1~C12烷基、取代或未取代的3~8元环烷基;或者,R16、R17相连形成取代或未取代的3~8元环。
2.根据权利要求1所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:
R1~R9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO2Ra、取代或未取代的C1~C8烷基、取代或未取代的C1~C8烷氧基、环烷基、芳基;
其中,Ra选自C1~C8烷基;
所述取代基为氘、氚、卤素、C1~C8烷基、芳基;
R10选自氢、C1~C8烷基。
3.根据权利要求2所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:
R1~R9各自独立地选自氢、氘、氚、卤素、取代或未取代的C1~C4烷基、取代或未取代的C1~C4烷氧基;
所述取代基为氘、氚、卤素、C1~C4烷基;
R10选自氢、C1~C4烷基。
4.根据权利要求3所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:
R1~R9各自独立地选自氢、氘、氚、卤素、取代或未取代的C1~C2烷基;
所述取代基为氘、氚、卤素;
R10选自氢。
5.根据权利要求1所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:
R11选自OR、SR’、NR12R13;
R、R’、R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C8烷基、取代或未取代的3~8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、
所述取代基为氘、氚、卤素、氰基、C1~C8烷基、C1~C8烷氧基;
R15选自C1~C8烷基;
R16、R17各自独立地选自氢、C1~C8烷基;或者,R16、R17相连形成3~8元环。
6.根据权利要求1~5任意一项所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅰ如式Ⅱ所示:
其中,
R1~R9各自独立地选自氢、氘、氚、F、Cl、Br、CF3、CH3;
R12、R13各自独立地选自氢、氘、氚、
其中,R14选自取代或未取代的C1~C4烷基、取代或未取代的3~6元环烷基、取代或未取代的3~6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R15、
所述取代基为氘、氚、卤素、氰基、C1~C2烷基;
R15选自C1~C4烷基;
R16、R17各自独立地选自氢、C1~C6烷基;或者,R16、R17相连形成3~6元环。
7.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:
R1、R3、R6各自独立地选自氢、氘、氚。
8.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅱ如式ⅢA所示:
式中,
R14’选自取代或未取代的C1~C4烷基;所述取代基为氘、氚、卤素。
9.根据权利要求8所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢA如式ⅢA-1所示:
式中,
R14’选自C1~C3烷基、CF3。
10.根据权利要求8或9所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢA-1为下述结构式之一:
11.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅱ如式ⅢB所示:
式中,
A环选自取代或未取代的3~6元环烷基、取代或未取代的3~6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代基选自氘、氚、卤素、氰基、C1~C2烷基。
12.根据权利要求11所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢB如式ⅢB-1所示:
式中,
R2、R3、R5、R7、R8、R9各自独立地选自F、Cl、Br、CF3、CH3;
A环选自3~6元环烷基、取代或未取代的4~6元杂环基、取代或未取代的苯基、取代或未取代的杂芳基;
所述取代基选自Cl、氰基、甲基。
13.根据权利要求12所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:A环为环丙烷。
14.根据权利要求11~13任意一项所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢB-1为下述结构式之一:
15.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅱ如式ⅢC所示:
式中,
R15选自C1~C4烷基。
16.根据权利要求15所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢC如式ⅢC-1所示:
式中,
R15选自C1~C4烷基。
17.根据权利要求15或16所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢC-1为下述结构式之一:
18.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅱ如式ⅢD所示:
式中,
R16、R17各自独立地选自氢、C1~C2烷基;
或者,R16、R17相连形成4~6元环。
19.根据权利要求18所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢD如式ⅢD-1所示:
式中,
R16、R17各自独立地选自氢、甲基;
或者,R16、R17相连形成5~6元杂环基。
20.根据权利要求18或19所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢD-1为下述结构式之一:
21.根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物Ⅱ如式ⅢE所示:
式中,
R14”选自C1~C4烷基、3~6元环烷基、3~6元杂环基、芳基。
22.根据权利要求21所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢE如式ⅢE-1所示:
式中,
R14”选自C1~C3烷基、3~5元环烷基、5~6元杂环基、苯基。
23.根据权利要求21或22所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,其特征在于:所述化合物ⅢE-1为下述结构式之一:
24.权利要求1~23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。
25.根据权利要求24所述的用途,其特征在于:所述癌症为乳腺癌、脑癌、前列腺癌,肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
26.根据权利要求25所述的用途,其特征在于:所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。
27.权利要求1~23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。
28.权利要求1~23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。
29.根据权利要求28所述的用途,其特征在于:所述癌细胞是下述癌症的癌细胞:乳腺癌、脑癌、前列腺癌,肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
30.根据权利要求29所述的用途,其特征在于:所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810231510 | 2018-03-20 | ||
CN2018102315108 | 2018-03-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110305045A true CN110305045A (zh) | 2019-10-08 |
Family
ID=67986702
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910209987.0A Pending CN110305045A (zh) | 2018-03-20 | 2019-03-19 | 一种酰胺类化合物及其在治疗癌症中的用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN110305045A (zh) |
WO (1) | WO2019179436A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110845341A (zh) * | 2019-11-08 | 2020-02-28 | 苏州开元民生科技股份有限公司 | 一种2-氨基-5-氯-n,3-二甲基苯甲酰胺的制备方法 |
CN111228250A (zh) * | 2020-03-03 | 2020-06-05 | 中国医学科学院医药生物技术研究所 | 2-苯磺酰胺基苯甲酰胺类化合物在制备治疗肝癌药物中的应用 |
CN111909053A (zh) * | 2020-08-06 | 2020-11-10 | 湖北省生物农药工程研究中心 | 基于二芳胺单元的酰胺类衍生物及其制备方法和应用 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3873479A4 (en) * | 2018-11-01 | 2022-08-03 | The Regents of the University of California | COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT OF ANDROGEN MEDIATED DISEASE |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1555364A (zh) * | 2001-09-21 | 2004-12-15 | �Ű˾ | 杀虫二酰胺类 |
WO2005085188A2 (en) * | 2004-03-02 | 2005-09-15 | Compass Pharmaceuticals Llc | Compounds and methods for anti-tumor therapy |
EP1815860A2 (en) * | 2001-12-26 | 2007-08-08 | Genzyme Corporation | Phosphate transport inhibitors |
CN103130696A (zh) * | 2013-03-21 | 2013-06-05 | 山东大学 | 邻氨基苯甲酰胺类化合物及其制备方法与应用 |
WO2013165606A1 (en) * | 2012-05-04 | 2013-11-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Modulators of the relaxin receptor 1 |
WO2016210289A1 (en) * | 2015-06-24 | 2016-12-29 | Duke University | Chemical modulators of signaling pathways and therapeutic use |
US20170190675A1 (en) * | 2015-12-30 | 2017-07-06 | Duke University | Chemical modulators of immune checkpoints and therapeutic use |
WO2018043400A1 (ja) * | 2016-08-30 | 2018-03-08 | 日本曹達株式会社 | スルホニルアミノベンズアミド化合物および有害生物防除剤 |
-
2019
- 2019-03-19 WO PCT/CN2019/078725 patent/WO2019179436A1/zh active Application Filing
- 2019-03-19 CN CN201910209987.0A patent/CN110305045A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1555364A (zh) * | 2001-09-21 | 2004-12-15 | �Ű˾ | 杀虫二酰胺类 |
EP1815860A2 (en) * | 2001-12-26 | 2007-08-08 | Genzyme Corporation | Phosphate transport inhibitors |
WO2005085188A2 (en) * | 2004-03-02 | 2005-09-15 | Compass Pharmaceuticals Llc | Compounds and methods for anti-tumor therapy |
WO2013165606A1 (en) * | 2012-05-04 | 2013-11-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Modulators of the relaxin receptor 1 |
CN103130696A (zh) * | 2013-03-21 | 2013-06-05 | 山东大学 | 邻氨基苯甲酰胺类化合物及其制备方法与应用 |
WO2016210289A1 (en) * | 2015-06-24 | 2016-12-29 | Duke University | Chemical modulators of signaling pathways and therapeutic use |
US20170190675A1 (en) * | 2015-12-30 | 2017-07-06 | Duke University | Chemical modulators of immune checkpoints and therapeutic use |
WO2018043400A1 (ja) * | 2016-08-30 | 2018-03-08 | 日本曹達株式会社 | スルホニルアミノベンズアミド化合物および有害生物防除剤 |
Non-Patent Citations (3)
Title |
---|
MASERUOGATA等: "Synthesis and Antiviral Activity of Sulfonamidobenzophenone Oximes and Sulfonamidobenzamides", 《J. MED.CHEM. 》 * |
无: ""CAS RN:1027944-42-8等"", 《ACS,STN-REGISTRY数据库》 * |
无: ""CAS RN:33900-95-7等"", 《ACS,STN-REGISTRY数据库》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110845341A (zh) * | 2019-11-08 | 2020-02-28 | 苏州开元民生科技股份有限公司 | 一种2-氨基-5-氯-n,3-二甲基苯甲酰胺的制备方法 |
CN110845341B (zh) * | 2019-11-08 | 2022-10-14 | 苏州开元民生科技股份有限公司 | 一种2-氨基-5-氯-n,3-二甲基苯甲酰胺的制备方法 |
CN111228250A (zh) * | 2020-03-03 | 2020-06-05 | 中国医学科学院医药生物技术研究所 | 2-苯磺酰胺基苯甲酰胺类化合物在制备治疗肝癌药物中的应用 |
CN111909053A (zh) * | 2020-08-06 | 2020-11-10 | 湖北省生物农药工程研究中心 | 基于二芳胺单元的酰胺类衍生物及其制备方法和应用 |
CN111909053B (zh) * | 2020-08-06 | 2022-12-06 | 湖北省生物农药工程研究中心 | 基于二芳胺单元的酰胺类衍生物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2019179436A1 (zh) | 2019-09-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110305045A (zh) | 一种酰胺类化合物及其在治疗癌症中的用途 | |
CN105555782B (zh) | 喹唑啉衍生物及其制备方法 | |
CN108929263B (zh) | 芳酰胺类Kv2.1抑制剂及其制备方法、药物组合物和用途 | |
CN107548391A (zh) | 嘧啶或吡啶类化合物、其制备方法和医药用途 | |
UA76590C2 (en) | Substituted amides acting on receptor of cannabinoid-1 | |
CN108689994A (zh) | 用作alk激酶抑制剂的化合物及其应用 | |
CN110092779B (zh) | 一种取代的苯基化合物及其应用 | |
CN114761003A (zh) | 具有雄激素受体降解活性的新型脲类及其用途 | |
JP6669868B2 (ja) | フタラジン誘導体、その製造方法、医薬組成物および使用 | |
CN110386927A (zh) | 组蛋白乙酰转移酶(hat)抑制剂及其用途 | |
WO2017121388A1 (zh) | 喹唑啉酮衍生物、其制备方法、药物组合物及应用 | |
CN113329999B (zh) | 具有雄激素受体降解活性的新型取代的喹啉-8-甲腈衍生物及其用途 | |
CN111196814B (zh) | 芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用 | |
CN106810559A (zh) | 成纤维细胞生长因子受体选择性抑制剂及其应用 | |
JP2012523393A (ja) | インダン誘導体 | |
JP6100755B2 (ja) | (2−ヘテロアリールアミノ)コハク酸誘導体 | |
CN110862397A (zh) | 二噁烷并喹唑啉与二噁烷并喹啉类化合物及其制备方法与应用 | |
JP2016539993A (ja) | N−置換ピラゾリルグアニジンf1f0−atpアーゼ阻害剤及びその治療用途 | |
KR20210148296A (ko) | 퀴놀린 함유 화합물, 의약 조성물 및 그의 용도 | |
CN114710956A (zh) | 抑制perk的吡咯并嘧啶化合物 | |
CN106687449B (zh) | 一种氨基磺酰基类化合物、其制备方法及用途 | |
CN101898985B (zh) | Bcl-2蛋白的N-取代苯磺酰基-取代苯甲酰胺类小分子抑制剂及其应用 | |
CN107176956B (zh) | 一种ido抑制剂化合物、药用组合物、用途 | |
CN105829304B (zh) | N,n’取代哌啶胺类化合物、其制备方法及用途 | |
WO2022161422A1 (zh) | 杂环酰胺衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: No.2 and No.3, floor 4, building 1, Rongyao building, No.5 Keyuan South Road, high tech Zone, Chengdu, Sichuan 610000 Applicant after: Haichuang Pharmaceutical Co.,Ltd. Address before: No.1, floor 4, building a, Rongyao building, No.5 Keyuan South Road, high tech Zone, Chengdu, Sichuan 610041 Applicant before: HINOVA PHARMACEUTICALS Inc. |
|
CB02 | Change of applicant information | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191008 |
|
RJ01 | Rejection of invention patent application after publication |