CN110292580A - 用于制备抗癌剂al3818、其结晶形式和其盐的方法 - Google Patents
用于制备抗癌剂al3818、其结晶形式和其盐的方法 Download PDFInfo
- Publication number
- CN110292580A CN110292580A CN201910452231.9A CN201910452231A CN110292580A CN 110292580 A CN110292580 A CN 110292580A CN 201910452231 A CN201910452231 A CN 201910452231A CN 110292580 A CN110292580 A CN 110292580A
- Authority
- CN
- China
- Prior art keywords
- methyl
- cancer
- base oxygroup
- base
- indole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 42
- 150000003839 salts Chemical class 0.000 title claims abstract description 33
- 239000013078 crystal Substances 0.000 title abstract description 23
- 239000002246 antineoplastic agent Substances 0.000 title description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims abstract description 94
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 51
- LPYZZLNGKUWISO-UHFFFAOYSA-N 1-fluoro-2-methylindole Chemical compound C1=CC=C2N(F)C(C)=CC2=C1 LPYZZLNGKUWISO-UHFFFAOYSA-N 0.000 claims abstract description 49
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 208000030533 eye disease Diseases 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims description 110
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 15
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 12
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 6
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- QJBXPIZGUYIVKB-UHFFFAOYSA-N cyclopropanamine;dihydrochloride Chemical compound Cl.Cl.NC1CC1 QJBXPIZGUYIVKB-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 230000001613 neoplastic effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229960003876 ranibizumab Drugs 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 4
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 206010028980 Neoplasm Diseases 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000000634 powder X-ray diffraction Methods 0.000 description 18
- 208000014829 head and neck neoplasm Diseases 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 229930012538 Paclitaxel Natural products 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- -1 RT: room temperature Chemical compound 0.000 description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
- 238000010511 deprotection reaction Methods 0.000 description 10
- 229960001592 paclitaxel Drugs 0.000 description 10
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 10
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 9
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 9
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 9
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 9
- 206010014759 Endometrial neoplasm Diseases 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 9
- 208000026037 malignant tumor of neck Diseases 0.000 description 9
- 229910052697 platinum Inorganic materials 0.000 description 9
- 206010005003 Bladder cancer Diseases 0.000 description 8
- 208000003174 Brain Neoplasms Diseases 0.000 description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 8
- 206010039491 Sarcoma Diseases 0.000 description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 description 8
- 208000024770 Thyroid neoplasm Diseases 0.000 description 8
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 8
- 206010017758 gastric cancer Diseases 0.000 description 8
- 210000003128 head Anatomy 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 201000007270 liver cancer Diseases 0.000 description 8
- 208000014018 liver neoplasm Diseases 0.000 description 8
- 201000005202 lung cancer Diseases 0.000 description 8
- 208000020816 lung neoplasm Diseases 0.000 description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 8
- 201000011549 stomach cancer Diseases 0.000 description 8
- 201000002510 thyroid cancer Diseases 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- 201000005112 urinary bladder cancer Diseases 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 7
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- 206010009944 Colon cancer Diseases 0.000 description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 7
- 206010060862 Prostate cancer Diseases 0.000 description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 7
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 7
- 229960004562 carboplatin Drugs 0.000 description 7
- 201000010881 cervical cancer Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 201000003914 endometrial carcinoma Diseases 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 201000001441 melanoma Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 229940123237 Taxane Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- ANHOWPBVPPIHML-UHFFFAOYSA-N benzyl n-cyclopropylcarbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CC1 ANHOWPBVPPIHML-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- ZFEJTYQUWRVCFW-UHFFFAOYSA-N 2-chloro-6-methoxyquinoline Chemical compound N1=C(Cl)C=CC2=CC(OC)=CC=C21 ZFEJTYQUWRVCFW-UHFFFAOYSA-N 0.000 description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 210000003161 choroid Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 230000000174 oncolytic effect Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001238 wet grinding Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- IDPWXVBDDIYDKT-UHFFFAOYSA-N 2-phenoxyquinoline Chemical compound C=1C=C2C=CC=CC2=NC=1OC1=CC=CC=C1 IDPWXVBDDIYDKT-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 238000011199 Dunnett post hoc test Methods 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- VAZQQRNYILEOGE-UHFFFAOYSA-N benzyl n-[1-(hydroxymethyl)cyclopropyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1(CO)CC1 VAZQQRNYILEOGE-UHFFFAOYSA-N 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000013534 fluorescein angiography Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229950008461 talimogene laherparepvec Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Endocrinology (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种新的合成1‑((4‑(4‑氟‑2‑甲基‑1H‑吲哚‑5‑基氧基)‑6‑甲氧基喹啉‑7‑基氧基)甲基)环丙胺(AL3818)的方法。已经制备Al3818的稳定结晶形式。也已经制备AL3818的盐和其结晶形式。已经进一步测试AL3818和其盐的抗癌和抗眼病活性。新方法已概述在流程I中。
Description
本申请是申请日为2016年05月03日,申请号为:201680025775.1,发明名称为“用于制备抗癌剂1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺、其结晶形式和其盐的方法”的中国发明专利申请的分案申请。
本申请案主张2015年5月4日提交的美国临时申请案62/156,734和2015年8月14日提交的美国临时申请案62/205,272的权益。
技术领域
本发明涉及一种新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的方法。已经制备Al3818的稳定结晶形式。也已经制备AL3818的盐和其结晶形式。已经进一步测试AL3818和其盐的抗癌和抗眼病活性。
背景技术
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)已经作为血管生成抑制剂在WO2008112407中公开结构,但具有极少制备方法。
发明内容
缩写和定义
为了易于参考,使用以下缩写并且所述缩写具有以下含义。
EtOH:乙醇,MeOH:甲醇,IPA:异丙醇,EtOAc:乙酸乙酯,RT:室温,DIPEA:二异丙基乙胺,DCM:二氯甲烷,DMF:N,N-二甲基甲酰胺,DMAP:4-N,N-二甲氨基吡啶,MsCl:甲磺酰氯,THF:四氢呋喃,TFA:三氟乙酸,TEA:三乙胺,Pd/C:钯/活性碳,
eq:当量,g:克,mg:毫克,ml:毫升,min:分钟,bis=di:二或双
DSC:差示扫描量热,TGA:热解重量分析,XRPD:X射线粉末衍射,Exo:放热,Endo:吸热。
ALL:急性淋巴细胞性或淋巴母细胞性白血病,CLL:慢性淋巴细胞性或淋巴母细胞性白血病,AML:急性骨髓性或骨髓白血病,CML:慢性骨髓性或骨髓白血病
除非另外指明,否则如本文所用的术语“C1-C6烷基”包括具有直链或分支链部分的1至6个饱和单价烃基团,包括(但不限于)甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等。
除非另外指明,否则如本文所用的术语“C1-C6烷氧基”包括-OC1-C6烷基,其中C1-C6烷基如上文所定义,如甲氧基和乙氧基。
本发明范围
本发明涉及一种新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的方法,在流程I中通过使中间物(X1)与(Y1)在溶剂中在KI或NaI存在下缩合或使中间物(X2)与(Y2)在溶剂中缩合形成中间物(Z),使其脱除保护基得到最终化合物(AL3818)。也已经制备1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式和其盐以及盐的结晶形式。
其中R选自H和C1-C6烷氧基。
附图说明
图1.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的结晶形式的DSC图
图2.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的结晶形式的TGA图
图3.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的结晶形式的XRPD图
图4.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐的结晶形式的DSC图
图5.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐的结晶形式的TGA图
图6.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐的结晶形式的XRPD图
图7.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐水合物的结晶形式的DSC图
图8.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐水合物的结晶形式的TGA图
图9.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐水合物的结晶形式的XRPD图
图10.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双马来酸盐的结晶形式的DSC图
图11.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双马来酸盐的结晶形式的TGA图
图12.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双马来酸盐的结晶形式的XRPD图
图13.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的丁二酸盐的结晶形式的DSC图
图14.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的丁二酸盐的结晶形式的TGA图
图15.1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的丁二酸盐的结晶形式的XRPD图
图16.AL3818和其盐对于人类子宫内膜癌Ishikawa异种移植无胸腺小鼠的作用
图17.AL3818盐与卡铂(Carboplatin,CBX)/太平洋紫杉醇(Paclitaxel,Taxol)的组合对于人类子宫内膜癌Ishikawa异种移植无胸腺小鼠的作用
图18.经口给予AL3818对于激光诱导的CNV的作用
图19.AL3818(0.15mg/kg体重)和玻璃体内抗VEGF抗体对于激光诱导的CNV的作用
具体实施方式
本发明涉及一种新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的方法,在流程I中通过使中间物(X1)与(Y1)在溶剂中在KI或NaI存在下缩合或使中间物(X2)与(Y2)在溶剂中缩合形成中间物(Z),使其脱除保护基得到最终化合物(AL3818)。
其中R选自H和C1-C6烷氧基,较佳选自H和-OMe;
本发明涉及制备1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式;
本发明涉及制备1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的盐或稳定结晶盐形式;
本发明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱形式。
本发明涉及制备一种药物组合物,其包含1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式和药学上可接受的载剂;
本发明涉及制备一种药物组合物,其包含1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的盐或稳定结晶盐形式和药学上可接受的载剂;
本发明涉及一种1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式或盐或稳定结晶盐形式,其用于治疗赘生性疾病的方法中;
本发明涉及一种1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式或盐或稳定结晶盐形式,其用于制造用于治疗赘生性疾病的方法的药剂;
本发明涉及一种1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的稳定结晶形式或盐或稳定结晶盐形式,其用于以单一疗法形式或与选自基于铂或基于紫杉烷(taxane)的药剂的化疗剂组合用于治疗以下疾病的方法:实体肿瘤,选自肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌;和血癌,选自ALL、CLL、AML、CML和多发性骨髓瘤;
本发明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱形式,其用于以单一疗法形式或与选自基于铂或基于紫杉烷的药剂的化疗剂组合用于治疗以下疾病的方法:实体肿瘤,选自肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌;和血癌,选自ALL、CLL、AML、CML和多发性骨髓瘤;
本发明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱形式,其用于以单一疗法形式或与选自基于铂或基于紫杉烷的药剂的化疗剂组合用于治疗以下疾病的方法:肺癌、结肠直肠癌、胃癌、甲状腺癌、胰腺癌、肝癌、***癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌。
本发明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱形式,其用于与选自以下的免疫治疗剂组合的方法:基于PD-1或PD-L1、SLAM7、溶瘤病毒疗法、双特异性T细胞衔接***(BiTE)和嵌合抗原受体(CAR)T细胞疗法的药剂,如尼沃单抗(nivolumab)、派立珠单抗(pembrolizumab)、伊匹单抗(ipilimumab)、布林莫单抗(blinatumomab)、埃罗妥珠单抗(elotuzumab)、达土木单抗(daratumumab)、塔力莫基因拉帕沃克(talimogene laherparepvec),用于治疗实体肿瘤,选自肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌;和血癌,选自ALL、CLL、AML、CML和多发性骨髓瘤;本发明涉及一种新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的方法,根据方法A通过使中间物(X1)与(Y1)在溶剂中在KI或NaI存在下缩合形成中间物(Z),使其脱除保护基得到最终化合物(AL3818)。
当R为H时,最终化合物(AL3818)是根据方法A1通过使中间物(Z-1)在如MeOH的醇溶剂中在25℃-80℃下用HCOONH4(甲酸铵)和Pd/C脱除保护基0.1-4小时来制备。(Z-1)是通过使中间物(X1)与(Y1-1)在KI或NaI以及K2CO3存在下在如丙酮或DMF的溶剂中在60℃-160℃的温度下反应2-24小时来制备。
当R为4-OMe时,最终化合物(AL3818)是根据方法A2通过使中间物(Z-2)在DCM中在0℃-30℃下用TFA脱除保护基1-24小时来制备。(Z-2)是通过使中间物(X1)与(Y1-2)在KI或NaI以及K2CO3存在下在如丙酮或DMF的溶剂中在60℃-160℃的温度下反应2-24小时来制备。
本发明涉及一种新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的方法,根据方法B通过使中间物(X2)与(Y2)在溶剂中反应形成中间物(Z),使其脱除保护基得到最终化合物(AL3818)。
当R为H时,最终化合物(AL3818)是根据方法B1通过使中间物(Z-1)在如MeOH的醇溶剂中在25℃-80℃下用HCOONH4(甲酸铵)和Pd/C脱除保护基0.1-4小时来制备。(Z-1)是通过使中间物(X2-1)与(Y2)在如吡啶或二甲基吡啶的溶剂中在60℃-160℃的温度下反应1-12小时来制备。
当R为4-OMe时,最终化合物(AL3818)是根据方法B2通过使中间物(Z-2)在DCM中在0℃-30℃下用TFA脱除保护基1-24小时来制备。(Z-2)是通过使中间物(X2-2)与(Y2)在如吡啶或二甲基吡啶的溶剂中在60℃-160℃的温度下反应1-12小时来制备。
以下实例进一步说明本发明,但是不应解释为以任何方式限制其范围。
实例1
方法A、方法A1的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的制备方法
向1-(羟甲基)环丙基氨基甲酸苯甲酯(50g)和DCM(200ml)的搅拌混合物中添加DIPEA(39g)。将所得溶液用冰/水冷却至0-5℃并且在此温度下进一步搅拌15分钟。经由加料漏斗逐滴添加MsCl(30g),使温度保持在5℃以下约1.5小时。在添加完成之后,使反应混合物在0-5℃下搅拌30分钟并且用饱和NaHCO3(150ml)淬灭。将溶液用150ml DCM萃取两次。将合并的DCM层用0.1N HCl(400ml)、随后用盐水洗涤。将其经Na2SO4干燥并且浓缩以获得60克灰白色固体作为甲磺酸(1-(苯甲氧基羰基氨基)环丙基)甲酯(Y1-1),MS:(M+1)300。
向(Y1-1)(16g)、X1[(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-羟基喹啉,12g]、K2CO3(21g)和KI(21g)的搅拌混合物中添加DMF(100ml),将反应悬浮液在80℃下加热10小时并且添加(Y1-1)(10g)以继续在80℃下加热10小时。将反应物接着用水(150ml)淬灭并且用150ml DCM萃取两次。将合并的DCM层用2N NaOH(100ml)、随后用水和盐水洗涤。将其经Na2SO4干燥并且浓缩,进一步从EtOH中再结晶以获得9.5g黄色固体作为1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙基氨基甲酸苯甲酯(Z-1)。MS:(M+1)542。
向(Z-1)(9.5g)、HCOONH4(4.7g)和Pd/C(10%,湿润50%,4.7g)的搅拌混合物中添加MeOH,将反应混合物在45℃下加热1.5小时。接着将其冷却并且经由硅藻土过滤,进一步蒸发。添加2N HCl(200ml)并且用DCM/MeOH(10/1,100ml)萃取两次。将水层用3N NaOH碱化以调节至pH 11-12,从而生成固体沉淀物。将固体过滤并且用水洗涤至中性,进一步抽吸干燥。将固体溶解于DCM/MeOH的混合物(250ml,10/1)中并且进一步用水和盐水洗涤。将其用MgSO4干燥并且过滤,进一步蒸发以得到5.5g淡黄色固体粗产物。通过在缓慢搅拌下将粗产物溶解于DCM/MeOH(40ml,10/1)中以便用石油醚(40ml)湿磨2小时来进行进一步纯化。过滤沉淀物并且在烘箱中干燥得到4.4g最终结晶产物(MP:203-208℃),其可以通过从EtOH中再结晶而进一步纯化得到呈相同结晶形式的较纯最终产物。MS:(M+1)408;1H NMR(DMSO-d6)δ0.60-0.63(d,4H),2.41(s,1H),2.42-2.51(t,2H),3.31(s,2H),3.96(s,3H),4.04(s,2H),6.27(s,1H),6.31-6.32(m,1H),6.97-7.02(t,1H),7.20-7.22(d,1H),7.36(s,1H),7.60(s,1H),8.40-8.42(d,1H),11.41(s,1H)。MP:208-210℃;DSC熔化范围(吸热):207-220℃,峰值温度=216℃。TGA证实为在约210℃下(在205-215℃之间)具有重量损失的非溶剂化材料。XRPD的图案包含强度%大于10%的10个特征峰,以如下d值和角度表示:
XRPD的图案包含所有强度%的26个特征峰,以如下d值和角度表示:
DSC、TGA和XRPD的图形分别由图1、图2和图3表示。
实例2
方法A、方法A2的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的制备方法
其是根据实例1中所述的(Z-1)的制备程序,通过使用1-(羟甲基)环丙基氨基甲酸4-甲氧基苯甲酯首先生成甲磺酸(1-((4-甲氧基苯甲氧基)羰基氨基)环丙基)甲酯(Y1-2),接着得到1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙基氨基甲酸4-甲氧基苯甲酯(Z-2)而类似地制备,MS:(M+1)572。
在0℃下,向(Z-2)(1.5g)于DCM(15ml)中的搅拌混合物中添加TFA(1.5ml)约30分钟并且升温至室温。将反应物在室温下搅拌2小时并且添加至水(30ml)中。将水层用DCM萃取两次(100ml×2)并且用2N NaOH碱化以调节至pH 11-12。将混合物用DCM(100ml×3)萃取并且进一步用盐水(100ml)洗涤。将其用MgSO4干燥并且过滤。蒸发溶液得到1.05g粗最终产物。进行进一步纯化以将粗产物溶解于DCM/MeOH中,用石油醚湿磨并且在烘箱中干燥,得到0.8g具有相同结晶形式的最终纯产物AL3818。
实例3
方法A、方法B1的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的制备方法
向1-((4-氯-6-甲氧基喹啉-7-基氧基)甲基)环丙基氨基甲酸苯甲酯(X2-1)(5g)、4-氟-2-甲基-1H-吲哚-5-醇(Y2)(5g)和DMAP(4g)的混合物中添加1,6-二甲基吡啶(15ml)。将反应物搅拌并且在135℃下加热5小时,冷却,接着在室温下添加IPA同时缓慢搅拌2小时。过滤固体并且进一步用IPA洗涤,干燥得到呈固体状的5.2g(Z-1)。其接着是根据实例1中所述的(Z-1)的脱除保护基程序而类似地制备,得到具有相同结晶形式的最终化合物AL3818。
实例4
方法A、方法B2的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(AL3818)的制备方法
(Z-2)是根据实例3中所述的程序,通过使用1-((4-氯-6-甲氧基喹啉-7-基氧基)甲基)环丙基氨基甲酸4-甲氧基苯甲酯(X2-2)和(Y2)而类似地制备。其接着是根据实例2中所述的(Z-2)的脱除保护基程序而类似地制备,得到具有相同结晶形式的最终化合物AL3818。
实例5
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺双盐酸盐和其结晶的制备
向25ml烧瓶中添加含250mg游离碱(AL3818)、0.625mL含4N HCl的二噁烷(2.5mmol,4eq.)的10ml EtOH,将反应物在75℃下加热30分钟,冷却至室温并且搅拌过夜。过滤固体并且用丙酮冲洗两次。将其在烘箱中在50℃下干燥4小时,得到126mg呈双盐酸盐结晶形式的白色固体,并且进一步从EtOH中再结晶,得到呈相同结晶形式的较纯产物。1HNMR(DMSO-d6)δ1.09-1.24(m,4H),2.43(s,3H),4.08(s,3H),4.40(s,2H),6.32(s,1H),6.76(s,1H),7.05-7.11(t,1H),7.27-7.30(d,1H),7.65(s,1H),7.82(s,1H),8.64(s,2H),8.70-8.73(m,1H),11.51(s,1H)。氯离子色谱显示2分子比率离子(16.1%)。DSC熔化范围(放热):249-280,峰值温度=268℃。TGA证实为在约230℃下(在225-235℃之间)具有重量损失的非溶剂化材料。XRPD的图案包含强度%大于10%的21个特征峰或所有强度%的27个峰,以如下d值和角度表示:
DSC、TGA和XRPD的图形分别由图4、图5和图6表示。
实例6
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺双盐酸盐水合物和其结晶的制备
向10mL烧瓶中装入140mg以上实例4的3818-2HCl盐和0.7mL(×5盐体积)含80%MeOH的H2O。将所得悬浮液加热至70℃以形成溶液,冷却至室温并且进一步搅拌过夜。过滤固体并且用丙酮冲洗两次。将其在烘箱中在50℃下干燥4小时,获得110mg呈结晶双盐酸盐水合物形式的灰白色固体。1H NMR(DMSO-d6)δ1.09(s,2H),1.22(s,2H),2.44(s,1H),2.52(s,2H),4.09(s,3H),4.44(s,2H),6.32(s,1H),6.81-6.82(d,1H),7.08-7.14(t,1H),7.29-7.32(d,1H),7.79(s,1H),7.85(s,1H),8.75-8.78(d,1H),8.85(s,2H),11.66(s.1H)。氯离子色谱显示2分子比率离子(17.8%)。DSC熔化范围(放热):207-260℃,峰值温度=226℃。TGA证实直到120℃(在115-125℃之间)的2.68%(~3%,1个水)重量损失并且在约170℃下(在165-175℃之间)的进一步重量损失。XRPD的图案包含强度%大于10%的9个特征峰或所有强度%的12个峰,以如下d值和角度表示:
DSC、TGA和XRPD的图形分别由图7、图8和图9表示。
实例7
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺双马来酸盐和其结晶的制备
向25mL烧瓶中添加含50mg游离碱(AL3818)的1.5mL EtOH,将反应物在搅拌下加热至70℃。向所得溶液中添加36mg(2.5eq)呈固体状的马来酸并且在70℃下搅拌0.5小时。将其冷却至室温并且搅拌过夜。过滤固体并且用丙酮冲洗两次,在烘箱中在50℃下进一步干燥4小时,获得呈结晶固体状的68mg,并且进一步从EtOH中再结晶,得到呈与两个(双)马来酸盐相同的结晶形式的较纯产物。1H NMR(DMSO-d6)δ0.73(s,2H),0.88(s,2H),3.43(s,2H),3.53(s,2H),3.59(s,2H),3.86(s,4H),3.97(s,3H),4.41(s,1H),6.07(s,2H),7.26(s,1H),7.44-7.50(t,1H),7.76-7.79(d,1H),7.88(s,1H),8.10-8.12(d,1H),8.55(s,1H),9.54(s.1H)。马来酸根离子色谱显示2分子比率离子(37.1%)。DSC熔化范围(吸热):165-202℃,峰值温度=183℃。TGA证实为在约160℃下(在155-165℃之间)具有重量损失的非溶剂化材料。XRPD的图案包含强度%大于10%的22个特征峰或所有强度%的35个峰,以如下d值和角度表示:
DSC、TGA和XRPD的图形分别由图10、图11和图12表示。
实例8
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺丁二酸盐和其结晶的制备
向50mL烧瓶中添加含100mg游离碱(AL3818)的4mL EtOH,将反应物在搅拌下加热至75℃。向所得溶液中添加36mg呈固体状的丁二酸(0.308mmol,1.25eq)并且在75℃下搅拌0.5小时。将其冷却至室温并且搅拌过夜。过滤固体并且用丙酮冲洗两次,在烘箱中在50℃下进一步干燥4小时,获得84mg结晶固体,并且进一步从EtOH中再结晶,得到呈相同结晶形式的较纯产物。1H NMR(DMSO-d6)δ0.72(s,4H),2.37-2.42(m,7H),3.99(s,3H),4.10(s,2H),6.27(s,1H),6.32-6.33(d,1H),6.97-7.02(t,1H),7.20-7.23(d,1H),7.39(s,1H),7.61(s,1H),8.42(s,2H),11.41(s,1H)。丁二酸根离子色谱显示1分子比率离子(23.2%)。DSC熔化范围:熔化范围(吸热):176-202℃,峰值温度=198℃。TGA证实为在约180℃下(在175-185℃之间)具有重量损失的非溶剂化材料。XRPD的图案包含强度%大于10%的11个特征峰或所有强度%的19个峰:
DSC、TGA和XRPD的图形分别由图13、图14和图15表示。
实例9
使用来自以上实例的化合物进行活体外MTT(增殖)分析以得到以下抑制结果:
实例10
基于发明人使用AL3818游离碱、其2HCl盐、其双马来酸盐和其丁二酸盐的研究经历,在根据实例9的MTT分析中预测以下肿瘤抑制结果。
预测对于以下各种细胞系的活体外抑制活性为2-10μM±1.7μM:实体肿瘤,如肾癌、黑素瘤、头/颈癌、膀胱癌、脑癌;和血癌,如ALL、CLL、AML、CML和多发性骨髓瘤。
实例11
使用子宫内膜Ishikawa细胞系(异种移植物)的动物抗肿瘤活性活体内测试进行如下:
将充分生长的子宫内膜癌Ishikawa的肿瘤组织切成3mm小块,并且将每一裸鼠皮下接种一小块至右腋窝中。将动物分组并且给药如下:
1)AL3818-H1(双盐酸盐,2HCl),MW:480,3.54mg/kg
2)AL3818-H2(双盐酸盐水合物,2HCl.H2O),MW:598,3.67mg/kg
3)AL3818-S(丁二酸盐),MW:525,3.87mg/kg
4)AL3818-M(双马来酸盐),MW:639,4.71mg/kg
5)AL3818-F(游离碱),MW:407,3mg/kg
6)对照物
在13天之后,当肿瘤尺寸达到100mm3以上时,开始处理。根据肿瘤尺寸,排除肿瘤尺寸过大或尺寸不足的动物,并且将动物分组成具有类似平均肿瘤体积。接着,如上所述,每日经口给予动物0.5ml/20g的体积连续14天。在接种13天之后,一周使用卡尺测量大直径a(mm)和小直径b(mm)两次。肿瘤体积通过下式计算得到:TV=ab2/2。相对肿瘤体积如下计算:RTV=Vt/Vo,Vo表示在第一天处理时的肿瘤体积;Vt表示在每一测量日的肿瘤体积。在接种之后30天(D18),将动物处死并且通过解剖获得肿瘤。接着,测定个体体重和肿瘤重量,并且如下式计算。
肿瘤抑制活性在50-95%之间。结果在图16中示出。
实例12
基于发明人使用AL3818游离碱、其HCl盐(单或双)、其双马来酸盐和其丁二酸盐的研究经历,根据实例11预测以下活体内肿瘤抑制结果(异种移植物)。
预测对于以下各种细胞系的活体内肿瘤抑制活性为50%-100%:实体肿瘤,如肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌;和血癌,如ALL、CLL、AML、CML和多发性骨髓瘤。
实例13
AL3818双HCl盐和双马来酸盐也与通过使用以下基于铂、基于紫杉烷或这两个的化学疗法组合来加以测试;如:组合顺铂、卡铂、太平洋紫杉醇或顺铂/太平洋紫杉醇、卡铂/太平洋紫杉醇。与卡铂/太平洋紫杉醇组合的实验是与实例11的描述类似地进行。肿瘤抑制活性在50至>100%之间。结果在图17中示出。
实例14
基于发明人使用AL3818游离碱、其HCl盐(单或双)、其双马来酸盐和其丁二酸盐的研究经历,根据实例13预测以下活体内组合化学疗法(护理标准,如基于铂、基于紫杉烷或这两个的化学疗法)肿瘤抑制结果(异种移植物),尤其与顺铂、卡铂、太平洋紫杉醇或顺铂/太平洋紫杉醇、卡铂/太平洋紫杉醇一起组合。
预测对于以下各种细胞系的活体内肿瘤抑制活性为50%至>100%消退:实体肿瘤,如肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌和子***;和血癌,如ALL、CLL、AML、CML和多发性骨髓瘤。
实例15
基于发明人使用AL3818游离碱、其HCl盐(单或双)、其双马来酸盐和其丁二酸盐的研究经历,预测以下活体内组合作用,其中与选自以下的免疫治疗剂组合:基于PD-1或PD-L1、SLAM7、溶瘤病毒疗法、双特异性T细胞衔接***(BiTE)和嵌合抗原受体(CAR)T细胞疗法的药剂,如(但不限于)尼沃单抗、派立珠单抗、伊匹单抗、布林莫单抗、埃罗妥珠单抗、达土木单抗、塔力莫基因拉帕沃克,用于治疗实体肿瘤,选自肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌、子***和子宫内膜癌;和血癌,选自ALL、CLL、AML、CML和多发性骨髓瘤
预测对于以下各种细胞系的活体内肿瘤抑制活性为50%至>100%消退:实体肿瘤,如肺癌、肾癌、结肠直肠癌、胃癌、黑素瘤、头/颈癌、甲状腺癌、胰腺癌、肝癌、***癌、膀胱癌、脑癌、肉瘤、乳腺癌、卵巢癌和子***;和血癌,如ALL、CLL、AML、CML和多发性骨髓瘤。
实例16
激光诱导的脉络膜新生血管(CNV)的小鼠模型
(1)对10至12周龄的C57BL/6小鼠进行实验。使用安装在裂隙灯上的532nm二极管激光器,使用50μm光斑尺寸、100ms持续时间和100mW激光能量诱导激光CNV。每只眼睛接受4次激光烧伤。AL3818-H1的储备溶液是通过将化合物溶解于水中达到25mg/mL浓度来制备,并且进一步在水中稀释成250或25μg/ml工作溶液。小鼠是以每kg体重2.5或0.25mg的剂量,以每20克体重200μl的体积经口管饲,在激光处理之前一天开始,每天一次,直至之后10天为止。对照组小鼠将接受管饲与用于溶解化合物的水。到实验结束时,对小鼠进行荧光血管造影以排除由程序引起的出血点和其它机械伤害。将小鼠处死并且通过用FITC结合的异凝集素B4和抗ICAM2抗体共染色的RPE/脉络膜铺片的免疫染色测量CNV尺寸。对于对照组0.25mg/kg和2.5mg/kg,我们检查RPE/脉络膜铺片上的眼43、44和49。在免疫染色之后,在蔡司(Zeiss)萤光显微镜上获取影像。在Image J软件中测量CNV尺寸。我们的结果(图18)显示用0.25或2.5mg/kg体重的AL3818处理的小鼠的激光诱导的CNV的平均尺寸几乎减小70%。
(2)还研究在AL3818-M与抗VEGF抗体之间的潜在协同或累加作用。紧接在激光烧伤之后,小鼠通过玻璃体内注射用1μg剂量来自安迪生物公司(R&D Systems)的单克隆VEGF中和抗体(mAb AF564)处理。我们具有4个实验组:对照(用水处理)、AL3818-M、抗VEGF和AL3818-M+抗VEGF。总共分析75个激光光斑。对照组或仅AL3818-M组中的小鼠接受相同2μl体积生理食盐水的玻璃体内注射。结果(图19)显示用0.15mg/kg AL3818和1μg抗VEGF抗体处理的眼的激光CNV与对照组相比减少几乎30%(P<0.01,单因素方差分析,邓尼特事后检验(Dunnett post-hoc test))。
实例17
基于发明人使用AL3818游离碱、其HCl盐(单或双)、其双马来酸盐和其丁二酸盐的研究经历,根据实例16明确预测与如但不限于AMD(年龄相关性黄斑变性)的眼病的有效治疗相关的活体内动物模型CNV功效;或也根据实例16明确预测这些化合物与抗VEGF抗体或VEGF捕获剂(如但不限于兰比珠单抗(ranibizumab)或阿柏西普(aflibercep))组合产生协同治疗作用。
实例18
已经进行常规水溶性测试,得到以下结果:
Claims (4)
1.一种药物组合物,其包含选自1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱形式作为活性成分和药学上可接受的载剂。
2.一种治疗赘生性疾病的方法,所述方法包含将1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱或包含其的药物组合物给予有需要的个体;或将所述化合物或药物组合物与化疗剂或免疫治疗剂组合给予有需要的个体。
3.一种治疗眼病的方法,所述方法包含将将1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺的双盐酸盐、双盐酸盐水合物、双马来酸盐和丁二酸盐、和其稳定结晶盐形式或稳定结晶游离碱或包含其的药物组合物给予有需要的个体;或将所述化合物或药物组合物与抗VEGF抗体或VEGF捕获剂组合给予有需要的个体。
4.根据权利要求3所述的治疗方法,其中疾病为AMD并且所述组合抗VEGF抗体为兰比珠单抗(ranibizumab),或所述VEGF捕获剂为阿柏西普(aflibercep)。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910452231.9A CN110292580B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562156734P | 2015-05-04 | 2015-05-04 | |
US62/156,734 | 2015-05-04 | ||
US201562205272P | 2015-08-14 | 2015-08-14 | |
US62/205,272 | 2015-08-14 | ||
US15/143,630 | 2016-05-02 | ||
US15/143,630 US9751859B2 (en) | 2015-05-04 | 2016-05-02 | Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts |
CN201680025775.1A CN107771078B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺、其结晶形式和其盐的方法 |
PCT/US2016/030483 WO2016179123A1 (en) | 2015-05-04 | 2016-05-03 | Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl) cyclopropanamine, its crystalline form and its salts |
CN201910452231.9A CN110292580B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680025775.1A Division CN107771078B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺、其结晶形式和其盐的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110292580A true CN110292580A (zh) | 2019-10-01 |
CN110292580B CN110292580B (zh) | 2023-08-04 |
Family
ID=57218545
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910452231.9A Active CN110292580B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN202111453058.8A Pending CN114129567A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201910452221.5A Active CN110292579B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201910543920.0A Active CN110172057B (zh) | 2015-05-04 | 2016-05-03 | 喹啉衍生物的盐及其结晶形式 |
CN202310823755.0A Pending CN116898849A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN202111450705.XA Pending CN114099510A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201680025775.1A Active CN107771078B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺、其结晶形式和其盐的方法 |
CN201910451534.9A Active CN110294741B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
Family Applications After (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111453058.8A Pending CN114129567A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201910452221.5A Active CN110292579B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201910543920.0A Active CN110172057B (zh) | 2015-05-04 | 2016-05-03 | 喹啉衍生物的盐及其结晶形式 |
CN202310823755.0A Pending CN116898849A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN202111450705.XA Pending CN114099510A (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
CN201680025775.1A Active CN107771078B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺、其结晶形式和其盐的方法 |
CN201910451534.9A Active CN110294741B (zh) | 2015-05-04 | 2016-05-03 | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 |
Country Status (11)
Country | Link |
---|---|
US (3) | US9751859B2 (zh) |
EP (1) | EP3291814A4 (zh) |
JP (2) | JP2018515482A (zh) |
KR (1) | KR102613409B1 (zh) |
CN (8) | CN110292580B (zh) |
AU (2) | AU2016257816A1 (zh) |
CA (1) | CA2984444A1 (zh) |
EA (1) | EA201792355A1 (zh) |
MX (1) | MX2017014108A (zh) |
TW (1) | TWI704142B (zh) |
WO (1) | WO2016179123A1 (zh) |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105311029A (zh) | 2014-06-06 | 2016-02-10 | 正大天晴药业集团股份有限公司 | 抗肿瘤活性的喹啉衍生物 |
CN105311030B (zh) | 2014-06-06 | 2020-03-24 | 正大天晴药业集团股份有限公司 | 用于抗肿瘤的螺取代化合物 |
CN105722840B (zh) | 2014-07-14 | 2018-01-05 | 杭州爱德程医药科技有限公司 | 作为PI3K、mTOR抑制剂的稠合喹啉化合物 |
AU2015360095B2 (en) | 2014-12-09 | 2020-02-27 | Advenchen Laboratories Nanjing Ltd | Quinoline derivative against non-small cell lung cancer |
US9751859B2 (en) * | 2015-05-04 | 2017-09-05 | Advenchen Pharmaceuticals, LLC | Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts |
AU2016293841B2 (en) | 2015-07-11 | 2020-10-08 | Advenchen Pharmaceuticals, LLC | Fused quinoline compunds as pi3k/mTor inhibitors |
CN107296811B (zh) * | 2016-04-15 | 2022-12-30 | 正大天晴药业集团股份有限公司 | 一种用于治疗胃癌的喹啉衍生物 |
CN108778336A (zh) | 2016-12-01 | 2018-11-09 | 江苏恒瑞医药股份有限公司 | 一种vegfr抑制剂与parp抑制剂联合在制备治疗胃癌的药物中的用途 |
CN110650741A (zh) * | 2017-05-26 | 2020-01-03 | 正大天晴药业集团股份有限公司 | 用于治疗结直肠癌的喹啉衍生物 |
CN109748902B (zh) * | 2017-11-02 | 2020-11-06 | 杭州科巢生物科技有限公司 | 一种盐酸安罗替尼的制备方法 |
TW201924720A (zh) | 2017-12-06 | 2019-07-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Parp抑制劑用於治療化療耐藥的卵巢癌或乳腺癌的用途 |
CN107970241B (zh) * | 2018-01-22 | 2020-05-22 | 正大天晴药业集团股份有限公司 | 一种新型酪氨酸激酶抑制剂安罗替尼在制备抑制骨肉瘤的药物中的应用 |
CN111630045A (zh) * | 2018-02-11 | 2020-09-04 | 正大天晴药业集团股份有限公司 | 喹啉衍生物的结晶 |
CN115057815A (zh) | 2018-03-02 | 2022-09-16 | 正大天晴药业集团股份有限公司 | 作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途 |
CN110357856B (zh) * | 2018-04-09 | 2021-02-26 | 新发药业有限公司 | 一种盐酸安罗替尼中间体及盐酸安罗替尼的制备方法 |
CN110483392A (zh) * | 2018-05-14 | 2019-11-22 | 上海海和药物研究开发有限公司 | 合成n-保护的喹啉-7-基氧基甲基环丙基胺衍生物的方法及合成中间体 |
EP3816161A4 (en) * | 2018-06-25 | 2022-03-30 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | CRYSTAL HABITUS OF A QUINOLINE DERIVATIVE AND PROCESS FOR PRODUCTION OF CRYSTALLINE POWDER |
CN112566661B (zh) * | 2018-07-18 | 2024-02-02 | 正大天晴药业集团股份有限公司 | 喹啉衍生物与抗体的药物组合 |
CN108864050B (zh) * | 2018-07-25 | 2019-12-10 | 上海博璞诺科技发展有限公司 | 一种合成安罗替尼及其盐酸盐的方法 |
CN117085017A (zh) * | 2018-09-18 | 2023-11-21 | 正大天晴药业集团股份有限公司 | 用于治疗小细胞肺癌的喹啉衍生物 |
CN112638385B (zh) * | 2018-09-18 | 2023-03-31 | 正大天晴药业集团股份有限公司 | 用于治疗脑肿瘤的喹啉衍生物 |
CN109748904A (zh) * | 2019-01-31 | 2019-05-14 | 正大天晴药业集团股份有限公司 | 喹啉衍生物的结晶 |
JP2022524761A (ja) * | 2019-03-07 | 2022-05-10 | アドヴェンチェン ファーマスーティカルズ,エルエルシー | 癌治療のための標準的な化学療法または免疫療法と組み合わせたカテケンチニブ(アンロチニブ)の順次使用 |
CA3137204A1 (en) * | 2019-04-19 | 2020-10-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma |
US20220211693A1 (en) * | 2019-05-10 | 2022-07-07 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Quinoline derivative used for soft tissue sarcoma combination therapy |
WO2020233602A1 (zh) * | 2019-05-20 | 2020-11-26 | 正大天晴药业集团股份有限公司 | 用于联合治疗小细胞肺癌的喹啉衍生物 |
WO2020233723A1 (zh) * | 2019-05-23 | 2020-11-26 | 正大天晴药业集团股份有限公司 | 用于治疗头颈癌的喹啉衍生物 |
CN113939315B (zh) * | 2019-05-30 | 2024-04-02 | 正大天晴药业集团南京顺欣制药有限公司 | 治疗黑色素瘤的联用药物组合物 |
EP4056200A4 (en) * | 2019-11-04 | 2024-01-10 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | COMBINATION OF DRUGS OF A QUINOLINE DERIVATIVE AND A PD -1 MONOCLONAL ANTIBODY |
CN114929225A (zh) * | 2020-01-19 | 2022-08-19 | 正大天晴药业集团股份有限公司 | 用于治疗类风湿性关节炎的喹啉衍生物 |
CN113262223A (zh) * | 2020-02-17 | 2021-08-17 | 上海交通大学医学院 | 安罗替尼及其药学上可接受的盐在制备治疗多发性骨髓瘤药物中的应用 |
EP4197554A1 (en) * | 2020-08-13 | 2023-06-21 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Combined medication for treating soft tissue sarcoma |
CN113116896A (zh) * | 2021-04-30 | 2021-07-16 | 厦门大学附属第一医院 | 安罗替尼在制备急性髓系白血病干细胞杀伤药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809012A (zh) * | 2007-03-14 | 2010-08-18 | 南京爱德程医药科技有限公司 | 作为血管生成抑制剂的螺取代化合物 |
CN102344438A (zh) * | 2010-08-01 | 2012-02-08 | 江苏正大天晴药业股份有限公司 | 喹啉衍生物的结晶及其制备方法 |
CN103664890A (zh) * | 2010-08-01 | 2014-03-26 | 正大天晴药业集团股份有限公司 | 喹啉衍生物的结晶及制备方法 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
US9370508B2 (en) | 2007-02-20 | 2016-06-21 | Novartis Ag | Imidazoquinolines as dual lipid kinase and mTOR inhibitors |
US8163923B2 (en) * | 2007-03-14 | 2012-04-24 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
US20110212053A1 (en) | 2008-06-19 | 2011-09-01 | Dapeng Qian | Phosphatidylinositol 3 kinase inhibitors |
MX2011004018A (es) * | 2008-10-14 | 2011-06-24 | Ning Xi | Compuestos y metodos de uso. |
IT1393351B1 (it) | 2009-03-16 | 2012-04-20 | Eos Ethical Oncology Science Spa In Forma Abbreviata Eos Spa | Procedimento per la preparazione della 6-(7-((1-amminociclopropil)metossi)-6-metossichinolin-4-ilossi)-n-metil-1-naftammide e suoi intermedi di sintesi |
WO2013071865A1 (en) | 2011-11-14 | 2013-05-23 | Centaurus Biopharma Co., Ltd. | Kinase modulating compounds, compositions containing the same and use thereof |
WO2014032019A2 (en) * | 2012-08-23 | 2014-02-27 | Georgetown University | Compounds and methods of use thereof for treating tumors |
WO2014113616A1 (en) | 2013-01-18 | 2014-07-24 | Advenchen Pharmaceuticals, LLC | Process for preparing the anti-tumor agent 6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and its crystalline |
BR112015020139A2 (pt) * | 2013-02-20 | 2017-07-18 | Kala Pharmaceuticals Inc | compostos terapêuticos e usos dos mesmos |
CN104513229A (zh) | 2013-09-28 | 2015-04-15 | 正大天晴药业集团股份有限公司 | 喹唑啉衍生物及其制备方法 |
CN105311030B (zh) * | 2014-06-06 | 2020-03-24 | 正大天晴药业集团股份有限公司 | 用于抗肿瘤的螺取代化合物 |
CN105311029A (zh) | 2014-06-06 | 2016-02-10 | 正大天晴药业集团股份有限公司 | 抗肿瘤活性的喹啉衍生物 |
CN105722840B (zh) | 2014-07-14 | 2018-01-05 | 杭州爱德程医药科技有限公司 | 作为PI3K、mTOR抑制剂的稠合喹啉化合物 |
AU2015360095B2 (en) | 2014-12-09 | 2020-02-27 | Advenchen Laboratories Nanjing Ltd | Quinoline derivative against non-small cell lung cancer |
US9751859B2 (en) * | 2015-05-04 | 2017-09-05 | Advenchen Pharmaceuticals, LLC | Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts |
AU2016293841B2 (en) | 2015-07-11 | 2020-10-08 | Advenchen Pharmaceuticals, LLC | Fused quinoline compunds as pi3k/mTor inhibitors |
CN107296811B (zh) | 2016-04-15 | 2022-12-30 | 正大天晴药业集团股份有限公司 | 一种用于治疗胃癌的喹啉衍生物 |
-
2016
- 2016-05-02 US US15/143,630 patent/US9751859B2/en active Active
- 2016-05-03 AU AU2016257816A patent/AU2016257816A1/en not_active Abandoned
- 2016-05-03 CA CA2984444A patent/CA2984444A1/en active Pending
- 2016-05-03 CN CN201910452231.9A patent/CN110292580B/zh active Active
- 2016-05-03 JP JP2017557130A patent/JP2018515482A/ja not_active Abandoned
- 2016-05-03 WO PCT/US2016/030483 patent/WO2016179123A1/en active Application Filing
- 2016-05-03 CN CN202111453058.8A patent/CN114129567A/zh active Pending
- 2016-05-03 MX MX2017014108A patent/MX2017014108A/es unknown
- 2016-05-03 EA EA201792355A patent/EA201792355A1/ru unknown
- 2016-05-03 CN CN201910452221.5A patent/CN110292579B/zh active Active
- 2016-05-03 CN CN201910543920.0A patent/CN110172057B/zh active Active
- 2016-05-03 CN CN202310823755.0A patent/CN116898849A/zh active Pending
- 2016-05-03 KR KR1020177034805A patent/KR102613409B1/ko active IP Right Grant
- 2016-05-03 CN CN202111450705.XA patent/CN114099510A/zh active Pending
- 2016-05-03 CN CN201680025775.1A patent/CN107771078B/zh active Active
- 2016-05-03 CN CN201910451534.9A patent/CN110294741B/zh active Active
- 2016-05-03 EP EP16789916.0A patent/EP3291814A4/en active Pending
- 2016-05-04 TW TW105113816A patent/TWI704142B/zh active
-
2017
- 2017-07-25 US US15/659,510 patent/US10100034B2/en active Active
-
2018
- 2018-09-07 US US16/125,401 patent/US10544125B2/en active Active
-
2020
- 2020-11-30 AU AU2020281003A patent/AU2020281003B2/en active Active
-
2021
- 2021-03-01 JP JP2021031318A patent/JP7195551B2/ja active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809012A (zh) * | 2007-03-14 | 2010-08-18 | 南京爱德程医药科技有限公司 | 作为血管生成抑制剂的螺取代化合物 |
CN103483319A (zh) * | 2007-03-14 | 2014-01-01 | 南京爱德程医药科技有限公司 | 作为血管生成抑制剂的螺取代化合物 |
CN102344438A (zh) * | 2010-08-01 | 2012-02-08 | 江苏正大天晴药业股份有限公司 | 喹啉衍生物的结晶及其制备方法 |
CN103664890A (zh) * | 2010-08-01 | 2014-03-26 | 正大天晴药业集团股份有限公司 | 喹啉衍生物的结晶及制备方法 |
CN103664892A (zh) * | 2010-08-01 | 2014-03-26 | 正大天晴药业集团股份有限公司 | 喹啉衍生物的结晶 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110292580A (zh) | 用于制备抗癌剂al3818、其结晶形式和其盐的方法 | |
JP5840763B2 (ja) | ブロモドメイン阻害剤として有用なテトラヒドロキノリン誘導体 | |
AU2016315360B2 (en) | Pyridinone dicarboxamide for use as bromodomain inhibitors | |
JP6971390B2 (ja) | 重水素化azd9291の結晶形、製造方法および使用 | |
CN109311843A (zh) | 作为PI3Kβ抑制剂的氮杂苯并咪唑衍生物 | |
US10689361B2 (en) | Quinoline derivative and use thereof | |
CN112119074A (zh) | Egfr抑制剂 | |
TW202246254A (zh) | 聯芳組成物和調控激酶級聯之方法 | |
TW202142541A (zh) | 用作激酶抑制劑的化合物及其應用 | |
EA040599B1 (ru) | Применение кристаллической формы 1-((4-(4-фтор-2-метил-1h-индол-5-илокси)-6-метоксихинолин-7-илокси)метил)циклопропанамина или его соли в комбинированной терапии для лечения рака | |
WO2017097215A1 (zh) | 内嵌脲类结构的wnt通路抑制剂 | |
ES2853981T3 (es) | Un derivado de bencimidazol sustituido como un modulador de la actividad de TNF | |
BR112017023639B1 (pt) | Forma cristalina de 1-((4-(4-fluoro-2-metil1h-indol-5-iloxi)-6-metoxi- quinolin-7- iloxi)metil)ciclopropanamina e forma cristalina de um sal de 1-((4-(4- fluoro-2-metil-1h-indol-5-iloxi)-6-metoxi-quinolin-7-iloxi)metil)ciclopropanamina | |
BR112018003827B1 (pt) | Composto, composição farmacêutica, combinação, e, uso de um composto |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |