WO2023169462A1 - 异色满类化合物的晶型 - Google Patents
异色满类化合物的晶型 Download PDFInfo
- Publication number
- WO2023169462A1 WO2023169462A1 PCT/CN2023/080261 CN2023080261W WO2023169462A1 WO 2023169462 A1 WO2023169462 A1 WO 2023169462A1 CN 2023080261 W CN2023080261 W CN 2023080261W WO 2023169462 A1 WO2023169462 A1 WO 2023169462A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- crystal form
- add
- ray powder
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 38
- -1 isochroman compound Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 20
- 238000001228 spectrum Methods 0.000 claims description 10
- 201000007270 liver cancer Diseases 0.000 claims description 9
- 208000014018 liver neoplasm Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 3
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000012065 filter cake Substances 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000005415 bioluminescence Methods 0.000 description 9
- 230000029918 bioluminescence Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000001028 anti-proliverative effect Effects 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 238000002038 chemiluminescence detection Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 238000003828 vacuum filtration Methods 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000002356 single layer Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 241000269627 Amphiuma means Species 0.000 description 3
- NWGZZGNICQFUHV-OAHLLOKOSA-N C[C@@H](OP(=O)(N1CC1)N1CC1)C1=CC(OC2=CC(=CC=C2)C(=O)N(C)C)=C(C=C1)[N+]([O-])=O Chemical compound C[C@@H](OP(=O)(N1CC1)N1CC1)C1=CC(OC2=CC(=CC=C2)C(=O)N(C)C)=C(C=C1)[N+]([O-])=O NWGZZGNICQFUHV-OAHLLOKOSA-N 0.000 description 3
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical group 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 241000872931 Myoporum sandwicense Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 1
- YQHJFPFNGVDEDT-UHFFFAOYSA-N 2-tert-butyl-1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(N(C)C)=NC(C)(C)C YQHJFPFNGVDEDT-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 229940126161 DNA alkylating agent Drugs 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 235000009161 Espostoa lanata Nutrition 0.000 description 1
- 240000001624 Espostoa lanata Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 1
- 239000002729 catgut Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- VZOPRCCTKLAGPN-UHFFFAOYSA-L potassium;sodium;2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O VZOPRCCTKLAGPN-UHFFFAOYSA-L 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 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
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- ZTWIEIFKPFJRLV-UHFFFAOYSA-K trichlororuthenium;trihydrate Chemical compound O.O.O.Cl[Ru](Cl)Cl ZTWIEIFKPFJRLV-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
Definitions
- the present invention relates to crystal forms of heterochromatic compounds and preparation methods thereof, specifically to compounds represented by formula (I) and their application in preparing drugs for treating related diseases.
- Cancer tumor is a major disease that seriously threatens human life and health.
- Current treatment methods mainly include surgical treatment, chemotherapy, targeted therapy, etc.
- Chemotherapy is a treatment method that uses chemical drugs to kill tumor cells and inhibit the growth of tumor cells. It is a systemic treatment method. Due to the heterogeneity of malignant tumors, chemotherapy remains an important method for treating tumors. However, it is this systemic treatment that causes chemotherapy to have significant side effects. There is a huge unmet clinical need for the development of targeted chemotherapeutics.
- Aldehyde-keto reductase is a member of the aldehyde-keto reductase family and is mainly involved in hormone synthesis and toxin removal.
- AKR1C3 can be overexpressed by factors such as smoking, alcohol, hepatitis B or hepatitis C infection.
- AKR1C3 is overexpressed in a variety of refractory cancers, such as liver cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, prostate cancer, acute lymphoblastic leukemia, especially liver cancer, with a high expression rate of more than 60%.
- AKR1C3 inhibitor drugs are currently being developed clinically, but no good progress has been made.
- Haoding Company reported a compound targeting the AKR1C3 enzyme, OBI-3424.
- OBI-3424 is a selective prodrug that releases a potent DNA alkylating agent in tumor cells that highly express the AKR1C3 enzyme, and selectively kills tumor cells that highly express AKR1C3, giving chemical drugs an obvious targeting effect.
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25 ⁇ 0.20°, 13.27 ⁇ 0.20°, 15.19 ⁇ 0.20°, 16.43 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.21 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25 ⁇ 0.20°, 13.27 ⁇ 0.20°, 15.19 ⁇ 0.20°, 16.43 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.76 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25 ⁇ 0.20°, 15.19 ⁇ 0.20°, 16.43 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.76 ⁇ 0.20°, 23.56 ⁇ 0.20°, 26.66 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25 ⁇ 0.20°, 12.56 ⁇ 0.20°, 12.89 ⁇ 0.20°, 13.27 ⁇ 0.20°, 15.19 ⁇ 0.20°, 16.01 ⁇ 0.20°, 16.43 ⁇ 0.20°, 17.60 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.21 ⁇ 0.20°, 19.91 ⁇ 0.20°, 20.21 ⁇ 0.20°, 20.52 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.76 ⁇ 0.20°, 23.02 ⁇ 0.20°, 23.56 ⁇ 0.20°, 24.71 ⁇ 0.20°, 25.12 ⁇ 0.20°, 25.88 ⁇ 0.20°, 26.66 ⁇ 0.20°, 27.10 ⁇ 0.20°, 27.43 ⁇ 0.20°, 27.84 ⁇ 0.20°, 28.38 ⁇ 0.20°, 29.13 ⁇ 0.20°, 30.01 ⁇ 0.20°, 30.83
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25°, 12.56°, 12.89°, 13.27°, 15.19°, 16.01° ⁇ 16.43° ⁇ 17.60° ⁇ 17.94° ⁇ 19.21° ⁇ 19.91° ⁇ 20.21° ⁇ 20.52° ⁇ 21.25° ⁇ 21.76° ⁇ 23.02° ⁇ 23.56° ⁇ 24.71° ⁇ 25.12° ⁇ 25.88° ⁇ 26.66° ⁇ 27.10° , 27.43°, 27.84°, 28.38°, 29.13°, 30.01°, 30.83°, 31.69°, 32.26°, 33.35°, 35.01°, 35.52°, 36.51°, 37.70°, 39.24°.
- the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) above has characteristic diffraction peaks at the following 2 ⁇ angles: 8.25 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.76 ⁇ 0.20°, It is also at and/or 12.56 ⁇ 0.20°, and/or 12.89 ⁇ 0.20°, and/or 13.27 ⁇ 0.20°, and/or 15.19 ⁇ 0.20°, and/or 16.01 ⁇ 0.20°, and/or 16.43 ⁇ 0.20° , and/or 17.60 ⁇ 0.20°, and/or 17.94 ⁇ 0.20°, and/or 19.91 ⁇ 0.20°, and/or 20.21 ⁇ 0.20°, and/or 20.52 ⁇ 0.20°, and/or 21.25 ⁇ 0.20°, and /or 23.02 ⁇ 0.20°, and/or 23.56 ⁇ 0.20°, and/or 24.71 ⁇ 0.20°, and/or 25.12 ⁇ 0.20°, and/or 25.88 ⁇ 0.20°, and
- the analytical data of the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) is as shown in Table 1:
- the X-ray powder diffraction pattern of Form A of the compound of formula (I) is basically as shown in Figure 1.
- the differential scanning calorimetry curve of the crystal form A of the compound of formula (I) has an endothermic peak at 89.2 ⁇ 3°C.
- the DSC spectrum of the crystal form A of the compound of formula (I) is basically as shown in Figure 2.
- thermogravimetric analysis curve of the crystal form A of the compound of formula (I) above has a weight loss of 1.03% at 100 ⁇ 3°C.
- the TGA spectrum of crystal form A of the compound of formula (I) is basically as shown in Figure 3.
- It includes: adding the compound of formula (I) in any form (crystalline or amorphous) into a solvent, stirring at a certain temperature for a certain time, filtering, and drying the filter cake to obtain crystalline form A.
- the above solvent is selected from alcohols, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, 1,4 -Dioxane, acetonitrile and alkanes.
- the above-mentioned solvents are alcohols, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, 1,4- A mixture of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 of dioxane, acetonitrile and alkanes.
- the above-mentioned alcohols are selected from ethanol, isopropanol and n-butanol.
- the above-mentioned alkanes are selected from n-hexane, n-heptane and cyclohexane.
- the above-mentioned certain temperature is selected from 0°C to 65°C.
- the above certain time is selected from 1 hour to 72 hours.
- the weight ratio of the compound of formula (I) to the solvent is selected from 1:1 to 30.
- the present invention also provides the use of the crystal form A of the compound of formula (I) or the crystal form A prepared according to the above method in the preparation of drugs for the treatment of liver cancer, prostate cancer, pancreatic cancer and/or T-cell acute lymphoblastic leukemia.
- the compound of the present invention has significant anti-proliferative activity against tumor cells that highly express the AKR1C3 enzyme, and the compound of the present invention exhibits significant anti-tumor efficacy in multiple in vivo efficacy models.
- the preparation method of crystal form A of the compound of the present invention is simple, has good physical and chemical stability, and has high industrial application value and economic value.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
- K 2 CO 3 represents potassium carbonate
- [Ru(p-cym)Cl 2 ] 2 represents dichloro(p-methylcumyl)ruthenium(II) dimer
- EtOH represents Ethanol
- MTBE represents tert-butyl methyl ether
- DCM dichloromethane
- PE represents petroleum ether
- DIBAL-H represents diisobutylaluminum hydride
- DMF represents N, N-dimethylformamide
- DMSO represents dimethyl sulfoxide
- EtOAc represents ethyl acetate
- MeOH represents methanol
- n-heptane represents n-heptane
- SiO 2 represents 100-200 mesh silica gel powder, used for column chromatography
- Et 3 SiH represents triethylsilane
- HOAc represents acetic acid
- NaIO 4 represents high Sodium iodate
- THF represents tetrahydrofuran
- DIPEA represents N
- Test method About 10 ⁇ 20mg sample is used for XRPD detection.
- Light tube voltage 40kV
- light tube current 30mA
- Step size 0.5 seconds
- DSC Differential Scanning Calorimeter
- Test method Take a sample (2 ⁇ 6 mg) and place it in a 30 ⁇ L DSC gold-plated high-pressure crucible for testing. Heat the sample from 40°C to 350°C at a heating rate of 10°C/min.
- TGA Thermal Gravimetric Analyzer
- Test method Take the sample (2 ⁇ 10mg) and place it in an aluminum crucible, and then place it in a platinum hanging basket for testing. Under nitrogen (N2) conditions, use a gas flow rate of 40mL/min and a heating rate of 10°C/min. , heating the sample from 40°C to 500°C.
- N2 nitrogen
- Tube current 50mA.
- Figure 1 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form A of the compound of formula (I);
- Figure 2 is the DSC spectrum of the crystal form A of the compound of formula (I);
- Figure 3 is the TGA spectrum of the crystal form A of compound (I);
- Figure 4 is an ellipsoid diagram of the single crystal X-ray diffraction three-dimensional structure of the compound of formula (I);
- Figure 5 is the tumor growth signal-time curve
- Figure 6 is a schematic diagram of tumor weight at the end point of the experiment.
- Figure 7 shows the animal body weight-time curve.
- Step A Add DMF (30L) to the reaction kettle, start mechanical stirring, then add starting material 1 (4kg, 35.37mol) and starting material 2 (6.6kg, 35.71mol). After the addition is completed, control the internal temperature to rise to Add K 2 CO 3 (12.2kg, 88.27mol) in batches at 30 ⁇ 40°C. If gas is generated, the internal temperature should be controlled at 40 to 50°C. After the addition is completed, stir at 45 to 55°C for 16 hours. Add 42L of ice water to the reaction solution, and slowly add 42L of 4mol/L hydrochloric acid while stirring. A large amount of yellow solid precipitates. Filter under reduced pressure and wash the filter cake with 45L of water. Vacuum drying gave intermediate 3.
- Step B Add 1,4-dioxane (27L) and H 2 O (2.7L) to the reaction kettle, add intermediate 3 (3230.60g, 11.613mol) and intermediate 4 (3230.60g, 11.613mol) in sequence while stirring. 11.613 mol), guanidine carbonate (1047.08 g, 5.812 mol), HOAc (662 mL, 11.575 mol). Blow nitrogen into the kettle for 15 minutes. Add [Ru(p-cym)Cl 2 ] 2 (355.37g, 0.580mol) all at once, raise the temperature to 90°C and stir for 17 hours. The reaction solution was cooled to 25°C, and 2.7L of water was added thereto.
- Step C Add anhydrous DCM (22L) to the reaction kettle, add intermediate 5 (2200g, 5.608mol) under stirring, and lower the reaction temperature to -60 ⁇ -50°C under nitrogen protection.
- DIBAL-H (6700 mL, 6.7 mol) was added dropwise to the kettle. After the dropwise addition, the internal temperature is between -60 and -50°C, and stirring is continued for 1.5 hours under nitrogen. MeOH (455 mL) was added dropwise to the kettle, and the internal temperature was controlled at -60 ⁇ -50°C.
- Step D Add DCM (9.4L) to the reaction kettle, add intermediate 6 (1880.00g, 4.767mol) and Et 3 SiH (2284mL, 14.300mol) under stirring. Turn on the nitrogen flow protection, and the internal temperature will be between 0 and 5°C after adding. Add boron trifluoride etherate complex (1765 mL, 614.301 mol) dropwise, control the internal temperature at 0-10°C, and continue stirring for 1 hour. Add K 2 CO 3 aqueous solution (1.05kg dissolved in 12L water) into the reaction solution in batches. After addition, continue stirring for 20 minutes. The reaction mixture was filtered under reduced pressure to obtain a filter cake.
- Step E Add DCM (7.0L), MeCN (7.0L), water (10.5L) to the reaction kettle, add intermediate 7 (1740.00g, 4.599mol) and ruthenium trichloride trihydrate (12.03g, under stirring) 0.0460mol), the internal temperature is controlled at 10 ⁇ 20°C. Add NaIO 4 (2147.72g, 14.717mol) in batches within 2 hours, and control the internal temperature at 10-20°C. After the addition is complete, continue stirring for 0.5 hours. DCM (14.0L) was added to the reaction solution, stirred for 5 minutes, and then the reaction solution was filtered through diatomaceous earth to remove excess inorganic salts.
- Step F Add 450 mL anhydrous THF and 147.6 mL (S)-CBS to the reaction kettle in sequence under nitrogen protection, cool the temperature to 0 ⁇ 10°C, and drop 296.2 mL borane dimethyl sulfide complex (10M) into the system. ), magnetic stirring reaction for 1 hour. Slowly add the THF solution of Intermediate 8 dropwise into the system (preparation method: weigh 450g of Intermediate 7 and dissolve it in 1800mL of THF), and control the temperature at 0 to 10°C for 1 hour. After the reaction is completed, 180 mL MeOH is slowly added dropwise to quench the reaction.
- Step G Add 137g of intermediate 9 and 2055mL of anhydrous THF into a 5L single-layer glass reactor under nitrogen protection, and cool to -40 ⁇ -30°C under magnetic stirring.
- the temperature of the temperature control system is -40 ⁇ -30°C, add 56.7mL phosphorus oxychloride at one time, and then slowly add 106.3mL 2-tert-butyl-1,1,3,3-tetramethylguanidine dropwise, and the dropwise addition is completed. Keep the reaction at -40 ⁇ -30°C for 4 ⁇ 5 hours.
- the concentrate and the extract were mixed, and washed sequentially with 1096 mL of 0.1 M hydrochloric acid, 1096 mL of 1% K 3 PO 4 aqueous solution, and 1096 mL of saturated brine. Separate the organic layer and add 274g anhydrous sodium sulfate to dry it. Vacuum filtration, and the filter cake was rinsed with 274 mL EtOAc. The filtrate is concentrated under reduced pressure until it is oily or semi-solid. Transfer the concentrate to the reaction kettle, add 411 mL of isopropyl acetate, raise the temperature to 75-80°C, stir and dissolve, and then slowly lower the temperature to 10°C. A large amount of off-white solid will precipitate and crystallize for 12 hours. Vacuum filtration, and the filter cake was rinsed with 50 mL of isopropyl acetate. The filter cake was vacuum dried to obtain intermediate 10.
- Step H Add 3L of acetone and 300g of intermediate 10 to the reaction kettle in sequence under nitrogen protection, and add 319.4g of K 3 PO 4 under stirring. The system was heated to 35-45°C and stirred for 12 hours. Then, 212.9g of K 3 PO 4 was added to continue the reaction for 5 hours. The reaction solution was cooled to 20-25°C, vacuum filtered, and then the filter cake was rinsed with 150 mL EtOAc. The filtrate was concentrated under reduced pressure. The K 3 PO 4 filter cake was transferred to a 5L single-layer glass reactor, and 1.5L EtOAc was added to beat and wash.
- the single crystal preparation method is as follows:
- DMEM medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal calf serum was purchased from Biosera.
- CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
- the HepG2 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Nivo multi-label analyzer (PerkinElmer).
- HepG2 cells liver cancer
- the cell plate was cultured overnight in a carbon dioxide incubator.
- the concentration of compounds transferred into the cell plate ranged from 1 ⁇ M to 0.15 nM.
- the cell plate was cultured in a carbon dioxide incubator for 5 days. Prepare another cell plate, and read the signal value on the day of adding the drug as the maximum value (Max value in the equation below) to participate in data analysis. Add 20 ⁇ M cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Take multi-label analyzer readings. Add 20 ⁇ M cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Take multi-label analyzer readings.
- Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate.
- the value of IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs.” in GraphPad Prism. response--Variable slope” mode).
- Table 5 provides the inhibitory activity of compounds of formula (I) on HepG2 cell proliferation.
- the compound of formula (I) has excellent anti-proliferative activity against HepG2, which highly expresses AKR1C3.
- EMEM medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal calf serum was purchased from Biosera.
- CellTiter-Glo cell viability chemiluminescence detection reagent
- the Hep3B cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Nivo multi-label analyzer (PerkinElmer).
- Hep3B cells liver cancer
- the cell plate was cultured overnight in a carbon dioxide incubator.
- the concentration of compounds transferred into the cell plate ranged from 10 ⁇ M to 0.0256 nM.
- the cell plate was cultured in a carbon dioxide incubator for 3 days. Prepare another cell plate, and read the signal value on the day of adding the drug as the maximum value (Max value in the equation below) to participate in data analysis.
- Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate.
- the value of IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. in GraphPad Prism. response--Variable slope” mode).
- Table 6 provides the inhibitory activity of compounds of formula (I) on Hep3B cell proliferation.
- the compound of formula (I) has no anti-proliferative activity against Hep3B with low expression of AKR1C3, and shows high selectivity.
- This experiment uses the HepG2 orthotopic xenograft tumor nude mouse model to evaluate the anti-tumor effect of the compound.
- mice Female Balb/C nude mice, 6-8 weeks old, weighing 18-22 grams, fetal bovine serum (PBS), culture medium EMEM (Cat. No. 30-2003), phosphate buffer, double antibodies (Cat. No. 15240-062), Matrigel, trypsin.
- the experimental indicator is whether tumor growth can be delayed or whether the tumor can be cured.
- the bioluminescence signal and animal weight of the animals were detected once a week until the end of the observation period.
- the bioluminescence signal value can be used to calculate T/C (where T is the administration group and C is the average bioluminescence intensity value of the blank control group at the set time).
- TGI (%) [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100, where Ti is the average bioluminescence intensity of the treatment group at the set time; T 0 is the average intensity of bioluminescence at the starting point of administration.
- V i is the average bioluminescence intensity of the blank control group at the set time; V 0 is the average bioluminescence intensity at the starting point of administration.
- This experiment evaluated the efficacy of the compound of formula (I) in the HepG2 liver cancer orthotopic xenograft tumor model. After administration for 21 days, the compound of formula (I) had a significant inhibitory effect on tumor growth at a dosage of 1 mg/kg, with p ⁇ 0.05 compared with the vehicle control group. Increasing the dosage of the compound of formula (I) to 3 mg/kg enhances the tumor inhibitory effect.
- Table 9 p value for comparison of relative tumor signal growth values (RBL) between various groups of HepG2 xenograft tumor model Note: The p value is obtained by analyzing the relative value of tumor volume (RBL) using one-way ANOVA. There is a significant difference in the F value between each group (p ⁇ 0.001). Use Games-Howell to test.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种异色满类化合物的晶型及其制备方法,具体涉及式(I)所示化合物及其在制备治疗相关疾病药物中的应用。
Description
本申请要求申请日为2022日3月10日的中国专利申请2022102345275的优先权。本申请引用上述中国专利申请的全文。
本发明涉及异色满类化合物的晶型及其制备方法,具体涉及式(I)所示化合物及其在制备治疗相关疾病药物中的应用。
恶性肿瘤是一种严重威胁人类生命健康的重大疾病。目前的治疗手段主要有手术治疗、化学治疗、靶向治疗等。化学治疗是利用化学药物杀死肿瘤细胞、抑制肿瘤细胞生长的一种治疗方式,是一种全身性治疗手段。由于恶性肿瘤的异质性,化学疗法仍然是治疗肿瘤的重要方法。然而正是这种全身性治疗,导致化学疗法具有很大的副作用。开发具有靶向作用的化疗药物存在巨大的未满足的临床需求。
醛酮还原酶(AKR1C3)是醛酮还原酶家族成员,主要参与激素合成和毒素的清除。AKR1C3可被吸烟、酒精、乙型肝炎或丙型肝炎感染等因素诱发过度表达。AKR1C3在多种难治性癌症中过度表达,如肝癌、肺癌、胃癌、食道癌、结直肠癌、前列腺癌,急性淋巴性白血病,尤其是肝癌,其高表比例在60%以上。
目前在临床上有开发AKR1C3抑制剂药物,但没有取得很好的进展。浩鼎公司报道了一种靶向AKR1C3酶化合物OBI-3424。OBI-3424是一个选择性前药,在高表达AKR1C3酶的肿瘤细胞中释放出强效DNA烷基化剂,选择性杀伤高表达AKR1C3的肿瘤细胞,使化学药物具有明显的靶向作用。
目前这个靶点的研究还处在早期阶段,只有OBI-3424进入临床1/2期,适应症主要是肝细胞癌(HCC)、去势性前列腺癌(CRPC)、胰腺癌和T细胞急性淋巴细胞白血病(T-ALL)等,其有效性和安全性还在验证中。所以这一领域还需要更多的探索和研究。
发明内容
式(I)化合物的晶型A
其使用Cu-Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、19.21±0.20°、21.76±0.20°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、13.27±0.20°、15.19±0.20°、16.43±0.20°、17.94±0.20°、19.21±0.20°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、13.27±0.20°、15.19±0.20°、16.43±0.20°、17.94±0.20°、19.21±0.20°、21.76±0.20°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、15.19±0.20°、16.43±0.20°、17.94±0.20°、19.21±0.20°、21.76±0.20°、23.56±0.20°、26.66±0.20°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、12.56±0.20°、12.89±0.20°、13.27±0.20°、15.19±0.20°、16.01±0.20°、16.43±0.20°、17.60±0.20°、17.94±0.20°、19.21±0.20°、19.91±0.20°、20.21±0.20°、20.52±0.20°、21.25±0.20°、21.76±0.20°、23.02±0.20°、23.56±0.20°、24.71±0.20°、25.12±0.20°、25.88±0.20°、26.66±0.20°、27.10±0.20°、27.43±0.20°、27.84±0.20°、28.38±0.20°、29.13±0.20°、30.01±0.20°、30.83±0.20°、31.69±0.20°、32.26±0.20°、33.35±0.20°、35.01±0.20°、35.52±0.20°、36.51±0.20°、37.70±0.20°、39.24±0.20°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25°、12.56°、12.89°、13.27°、15.19°、16.01°、16.43°、17.60°、17.94°、19.21°、19.91°、20.21°、20.52°、21.25°、21.76°、23.02°、23.56°、24.71°、25.12°、25.88°、26.66°、27.10°、27.43°、27.84°、28.38°、29.13°、30.01°、30.83°、31.69°、32.26°、33.35°、35.01°、35.52°、36.51°、37.70°、39.24°。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、19.21±0.20°、21.76±0.20°,其还在和/或12.56±0.20°、和/或12.89±0.20°、和/或13.27±0.20°、和/或15.19±0.20°、和/或16.01±0.20°、和/或16.43±0.20°、和/或17.60±0.20°、和/或17.94±0.20°、和/或19.91±0.20°、和/或20.21±0.20°、和/或20.52±0.20°、和/或21.25±0.20°、和/或23.02±0.20°、和/或23.56±0.20°、和/或24.71±0.20°、和/或25.12±0.20°、和/或25.88±0.20°、和/或26.66±0.20°、和/或27.10±0.20°、和/或27.43±0.20°、和/或27.84±0.20°、和/或28.38±0.20°、和/或29.13±0.20°、和/或30.01±0.20°、和/或30.83±0.20°、和/或31.69±0.20°、和/或32.26±0.20°、和/或33.35±0.20°、和/或35.01±0.20°、和/或35.52±0.20°、和/或36.51±0.20°、和/或37.70±0.20°、和/或39.24±0.20°处具有特征衍射峰。
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱的解析数据如表1所示:
表1
在本发明的一些方案中,上述式(I)化合物的晶型A,其X射线粉末衍射图谱基本上如图1所示。
在本发明的一些方案中,上述式(I)化合物的晶型A,其差示扫描量热曲线在89.2±3℃处具有吸热峰的峰值。
在本发明的一些方案中,上述式(I)化合物的晶型A,其DSC图谱基本上如图2所示。
在本发明的一些方案中,上述式(I)化合物的晶型A,其热重分析曲线在100±3℃时失重达1.03%。
在本发明的一些方案中,上述式(I)化合物的晶型A,其TGA图谱基本上如图3所示。
式(I)化合物晶型A的制备方法
包括:将任意形式(晶型或无定形)的式(I)化合物加入到溶剂中,在一定温度下搅拌一定时间,过滤,滤饼烘干得到晶型A。
在本发明的一些方案中,上述溶剂选自醇类、丙酮、甲基异丁基酮、乙酸乙酯、醋酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲苯、二氯甲烷、1,4-二氧六环、乙腈和烷烃类。
在本发明的一些方案中,上述溶剂为醇类、丙酮、甲基异丁基酮、乙酸乙酯、醋酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲苯、二氯甲烷、1,4-二氧六环、乙腈和烷烃类中的任意2、3、4、5、6、7、8、9、10、11或12个的混合。
在本发明的一些方案中,上述醇类选自乙醇、异丙醇和正丁醇。
在本发明的一些方案中,上述烷烃类选自正己烷、正庚烷和环己烷。
在本发明的一些方案中,上述一定温度选自0℃~65℃。
在本发明的一些方案中,上述一定时间选自1小时~72小时。
在本发明的一些方案中,上述一定式(I)化合物与溶剂的重量比选自1:1~30。
本发明还提供了上述式(I)化合物晶型A或根据上述方法制备得到得晶型A在制备治疗肝癌、前列腺癌、胰腺癌和/或T细胞急性淋巴细胞白血病药物上的应用。
技术效果
本发明化合物对高表达AKR1C3酶的肿瘤细胞具有显著的抗增殖活性,本发明的化合物在多个体内药效模型中展示出显著的抗肿瘤药效。本发明化合物的A晶型制备方法简单,物理稳定性和化学稳定性均较好,具有很高的工业应用价值和经济价值。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合
成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
化合物经手工或者软件命名,市售化合物采用供应商目录名称。
本发明采用下述缩略词:K2CO3代表碳酸钾;[Ru(p-cym)Cl2]2代表二氯(p-甲基异丙苯)钌(II)二聚体;EtOH代表乙醇;MTBE代表叔丁基甲醚;DCM代表二氯甲烷;PE代表石油醚;DIBAL-H代表二异丁基氢化铝;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;MeOH代表甲醇;n-heptane代表正庚烷;SiO2代表100-200目硅胶粉,用于柱层析;Et3SiH代表三乙基硅烷;HOAc代表乙酸;NaIO4代表高碘酸钠;THF代表四氢呋喃;DIPEA代表N,N-二异丙基乙胺;(S)-CBS代表(S)-3,3-二苯基-1-甲基吡咯烷[1,2-c]-1,3,2-恶唑硼烷;K3PO4代表磷酸钾;HP-β-CD代表环糊精;QW代表给药频次。本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:丹东浩元DX-2700BH X-射线衍射仪
测试方法:大约10~20mg样品用于XRPD检测。
详细的XRPD参数如下:
光管:Cu,kα,
光管电压:40kV,光管电流:30mA
发散狭缝:1mm
探测器狭缝:0.3mm
防散射狭缝:1mm
扫描范围:3-40deg
步径:0.02deg
步长:0.5秒
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:METTLER TOLEDO DSC1差示扫描量热仪
测试方法:取样品(2~6mg)置于30μL的DSC镀金高压坩锅内进行测试,以10℃/min的升温速率,加热样品从40℃到350℃。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA TGA550热重分析仪
测试方法:取样品(2~10mg)置于铝坩埚内,然后放置于铂金吊篮内进行测试,在氮气(N2)条件下,以40mL/min的气体流速,以10℃/min的升温速率,加热样品从40℃到500℃。
本发明单晶X射线衍射检测仪器参数
仪器型号:Bruker D8 VENTURE CMOS Photon II diffractometer.
低温系统:Oxford Cryostream 800
光源:Cu:2.5kW,
晶体到探测器的距离:d=45mm
管电压:50kV
管电流:50mA。
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图;
图2为式(I)化合物A晶型的DSC谱图;
图3为式(I)化合物A晶型的TGA谱图;
图4为式(I)化合物的单晶X射线衍射立体结构椭球图;
图5为肿瘤生长信号-时间曲线;
图6为实验终点肿瘤重量示意图;
图7为动物体重-时间曲线。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1:式(I)化合物的制备
步骤A:在反应釜中加入DMF(30L),开启机械搅拌,随后加入起始物料1(4kg,35.37mol)和起始物料2(6.6kg,35.71mol),加完后控制内温升到30~40℃分批加入K2CO3(12.2kg,88.27mol)。有气体产生,内温控制在40~50℃。加完后在45~55℃下搅拌16小时。反应液加入42L冰水,在搅拌下缓慢加入42L 4mol/L盐酸,有大量黄色固体析出,减压抽滤,滤饼用45L水洗涤。真空干燥得到中间体3。1H NMR(400MHz,DMSO-d6)δ13.81-13.38(m,1H),8.55(d,J=2.1Hz,1H),8.24-8.12(m,2H),7.97(ddd,J=1.6,8.1,10.0Hz,1H),7.50(ddd,J=0.7,4.8,7.9Hz,1H),7.29(d,J=8.7Hz,1H)。
步骤B:在反应釜中加入1,4-二氧六环(27L)和H2O(2.7L),搅拌下依次加入中间体3(3230.60g,11.613mol),中间体4(3230.60g,11.613mol),碳酸胍(1047.08g,5.812mol),HOAc(662mL,11.575mol)。向釜中鼓入氮气,持续15分钟。一次性加入[Ru(p-cym)Cl2]2(355.37g,0.580mol),升温至90℃搅拌17小时。将反应液冷却到25℃,再向其中加入2.7L水。5℃左右静置约23小时,固体析出。过滤,滤饼加入加入10L EtOH/H2O(体积比1:1),室温搅拌4小时,抽滤。将滤饼加入8L EtOAc/MTBE(体积比2:1),室温搅拌17小时,抽滤。滤饼用EtOAc/MTBE(体积比2:1)洗涤(1L*2),滤饼真空干燥得到中间体5。1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.18-8.11(m,1H),7.92(ddd,J=1.4,8.2,10.0Hz,1H),7.80(s,1H),7.60(s,1H),7.51-7.40(m,4H),7.35(d,J=6.9Hz,2H),5.42(d,J=0.9Hz,2H)。
步骤C:在反应釜中加入无水DCM(22L),搅拌下加入中间体5(2200g,5.608mol),氮气保护下反应温度降至-60~-50℃。向釜中滴加DIBAL-H(6700mL,6.7mol)。滴加完后内温在-60~-50℃,在氮气保下继续搅拌1.5小时。向釜中滴加MeOH(455mL),内温控制在-60~-50℃。滴加完毕后,内温缓慢升至0℃,依次加入异丙醇(7.3L),二氯甲烷(15L),四水合L(+)酒石酸钾钠水溶液(3.5kg,22L水溶液)。加完后室温搅拌4小时,静置12小时分液,有机相浓缩得到产物为黄色固体,真空干燥得到中间体6。1H NMR
(400MHz,DMSO-d6)δ8.10(s,1H),8.03-8.00(m,1H),7.98(s,1H),7.61(ddd,J=1.4,8.2,10.1Hz,1H),7.52(s,1H),7.48-7.41(m,2H),7.40-7.33(m,4H),7.29(d,J=5.8Hz,1H),5.94(d,J=5.6Hz,1H),4.94(dd,J=1.3,14.4Hz,1H),4.69(dd,J=0.9,14.4Hz,1H)。
步骤D:在反应釜中加入DCM(9.4L),搅拌下加入中间体6(1880.00g,4.767mol),Et3SiH(2284mL,14.300mol)。开启氮气流保护,加完后内温在0~5℃。滴加三氟化硼乙醚络合物(1765mL,614.301mol),内温控制在0~10℃,继续搅拌1小时。向反应液中分批加入K2CO3水溶液(1.05kg溶于12L水中)。加完后继续搅拌20分钟。反应混合液减压抽滤得到滤饼。滤液分液,将得到的有机相浓缩至5L,析出黄色固体,过滤,得到滤饼与之前滤饼合并。滤饼真空干燥得到中间体7。1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.04(s,1H),7.99(td,J=1.5,4.8Hz,1H),7.58(ddd,J=1.6,8.2,10.2Hz,1H),7.52(s,1H),7.48-7.40(m,2H),7.38-7.30(m,4H),4.84(s,2H),4.76(d,J=1.3Hz,2H)。
步骤E:在反应釜中加入DCM(7.0L),MeCN(7.0L),水(10.5L),搅拌下加入中间体7(1740.00g,4.599mol),三水合三氯化钌(12.03g,0.0460mol),内温控制在10~20℃。在2小时内分批加入NaIO4(2147.72g,14.717mol),内温控制在10~20℃。加完之后继续搅拌0.5小时。向反应液中加入DCM(14.0L),搅拌5分钟,然后将反应液通过硅藻土过滤,除去多余的无机盐。滤液分液,有机相加入NaOH水溶液(8L,1mol/L),通过硅藻土过滤,然后再次分液,有机相依次用8L饱和亚硫酸钠水溶液洗涤,8L饱和食盐水洗涤。有机相浓缩得到粗品。粗品柱层析纯化(SiO2,n-heptane:EtOAc=100:0-10:1)得到中间体8。1H NMR(400MHz,CDCl3)δ8.05(td,J=1.6,4.8Hz,1H),7.76(s,1H),7.52(ddd,J=1.6,7.8,9.5Hz,1H),7.45(s,1H),7.22(ddd,J=0.7,4.8,7.8Hz,1H),4.86(s,2H),4.32(s,2H)。
步骤F:氮气保护下向反应釜中依次加入450mL无水THF、147.6mL(S)-CBS,降温至0~10℃,向体系中滴加296.2mL硼烷二甲硫醚络合物(10M),磁力搅拌反应1h。向体系中缓慢滴加中间体8的THF溶液(配置方法:称取450g中间体7溶解到1800mL THF中),控温0~10℃反应1h。反应完毕后,缓慢滴加180mL MeOH淬灭反应。量取2250mL 2.0mol/L盐酸缓慢滴加到体系中,有大量固体析出。减压过滤,滤饼待用,滤液分层,分出有机相,水相加入4500mL EtOAc萃取,合并有机相,在35~40℃减压浓缩至固状。将浓缩物与滤饼合并,加入1350mL乙醇/2.0M盐酸(体积比2:1)溶液中升温至60~70℃搅拌1h。反应液降至20℃~25℃,减压过滤,滤饼用900mL纯化水淋洗。将滤饼(湿品)直接加入到1350mL乙醇/纯化水(体积比1:1)混合溶液中,20~25℃搅拌2h。减压过滤,滤饼用900mL纯化水淋洗。将滤饼放入真空干燥箱的烘盘中,40℃真空干燥得到中间体9。
步骤G:氮气保护下向5L单层玻璃反应釜中加入137g中间体9及2055mL无水THF,磁力搅拌下,降温至-40~-30℃。控温体系温度-40~-30℃,一次性加入56.7mL三氯氧磷,然后缓慢滴加106.3mL 2-叔丁基-1,1,3,3-四甲基胍,滴加完毕,保持-40~-30℃反应4~5h。反应完毕,反应液降温至-50~-40℃,一次性加入548g溴乙胺氢溴酸盐,然后控温-50~-40℃缓慢滴加467.3mL DIPEA,滴加完毕保持-50~-40℃反应12h。向反应液中缓慢滴加2055mL纯化水淬灭反应。自然升温至0~10℃,静置分层,分出有机层进
行浓缩,水层用1781mL萃取一次。将浓缩物和萃取液混合,依次用1096mL 0.1M盐酸、1096mL 1%K3PO4水溶液、1096mL饱和食盐水洗涤。分出有机层加入274g无水硫酸钠干燥。真空抽滤,滤饼用274mL EtOAc淋洗。滤液减压浓缩至油状物或是半固状。将浓缩物转移至反应釜中,加入411mL乙酸异丙酯升温至75~80℃搅拌溶清,再缓慢降温至10℃,有大量类白色固体析出,析晶12h。真空抽滤,滤饼用50mL乙酸异丙酯淋洗。滤饼真空干燥得到中间体10。
步骤H:氮气保护下向反应釜中依次加入3L丙酮和300g中间体10,搅拌下加入319.4g K3PO4。体系升温至35~45℃搅拌反应12h后,再加入212.9g K3PO4继续反应5h。反应液降温至20-25℃,真空抽滤,再用150mL EtOAc淋洗滤饼。滤液减压浓缩。K3PO4滤饼转移至5L单层玻璃反应釜,加入1.5L EtOAc打浆洗涤。过滤,将滤液和浓缩物合并补加0.75L EtOAc,加入1.5L冰水进行洗涤,分液,水层用1.5L EtOAc萃取一次,合并有机层,再用2.25L 10%食盐水洗涤一次,静置分液分出有机层。有机相加入600g无水硫酸钠干燥30分钟。真空抽滤,滤去无水硫酸钠,60mL EtOAc淋洗。滤液减压浓缩得到油状物。油状物迅速加入328mL乙酸异丙酯,磁力搅拌析晶10h。真空抽滤,滤饼用母液淋洗后抽干的得到式(I)化合物。
实施例2:式(I)化合物晶型A的制备
向2L单层玻璃反应釜中依次加入式(I)化合物320g及1280mL乙酸异丙酯,磁力搅拌下油浴升温至60~65℃,固体完全溶清后趁热过滤,滤液降至20~25℃析晶2h。真空抽滤,滤饼用120mL乙酸异丙酯淋洗。滤饼真空干燥得到白色固体即为晶型A。晶型A的XRPD谱图如图1所示,DSC谱图如图2所示,TGA谱图如图3所示。
实施例3:式(I)化合物单晶X射线衍射检测分析
单晶制备方法如下:
将式(I)化合物(0.5g)溶解在醋酸异丙酯(10毫升)的试管中,10~15℃下静止敞口缓慢挥发,经过20天培养获得单晶。晶系为单斜晶体,空间群P2(1),晶胞参数为
α=γ=90,β=95.3960(10),体积绝对构型参数Flack值为0.049(9)。式(I)化合物单分子立体结构椭球图见附图4。
表2式(I)化合物晶体的原子坐标(×104)和等价各向同性移位参数
表3式(I)化合物晶体的键长[A]和键角[deg]
表4式(I)化合物扭转角度[deg].
实验例1:式(I)化合物对HepG2细胞系的抗增殖活性
实验材料:
DMEM培养基,盘尼西林/链霉素抗生素购自维森特,胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。HepG2细胞系购自中国科学院细胞库。Nivo多标记分析仪(PerkinElmer)。
实验方法:
将HepG2细胞(肝癌)种于白色384孔板中,25μM细胞悬液每孔,其中包含1000个HepG2细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进行3倍稀释至第9个浓度,即从200μM稀释至30nM,设置双复孔实验。向中间板中加入99μM培养基,再按照对应位置,转移1μM每孔的梯度稀释化合物至中间板,混匀后转移25μM每孔到细胞板中。转移到细胞板中的化合物浓度范围是1μM至0.15nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板,在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入20μM细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔20μM的细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。表5提供了式(I)化合物对HepG2细胞增殖的抑制活性。
表5本发明化合物对HepG2细胞系的抗增殖活性数据
结论:式(I)化合物对高表达AKR1C3的HepG2具有优异的抗增殖活性。
实验例2:式(I)化合物对Hep3B细胞系的抗增殖活性
实验材料:
EMEM培养基,盘尼西林/链霉素抗生素购自维森特,胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。Hep3B细胞系购自中国科学院细胞库。Nivo多标记分析仪(PerkinElmer)。
实验方法:
将Hep3B细胞(肝癌)种于白色96孔板中,80μL细胞悬液每孔,其中包含3000个Hep3B细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进行5倍稀释至第9个浓度,即从2mM稀释至5.12nM,设置双复孔实验。向中间板中加入78μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至中间板,混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.0256nM。细胞板置于二氧化碳培养箱中培养3天。另准备一块细胞板,在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光
检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。表6提供了式(I)化合物对Hep3B细胞增殖的抑制活性。
表6式(I)化合物对Hep3B细胞系的抗增殖活性数据
结论:式(I)化合物对低表达AKR1C3的Hep3B无抗增殖活性,显示出很高的选择性。
实验例3:式(I)化合物对人肝癌Hep G2原位异种移植瘤模型的体内药效学研究
实验目的:
本试验使用HepG2原位异种移植肿瘤裸小鼠模型评价化合物的抗肿瘤作用。
实验材料:
雌性Balb/C裸小鼠,周龄为6-8周龄,体重为18~22克,胎牛血清(PBS),培养基EMEM(货号30-2003),磷酸盐缓冲液,双抗(货号15240-062),Matrigel基质胶,胰酶。
实验方法与步骤
1.细胞培养准备:HepG2-luc细胞体外单层培养,培养条件为EMEM培养基中加10%热灭活胎牛血清,于37℃含5%CO2培养箱中培养。一周两次用胰酶-EDTA进行消化处理传代。当细胞饱和度为80%-90%时,细胞用胰酶-EDTA消化,计数,重悬于PBS和基质胶中(PBS:基质胶=1:1),密度为166.67×106个细胞/mL。
2.肿瘤细胞接种分组:经肌肉注射60mg/kg舒泰50+1.5mg/kg甲苯噻嗪将动物麻醉,待动物至深麻时,将动物进行适当固定,用75%酒精棉球清洁腹部皮肤,用手术剪开约10mm的创口,将0.03mL(PBS:Matrigel=1:1)的HepG2-luc细胞原位接种于每只小鼠的肝左大叶上,然后将肌肉层创口用可吸收肠线缝合,皮肤创伤口用缝合器缝合。将手术完成的动物放置在保温毯上保温至苏醒。为减少动物的疼痛,将在术后连续3天给予2mg/kg的美洛昔康(皮下注射给药,每天一次)。随机择取15只动物检测信号生长情况,当信号开始上升时,根据生物荧光信号值随机分组,开始给药治疗,详细治疗方案见表7。
表7实验动物分组及给药方案
3.实验指标
实验指标是肿瘤生长能否被延迟或肿瘤能否被治愈。肿瘤接种后每周检测1次动物的生物发光信号和动物体重,持续至观察期结束。生物发光信号数值可被用来计算T/C(其中T为给药组,C为空白对照组在设定时间的生物发光平均强度值)。肿瘤抑制率TGI计算公式:TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100,其中Ti为治疗组在设定时间的生物发光平均强度;T0为给药起始点的生物发光平均强度。Vi为空白对照组在设定时间的生物发光平均强度;V0为给药起始点生物发光平均强度。
4.化合物对HepG2肝癌裸鼠皮下移植肿瘤生长的抑制作用
本实验评价了式(I)化合物在HepG2肝癌原位异种移植瘤模型中的药效。给药21天时,式(I)化合物在1mg/kg给药剂量下具有显著的抑制肿瘤生长作用,于溶媒对照组相比均为p<0.05。增加式(I)化合物的给药剂量至3mg/kg,抑瘤效果增强。
实验结果:见图5、6和表8、9、10。
表8式(I)化合物对HepG2原位异种移植瘤模型的抑瘤效果
注:a.平均值±SEM,n=6。
注:a.平均值±SEM,n=6。
表9 HepG2异种移植瘤模型各组间相对肿瘤信号生长值(RBL)比较的p值
注:p值运用one-way ANOVA进行分析肿瘤体积相对值(RBL)所得,各组间F值有显著差异(p<0.001),
运用Games-Howell发进行检验。
注:p值运用one-way ANOVA进行分析肿瘤体积相对值(RBL)所得,各组间F值有显著差异(p<0.001),
运用Games-Howell发进行检验。
表10各组不同时间点的瘤组织生物发光信号值
注:a.平均值±SEM,n=6
注:a.平均值±SEM,n=6
表11各组肿瘤重量
注:a.平均值±SEM,n=6。
b.肿瘤生长抑制由T/Cweight=TWtreatment/TW溶媒计算。
c.p值运用one-way ANOVA与溶媒治疗组进行分析肿瘤重量所得,F值有显著性差异(p<0.001),
应用Games-Howell法进行分析。
注:a.平均值±SEM,n=6。
b.肿瘤生长抑制由T/Cweight=TWtreatment/TW溶媒计算。
c.p值运用one-way ANOVA与溶媒治疗组进行分析肿瘤重量所得,F值有显著性差异(p<0.001),
应用Games-Howell法进行分析。
5.体重变化情况
此模型中,所有治疗组动物体重均没有较大的波动,整体动物体重均值下降未超过5%,详见图7。6.结论:式(I)化合物具有显著地抑制肿瘤生长的作用,且给药组动物体重没有明显降低,显示出良好的安全性。
Claims (10)
- 式(I)化合物的晶型A
其使用Cu-Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、19.21±0.20°、21.76±0.20°。 - 根据权利要求1所述的式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、13.27±0.20°、15.19±0.20°、16.43±0.20°、17.94±0.20°、19.21±0.20°、21.76±0.20°。
- 根据权利要求1所述的式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25±0.20°、15.19±0.20°、16.43±0.20°、17.94±0.20°、19.21±0.20°、21.76±0.20°、23.56±0.20°、26.66±0.20°。
- 根据权利要求3所述的式(I)化合物的晶型A,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.25°、12.56°、12.89°、13.27°、15.19°、16.01°、16.43°、17.60°、17.94°、19.21°、19.91°、20.21°、20.52°、21.25°、21.76°、23.02°、23.56°、24.71°、25.12°、25.88°、26.66°、27.10°、27.43°、27.84°、28.38°、29.13°、30.01°、30.83°、31.69°、32.26°、33.35°、35.01°、35.52°、36.51°、37.70°、39.24°。
- 根据权利要求4所述的式(I)化合物的晶型A,其X射线粉末衍射图谱基本上如图1所示。
- 根据权利要求1-5任意一项所述的式(I)化合物的晶型A,其差示扫描量热曲线在89.2±3℃处具有吸热峰的峰值。
- 根据权利要求6所述的式(I)化合物的晶型A,其DSC图谱基本上如图2所示。
- 根据权利要求1-5任意一项所述的式(I)化合物的晶型A,其热重分析曲线在100±3℃时失重达1.03%。
- 根据权利要求8所述的式(I)化合物的晶型A,其TGA图谱基本上如图3所示。
- 根据权利要求1-9任意一项所述的式(I)化合物的晶型A在制备治疗肝癌、前列腺癌、胰腺癌和/或T细胞急性淋巴细胞白血病药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210234527.5 | 2022-03-10 | ||
CN202210234527 | 2022-03-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023169462A1 true WO2023169462A1 (zh) | 2023-09-14 |
Family
ID=87936100
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/080261 WO2023169462A1 (zh) | 2022-03-10 | 2023-03-08 | 异色满类化合物的晶型 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023169462A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107530556A (zh) * | 2015-03-10 | 2018-01-02 | 深圳艾衡昊医药科技有限公司 | Dna烷化剂 |
CN108290911A (zh) * | 2015-11-16 | 2018-07-17 | 深圳艾衡昊医药科技有限公司 | (r)-及(s)-1-(3-(3-n,n-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-n,n’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法 |
WO2021068952A1 (zh) * | 2019-10-12 | 2021-04-15 | 南京明德新药研发有限公司 | 靶向醛酮还原酶1c3的苯并二氢吡喃类化合物 |
WO2022057838A1 (zh) * | 2020-09-18 | 2022-03-24 | 南京明德新药研发有限公司 | 异色满类化合物 |
-
2023
- 2023-03-08 WO PCT/CN2023/080261 patent/WO2023169462A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107530556A (zh) * | 2015-03-10 | 2018-01-02 | 深圳艾衡昊医药科技有限公司 | Dna烷化剂 |
CN108290911A (zh) * | 2015-11-16 | 2018-07-17 | 深圳艾衡昊医药科技有限公司 | (r)-及(s)-1-(3-(3-n,n-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-n,n’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法 |
WO2021068952A1 (zh) * | 2019-10-12 | 2021-04-15 | 南京明德新药研发有限公司 | 靶向醛酮还原酶1c3的苯并二氢吡喃类化合物 |
WO2022057838A1 (zh) * | 2020-09-18 | 2022-03-24 | 南京明德新药研发有限公司 | 异色满类化合物 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
BRPI0912475B1 (pt) | compostos como inibidores de quinase, método para produção dos ditos compostos e composição farmacêutica | |
CN104203242A (zh) | 取代的喹啉类作为布鲁顿酪氨酸激酶抑制剂 | |
CN100509790C (zh) | 芳基羰基哌嗪和杂芳基羰基哌嗪及其治疗良性和恶性肿瘤疾病的用途 | |
CN112010839B (zh) | 靶向丝/苏氨酸激酶抑制剂的晶型 | |
CN114920704B (zh) | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 | |
CN114437077A (zh) | 用作激酶抑制剂的化合物及其应用 | |
JP2019526605A (ja) | 置換2−h−ピラゾール誘導体の結晶形、塩型及びその製造方法 | |
WO2015117551A1 (zh) | 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 | |
WO2021088987A1 (zh) | 作为选择性her2抑制剂的盐型、晶型及其应用 | |
WO2023169462A1 (zh) | 异色满类化合物的晶型 | |
CA2702301A1 (en) | Crystalline forms of dmxaa sodium salt | |
JP2010510990A (ja) | 癌の治療方法 | |
CN110590681B (zh) | 一种新型喹唑啉酮类化合物及其制备方法和应用 | |
WO2020206603A1 (zh) | 2-(2,4,5-取代苯氨基)嘧啶衍生物及其晶形b | |
CA2966709A1 (en) | Cytidine derivative dimers and applications thereof | |
JP7350374B2 (ja) | キナゾリン系化合物の結晶体、塩およびその調製方法 | |
JP2024531043A (ja) | アビラテロン誘導体、その製造及び使用 | |
CN113444074B (zh) | 一种具有EGFR和Wnt双重抑制作用的化合物及其制备方法和应用 | |
CN110981865B (zh) | 一种用于治疗脑胶质瘤的药物及其制备方法 | |
WO2021036814A1 (zh) | 吡唑衍生物及其用途 | |
JP2023543281A (ja) | アリールアミノキナゾリン含有化合物の塩、およびその製造方法と使用 | |
CN118871429A (zh) | 异色满类化合物的晶型 | |
CN113493414A (zh) | 一种氘代取代丁烯酰胺及其制备方法与应用 | |
CN113444078A (zh) | 抗凋亡蛋白Bcl-2抑制剂及其制备方法和应用 | |
CN106349180B (zh) | 4,5-二苯基异噁唑衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23766039 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023766039 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2023766039 Country of ref document: EP Effective date: 20241010 |