CN114746426B - 作为acc1和acc2抑制剂的晶型及其制备方法和应用 - Google Patents
作为acc1和acc2抑制剂的晶型及其制备方法和应用 Download PDFInfo
- Publication number
- CN114746426B CN114746426B CN202080084236.1A CN202080084236A CN114746426B CN 114746426 B CN114746426 B CN 114746426B CN 202080084236 A CN202080084236 A CN 202080084236A CN 114746426 B CN114746426 B CN 114746426B
- Authority
- CN
- China
- Prior art keywords
- compound
- added
- reaction
- application
- acc1
- 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.)
- Active
Links
- 101000677540 Homo sapiens Acetyl-CoA carboxylase 2 Proteins 0.000 title claims abstract description 12
- 102100039164 Acetyl-CoA carboxylase 1 Human genes 0.000 title claims abstract description 11
- 101710190443 Acetyl-CoA carboxylase 1 Proteins 0.000 title claims abstract description 10
- 102100021641 Acetyl-CoA carboxylase 2 Human genes 0.000 title claims abstract description 10
- 101000894929 Homo sapiens Bcl-2-related protein A1 Proteins 0.000 title claims abstract description 10
- 239000003112 inhibitor Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 239000013078 crystal Substances 0.000 title abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000002411 thermogravimetry Methods 0.000 claims description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 230000004580 weight loss Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 44
- 239000000243 solution Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000012043 crude product Substances 0.000 description 14
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 6
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 6
- 108010018763 Biotin carboxylase Proteins 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 230000004136 fatty acid synthesis Effects 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000011740 C57BL/6 mouse Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101000963424 Homo sapiens Acetyl-CoA carboxylase 1 Proteins 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-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
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- LTYOQGRJFJAKNA-VFLPNFFSSA-N malonyl-coa Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-VFLPNFFSSA-N 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 230000004783 oxidative metabolism Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000004276 BCL2-related protein A1 Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 102000047784 human ACACB Human genes 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012263 liquid product Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000013234 NASH mouse model Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 241000826860 Trapezium Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229940121373 acetyl-coa carboxylase inhibitor Drugs 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- -1 apoptosis Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
一种作为ACC1和ACC2抑制剂(I)的晶型及其制备方法,以及在制备作为ACC1和ACC2抑制剂的药物中的应用。
Description
本申请主张如下优先权:
CN201911235373.6,申请日2019.12.05。
技术领域
本发明涉及一种作为ACC1和ACC2抑制剂的晶型及其制备方法,以及在制备作为ACC1和ACC2抑制剂的药物中的应用。
背景技术
由脂肪酸合成增多、脂肪酸氧化降低,或者两者同时存在引起的脂肪酸代谢失调,是多种代谢紊乱的标志,包括胰岛素抵抗、肝脂肪变性、血脂异常、肥胖、代谢综合征(MetSyn)、非酒精性脂肪肝(NAFLD)等。同时可能导致2型糖尿病(T2DM)的发展,以及非酒精性脂肪肝炎(NASH)、动脉粥样硬化等血管疾病。脂肪酸代谢紊乱也是癌症的一个标志,可导致异常和持续的恶性肿瘤细胞增殖,因此抑制脂肪酸的合成和/或刺激脂肪酸的氧化代谢,有可能对这些疾病有利(PNAS,2016,E1796-E1805)。
乙酰辅酶A羧化酶(ACC)催化了乙酰辅酶A向丙二酰辅酶A的转化,这是脂肪酸合成的第一步,同时也是决速步。ACC存在两种亚型,ACC1和ACC2。ACC1主要分布于肝脏和脂肪组织中,ACC2则主要分布于肝脏、心脏及肌肉组织中。在肝脏中,由细胞质中的ACC1催化形成的丙二酰辅酶A,主要负责脂肪酸的合成及延长;由线粒体表面的ACC2催化形成的丙二酰辅酶A则主要通过抑制肉碱转移酶I,调节脂肪酸的氧化代谢(PNAS,2016,E1796-E1805)。因此,同时抑制ACC的两个亚型,可以降低脂肪酸的合成,并刺激脂肪酸的氧化代谢。
WO2013071169A1公开了ACC抑制剂I-181在治疗相关疾病中的应用。
发明内容
本发明提供式(I)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.54±0.20°、17.64±0.20°和24.81±0.2°;
本发明的一些方案中,上述式(I)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.54±0.20°、10.87±0.20°、15.55±0.20°、16.56±0.20°、17.64±0.20°、21.32±0.20°、23.53±0.20°和24.81±0.20°。
本发明的一些方案中,上述式(I)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射:6.91°、8.54°、8.80°、9.51°、10.87°、11.30°、12.38°、12.81°、13.84°、14.10°、15.55°、16.56°、17.64°、17.99°、18.76°、19.07°、20.27°、20.63°、21.32°、22.19°、22.71°、23.53°、24.07°、24.81°、26.80°、27.40°、27.79°、28.34°、29.94°、30.86°、30.86°、31.34°、31.98°、33.17°、33.69°、35.21°、35.64°、36.25°、36.75°、37.79°和38.98°。
本发明的一些方案中,上述式(I)化合物的A晶型,其XRPD图谱如图1所示。
本发明的一些方案中,上述A晶型的XRPD图谱解析数据如表1所示:
表1.A晶型的XRPD图谱解析数据
本发明的一些方案中,上述A晶型的差示扫描量热曲线在234.9℃处具有吸热峰的起始点。
本发明的一些方案中,上述A晶型的DSC图谱如图2所示。
本发明的一些方案中,上述A晶型的热重分析曲线在200.0±3℃时失重达0.86%。
本发明的一些方案中,上述A晶型的TGA图谱如图3所示。
技术效果
本发明式(I)化合物的A晶型稳定、受光热湿度影响小;且本发明式(I)化合物及其A晶型具有良好的体内给药药效,成药前景广阔。
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。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:EtOH代表乙醇;MeOH代表甲醇;TFA代表三氟乙酸;TsOH代表对甲苯磺酸;mp代表熔点;EtSO3H代表乙磺酸;MeSO3H代表甲磺酸;THF代表四氢呋喃;EtOAc代表乙酸乙酯;RuPhos代表2-双环已基膦-2′,6′-二异丙氧基联苯;AcCl代表乙酰氯;DCM代表二氯甲烷;DMSO代表二甲基亚砜。
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X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:PANalytical(帕纳科)公司的X’Pert3/Empyrean型X-射线衍射仪
测试方法:大约10mg样品用于XRPD检测。
详细的XRPD参数如下:
射线源:Cu,kα(Kα2/Kαl强度比例:0.5)
光管电压:45kV,光管电流:40mA
发散狭缝:固定1/8deg
第一索拉狭缝:0.04rad,第二索拉狭缝:0.04rad
接收狭缝:无,防散射狭缝:7.5mm
测量时间:5min
扫描角度范围:3-40deg
步宽角度:0.0263deg(X’Pert3)/0.0167deg(Empyrean)
步长:46.665秒(X’Pert3)/17.780秒(Empyrean)
样品盘转速:15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TA Q2000/Discovery DSC 2500差示扫描量热仪
测试方法:取样品(~1-5mg)置于DSC铝盘内进行测试,在50mL/min N2条件下,以10℃/min的升温速率,加热样品从25℃(室温)到样品分解前。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA Discovery TGA 5500热重分析仪
测试方法:取样品(~1-5mg)置于TGA铝盘内进行测试,在10mL/min N2条件下,以10℃/min的升温速率,加热样品从室温到350℃。
附图说明
图1为式(I)化合物的A晶型的Cu-Kα辐射的XRPD谱图。
图2为式(I)化合物的A晶型的DSC谱图。
图3为式(I)化合物的A晶型的TGA谱图。
具体实施方式
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:式(I)化合物A晶型的制备
第一步:化合物I-02的制备
在20℃下,向干燥的三口瓶中加入原料I-01(650g,6.62mol)和DCM(1.5L)。降温至0℃,快速滴加SO2Cl2(1.88kg,13.90mol),1小时左右加完,保持温度在0-10℃。滴加完毕,混合物在15-20℃下继续搅拌16小时(滴加过程中溶液逐渐变黑,持续有气体冒出,用氢氧化钠水溶液吸收尾气)。将反应液在40℃下减压浓缩,得到黄色液体粗品I-02直接用于下一步。1H NMR(400MHz,CDCl3)δ6.62(s,1H),2.13(s,3H)。
第二步:化合物I-03的制备
向干燥的5L三口瓶中加入将化合物I-02(500g,2.99mol),AcCl(481.6g,2.05eq)和DCM(2.5L),降温至0℃。然后分批(每批100g左右)加入AlCl3(478.4g,3.59mol),控制内温在0-10℃,1小时左右加完。反应体系缓慢升温至20℃,继续搅拌12小时。将反应液缓慢倒入2公斤左右碎冰中淬灭,边倒边搅拌,保持体系中始终有大量碎冰存在。待冰全部融化后分液。水相用DCM(500mL×2)萃取。合并的有机相用水(1L×2)和饱和食盐水(1L×2)洗涤,无水硫酸钠干燥,减压浓缩得到黄色液体产物I-03。1H NMR(400MHz,CDCl3)δ2.53(s,3H),2.15(s,3H)。
第三步:化合物I-04的制备
在20℃下,向干燥的5L三口瓶中加入原料I-03(500g,2.39mol)和DMSO(2.5L),然后快速滴加aq.HBr(1.45kg,7.17mol),1小时左右滴加完毕(滴加过程温度升高,体系温度升至52℃)。混合物缓慢升至60℃,继续搅拌12小时。将反应液缓慢倒入5公斤左右碎冰中淬灭,加入石油醚(1.5L),快速搅拌20分钟左右,析出大量黄色固体,过滤。滤饼用石油醚(500mL×3)洗涤后,减压抽干得到黄色固体产物I-04,粗品直接用于下一步。
第四步:化合物I-05的制备
在20℃下,向干燥的5L三口瓶中加入原料I-04(300g,1.25mol)和2-MeTHF(3L),然后加入HOAc(75g,1.25mol)和BocNHNH2(165.2g,1.25mol),混合物继续搅拌16小时。反应液依次用水(1L),20%碳酸钾水溶液(500mL×2)和饱和食盐水(1L×2)洗,无水硫酸钠干燥,减压浓缩得到黑色油状液体产物I-05,粗品直接用于下一步。
第五步:化合物I-06的制备
在20℃下,向干燥的5L三口瓶中加入原料I-05(560g,1.66mol)和DMSO(2.5L),然后加入K2CO3(229.5g,1.66mol),混合物升温至100℃搅拌16小时。反应液冷却至室温,然后将其倒入水(4L)和石油醚乙酸乙酯(4/1,1L)的混合液里,搅拌5分钟,然后用饱和的硫酸氢钾水溶液调节pH至3,有沙状固体析出,过滤,得到黑色的粗产品固体。继续用乙腈(1L)室温搅拌1小时,得到棕色固体产物I-06,粗品直接用于下一步。1H NMR(400MHz,d6-DMSO)δ2.47(s,3H)。
第六步:化合物I-07的制备
在20℃下,向干燥的50L反应釜中加入原料I-06(3.0kg,15.0mol)和DMF(15L),然后分批(每批250g)加入NIS(2.5kg,11.1mol)。投料完毕,然后将反应混合液升温至50℃下搅拌1.5小时。反应液冷却至室温,然后将其倒入45L溶解有500g亚硫酸氢钠的水溶液里,搅拌5分钟,有棕色固体析出,过滤,得到棕色的粗品。继续用乙腈(15L)室温搅拌1小时,过滤,滤饼真空干燥得到棕色固体产物I-07,粗品直接用于下一步。1H NMR(400MHz,d6-DMSO)δ2.47(s,3H)。
第七步:化合物I-08的制备
在20℃下,向干燥的50L夹套釜中加入DMF(25L),开启搅拌,然后加入原料I-07(5.2kg,15.9mol)和I-09(4.0kg,12.7mol)和K2CO3(1.75kg,12.7mol)。投料完毕,升温至115℃下搅拌24小时。反应液冷却至室温。与另一批次(4.5kg原料I-07)合并后处理,将合并反应液加到水(37.5L)和乙酸乙酯(8L)的混合液里,有固体析出,过滤。滤液分液,水相用乙酸乙酯(8L×2)萃取,合并有机相用无水硫酸钠干燥、过滤、加压浓缩得到残余物。滤饼和浓缩残余物合并,加入甲醇(15L),室温搅拌1小时后过滤。滤液减压浓缩,向残余物中加入正庚烷(5L),搅拌1小时。倒出正庚烷,加入叔丁基甲醚(4L),加热至60℃,快速搅拌0.5小时,降温至25℃,继续搅拌1小时后过滤。合并所有的滤饼,40℃真空干燥得到黄色固体产物I-08。1HNMR(400MHz,d6-DMSO)δ7.48-7.46(m,1H),7.36-7.33(m,1H),7.07-7.02(m,2H),5.30(dd,J=9.2,3.6Hz,1H),4.41(dd,J=14.4,3.6Hz,1H),4.17(dd,J=14.4,9.2Hz,1H),3.85(s,3H),3.38-3.36(m,1H),3.35-3.24(m,2H),3.24-3.14(m,2H),2.45(s,3H),1.63-1.62(m,1H),1.56-1.54(m,1H),1.34-1.31(m,1H),1.05-1.00(m,1H)。
第八步:化合物I-10的制备
向50L的反应釜内加入试剂甲苯(22L)和二环己基胺(1422.0mL,2eq),氮气鼓泡5分钟,调节反应釜温度至-10~5℃,氮气保护下将丁基锂(2.86L,2eq)缓慢滴加入反应液内(内温控制在-10~5℃),控制反应液内温在-10~5℃,搅拌50~70分钟;然后在氮气保护下将异丁酸甲酯(817.2mL,2eq)缓慢滴加入反应液内(内温控制在-10~5℃),控制反应液内温在-10~5℃,搅拌50~70分钟。氮气鼓泡下将I-08(2001.6g,1eq)加入反应液内,然后在氮气保护下将Pd2(dba)3(32.4g,0.01eq)和PtBu3(10%甲苯溶液,251.6mL,0.03eq)加入反应液内,反应液缓慢升温至20℃,然后在20℃下搅拌50~70分钟。
将水(8L)加入反应液内,分液分出水相,然后将盐酸水溶液(3M,5L)缓慢加入反应液内,调节pH至约为4~5,硅藻土过滤,滤饼用乙酸乙酯(15L)洗涤,将滤液静置分层,分出水相;有相用盐酸水溶液(1M,10L)洗涤,然后用碳酸钾水溶液(0.2M,10L)洗涤,分出水相,水相有大量絮状物包含产物,故继续垫硅藻土过滤,用乙酸乙酯(10L)洗涤滤饼,分液分出水相;合并有机相并用饱和氯化钠水溶液(15L)洗涤,有机相减压浓缩得到该批次粗产品(照此方法,另外投料2kg和1.4kg批次的反应,分别后处理得到粗产品)。所有批次粗产品合并,用乙酸乙酯和正庚烷做洗脱剂进行硅胶柱层析(正庚烷:乙酸乙酯=10:1至3:1)分离纯化,得到黄色固体I-10。LCMS:[M+H]+=431.3,1HNMR(400MHz,CDCl3)δppm 7.51(dd,J=7.6,1.6Hz,1H),7.36-7.32(m,1H),7.05-7.02(m,1H),6.91(d,J=8.0Hz,1H),5.44(dd,J=8.8,3.2Hz,1H),4.35(dd,J=14.0,3.2Hz,1H),4.06(dd,J=14.0,8.8Hz,1H),3.87(s,3H),3.80-3.74(m,1H),3.68(s,3H),3.58-3.52(m,1H),3.43-3.23(m,3H),2.56(s,3H),1.76-1.72(m,1H),1.60-1.45(m,8H),1.28-1.20(m,1H).
第九步:化合物I-11的制备
向10L的三口反应瓶内依次加入2-甲基四氢呋喃(1L)和噁唑(96.0mL,4.0eq),氮气鼓泡5分钟,调节反应瓶内温度至-30~-15℃,氮气保护下将TMPMgCl.LiCl(1.8L,4.8eq)缓慢滴加入反应液内(内温控制在-30~-15℃),控制反应液内温在-30~-15℃,搅拌30~40分钟;然后在氮气保护下将ZnCl2(1.5L,8eq)缓慢滴加入反应液内(内温控制在-30~-15℃),滴加完毕,撤去冷浴,反应液搅拌缓慢升温至15~20℃,得到噁唑的锌试剂。
另取一个10L三口反应瓶,依次加入2-甲基四氢呋喃(2L)和中间体I-10(200g),氮气鼓泡5分钟,氮气保护下将Pd2(dba)3(34.6g,0.1eq)和RuPhos(34.9g,0.3eq)加入反应瓶内,然后反应液升温至60~70℃,搅拌30~50分钟,然后将噁唑的锌试剂加入反应液内,反应液升温至90~95℃,继续在此温度下搅拌13~16小时。
合并5锅平行反应后处理;反应液冷却至室温,然后将反应液加入到盐酸水溶液(1M,20L,0-5℃)中,调节pH至3~4,分液分出水相,水相用乙酸乙酯(5L)萃取,合并有机相并用饱和氯化钠水溶液(10L×2)洗涤,有机相减压浓缩得到粗产品(照此方法,另外投料200g 15锅反应,分三批次后处理,每批1公斤,得到粗产品),硅胶柱层析分离纯化。将纯化得到的固体加入至异丙醇(4L)中,升温至50~55℃搅拌至固体完全溶解,再搅拌30~40分钟,然后自然降温至25~30℃,搅拌2.0~2.5小时,将正庚烷(4L)加入反应液内,并在25~30℃下搅拌12~13小时,过滤,并用正庚烷(2L)淋洗滤饼后抽干,将滤饼减压浓缩得到黄色固体I-11。LCMS:[M+H]+=568.3,1HNMR(400MHz,CDCl3)δppm 7.75(s,1H),7.54(dd,J=7.6,1.2Hz,1H),7.33(td,J=7.8,1.6Hz,1H),7.26(s,1H),7.06-7.04(m,1H),6.91(d,J=8.0Hz,1H),5.49(dd,J=8.8,3.2Hz,1H),4.41(dd,J=14.0,3.2Hz,1H),4.17(dd,J=14.0,8.8Hz,1H),3.87(s,3H),4.23-4.12(m,1H),3.78-3.71(m,1H),3.70(s,3H),3.56-3.49(m,1H),3.45-3.21(m,3H),3.00(s,3H),1.71-1.70(m,1H),1.64-1.48(m,8H),1.27-1.21(m,1H).
第十步:化合物I粗品的制备
向50L的反应釜内依次加入乙醇(25L)和中间体I-11,升温至55~60℃,搅拌至固体完全溶解,将配好的NaOH(1091.1g)的水(5L)溶液加入反应釜内,反应釜升温至70~80℃后,继续在此温度搅拌17~19小时。
反应液降至室温,减压浓缩除去乙醇;然后用3M盐酸水溶液(10L)调节pH至2~3(调节过程内温为15~25℃),过滤,过滤所得的粗产品内加入0.3M盐酸去离子水溶液(10L),并且在25~30℃下搅拌50~60分钟,过滤,过滤所得固体加入乙醇(2L)搅拌15~20分钟,再过滤,并将过滤所得的固体减压浓缩得到类白色的固体式(I)化合物的粗品。LCMS:[M+H]+=554.3,1HNMR(400MHz,CDCl3)δppm 776(s,1H),753(dd,J=7.6,1.6Hz,1H),7.37-7.30(m,1H),7.27(s,1H),7.06-7.02(m,1H),6.90(d,J=8.0Hz,1H),5.49(dd,J=8.8,4.0Hz,1H),4.44(dd,J=14.0,4.0Hz,1H),4.21(dd,J=14.0,8.8Hz,1H),3.86(s,3H),3.79-3.70(m,1H),3.61-3.49(m,1H),3.47-3.20(m,3H),3.02(s,3H),1.74-1.70(m,1H),1.63-1.50(m,8H),1.28-1.20(m,1H)。
第十一步:式(I)化合物的A晶型的制备
向10L的三口反应瓶内依次加入乙醇(2.5L)和式(I)化合物的粗品(850.0g),然后将反应液加热到75~80℃搅拌30~35分钟,然后自然冷却至室温(25~30℃),过滤,用乙醇(300mL×4次)洗涤滤饼,滤饼减压浓缩,所得固体真空烘干至恒重,得到式(I)化合物的A晶型。LCMS:[M+H]+=554.2,1HNMR(400MHz,CDCl3)δppm 776(d,J=0.8Hz,1H),7.53(dd,J=7.2,1.2Hz,1H),7.35-7.31(m,1H),7.27(s,1H),7.06-7.02(m,J=7.2Hz,1H),6.90(d,J=8.0Hz,1H),5.49(dd,J=8.8,4.0Hz,1H),4.44(dd,J=14.0,4.0Hz,1H),4.21(dd,J=14.0,8.8Hz,1H),3.86(s,3H),3.79-3.70(m,1H),3.59-3.49(m,1H),3.44-3.20(m,3H),3.02(s,3H),1.74-1.69(m,1H),1.64-1.50(m,8H),1.30-1.19(m,1H)。
实施例2:A晶型在不同温度和湿度及光照条件下固体物理稳定性试验
为评估A晶型的固体稳定性,对晶型A进行了影响因素(高温、高湿及光照)、加速条件稳定性及中间条件稳定性的考察。
将A晶型在高温(60℃,闭口)、高湿(室温,92.5%RH(相对湿度),封口膜包裹并扎5~10个小孔)下放置5天、10天,按照ICH条件(可见光照度达到1.2E06Lux·hrs,紫外光照度达到200W·hrs/m2)闭口放置在可见光及紫外光下(遮光对照组用锡箔纸包裹),同时在加速条件稳定性(60℃/75%RH,封口膜包裹并扎5~10个小孔)下放置1、2个月,中间条件稳定性(40℃/75%RH,封口膜包裹并扎5~10个小孔)下放置1、2、3个月。对放置后的样品进行XRPD表征,以检测晶型的变化;结果显示,晶型A在所有稳定性条件下,晶型均未发生变化。
实验例1:体外评价
实验目的:
通过测定IC50值来评价受试化合物对乙酰辅酶A羧化酶(ACC)的抑制能力。
实验材料:
1.蛋白:人源乙酰辅酶A羧化酶1(hACC1)和人源乙酰辅酶A羧化酶2(hACC2)。
2.底物:NaHCO3
3.辅因子:乙酰辅酶A,ATP(三磷酸腺苷)
4.激活剂:柠檬酸钾
实验方法:
1.在孔板的微孔中加入1倍的酶/底物/辅因子。
2.利用Acoustic技术,向上述酶的混合物中,加入化合物的DMSO溶液,预孵化15分钟。
3.向其中加入ATP引发反应,摇匀。
4.室温下孵化1小时。
5.淬灭反应后,继续孵化40分钟。
6.加入检测试剂,孵化30分钟。
7.测试荧光。
8.分析数据:基于ADP的标准曲线,将荧光信号转化成ADP产物浓度并计算酶活。利用Graphpad Prism软件拟合曲线,得到IC50值。实验结果如表2所示。
表2.本发明化合物体外筛选试验结果
化合物 | hACC1(nM) | hACC2(nM) |
式(I)化合物 | 14.1 | 10.3 |
结论:本发明化合物对人源ACC1/ACC2酶很强的抑制活性。
实验例2:化合物的药代动力学评价
实验目的:
测试化合物在C57BL/6小鼠体内的药代动力学
实验材料:
C57BL/6小鼠(雄性,18-30g,7~9周龄,上海灵畅生物科技有限公司)
实验操作:
将试验化合物的澄清溶液(0.5mg/ml 10%DMSO、10%聚乙二醇硬脂酸酯、80%水)经尾静脉注射到4只雄性C57BL/6小鼠体内(过夜禁食,7-9周龄),给药剂量为2.0mg/kg。将试验化合物的混悬液或澄清溶液(1mg/ml 10%PEG400、90%(0.5%甲基纤维素+0.2%Tween 80))灌胃给予4只雄性C57BL/6小鼠(过夜禁食,7-9周龄),给药剂量为10mg/kg。
每两只小鼠一组,交叉采血,每只小鼠采4~5个时间点。小鼠静脉或灌胃给药后于0.0833h(仅IV组)、0.25h、0.5h、1.0h、2.0h、4.0h、6.0h、8.0h和24h从隐静脉穿刺采血约30μL置于添加了EDTA-K2的抗凝管中,离心分离血浆。采用LC-MS/MS法测定血药浓度,使用WinNonlinTM Version 6.3(Pharsight,Mountain View,CA)药动学软件,以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果如表3所示:
表3.药代动力学测试结果
结论:本发明式(I)化合物可以显著提高小鼠药代动力学单项或部分指标。
实验例3:HFD+CCl4诱导的NASH小鼠模型中的体内药效学研究
实:验目的:
本研究的目的为研究化合物在HFD+CCl4小鼠模型中对NASH及肝纤维化的改善作用,以I-181为参比化合物。
I-181为Acetyl-CoACarboxylase抑制剂,目前正在进行非酒精性脂肪性肝疾病(Non Alcoholic Fatty Liver Disease,NAFLD)的临床II期研究。本研究所用的HFD+CCl4小鼠模型是一种模拟人类非酒精性脂肪性肝病进展为NASH过程的动物模型,高脂饲料导致脂肪在肝细胞中堆积、变性;CCl4(腹腔注射,每周两次)模拟肝损伤的“二次打击”。该模型稳定可靠,与人NASH的发病机制具有很高的相似性,具备了NASH主要病理特点,包括脂肪变、凋亡、炎症和纤维化,同时也表现出血浆转氨酶(ALT和AST)水平升高。
实验设计:
本试验的造模包括高脂饲料喂养和CCl4诱导两个步骤,首先以高脂饲料喂养小鼠诱导产生非酒精性脂肪肝,挑选体重>38g的小鼠,继续饲喂高脂饲料的同时,腹腔注射给与25%CCl4,0.5mg/kg,每周两次,共四周。将开始给CCl4的当天定为第0天,开始CCl4的时间定为第0小时,在开始给CCl4的当天,开始灌胃给药,各组的给药体积为5mL/kg,每天一次,持续4周(28天)。CCl4的注射时间应与当天的第一次给药时间点间隔4小时以上。实验一共分为6组,即健康对照组、模型组、参比化合物组(GS-0976)、受试化合物组(式(I)化合物,三个剂量)。健康对照组为10只正常小鼠,实验期间给予普通饲料喂养,不注射CCl4;50只肥胖小鼠用于模型组及给药组,每组为10只小鼠,分组后开始腹腔注射CCl4并分别给予不同剂量的药物。分组和剂量设计如表4所示。
表4.动物分组及给药方案
实验结果:
在高脂饮食和CCl4联合诱导的小鼠模型中,式(I)化合物不论在NAS以及纤维化两个维度均达到与参比化合物更高剂量下相同的药效。
Claims (8)
1.式(Ⅰ)化合物的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.54±0.20°、10.87±0.20°、15.55±0.20°、16.56±0.20°、17.64±0.20°、21.32±0.20°、23.53±0.20°和24.81±0.20°;
2.根据权利要求1所述A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射:6.91°、8.54°、8.80°、9.51°、10.87°、11.30°、12.38°、12.81°、13.84°、14.10°、15.55°、16.56°、17.64°、17.99°、18.76°、19.07°、20.27°、20.63°、21.32°、22.19°、22.71°、23.53°、24.07°、24.81°、26.80°、27.40°、27.79°、28.34°、29.94°、30.86°、31.34°、31.98°、33.17°、33.69°、35.21°、35.64°、36.25°、36.75°、37.79°和38.98°。
3.根据权利要求2所述A晶型,其XRPD图谱如图1所示。
4.根据权利要求1~3任意一项所述A晶型,其差示扫描量热曲线在234.9℃处具有吸热峰的起始点。
5.根据权利要求4所述A晶型,其DSC图谱如图2所示。
6.根据权利要求1~3任意一项所述A晶型,其热重分析曲线在200℃±3℃时失重达0.86%。
7.根据权利要求6所述A晶型,其TGA图谱如图3所示。
8.根据权利要求1~7任意一项所述A晶型在制备作为ACC1和ACC2抑制剂的药物中的应用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019112353736 | 2019-12-05 | ||
CN201911235373 | 2019-12-05 | ||
PCT/CN2020/133892 WO2021110135A1 (zh) | 2019-12-05 | 2020-12-04 | 作为acc1和acc2抑制剂的晶型及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114746426A CN114746426A (zh) | 2022-07-12 |
CN114746426B true CN114746426B (zh) | 2023-12-01 |
Family
ID=76221501
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080084236.1A Active CN114746426B (zh) | 2019-12-05 | 2020-12-04 | 作为acc1和acc2抑制剂的晶型及其制备方法和应用 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11578081B1 (zh) |
EP (1) | EP4071154B1 (zh) |
JP (1) | JP7265681B2 (zh) |
CN (1) | CN114746426B (zh) |
ES (1) | ES2965380T3 (zh) |
WO (1) | WO2021110135A1 (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105358154A (zh) * | 2013-05-10 | 2016-02-24 | 尼普斯阿波罗有限公司 | Acc抑制剂和其用途 |
CN105358152A (zh) * | 2013-05-10 | 2016-02-24 | 尼普斯阿波罗有限公司 | Acc抑制剂和其用途 |
WO2017147161A1 (en) * | 2016-02-23 | 2017-08-31 | Raju Mohan | Treatment of dermatological disorders or conditions |
CN108368125A (zh) * | 2015-10-26 | 2018-08-03 | 吉利德阿波罗公司 | Acc抑制剂及其用途 |
CN108699078A (zh) * | 2016-03-02 | 2018-10-23 | 吉利德阿波罗公司 | 噻吩并嘧啶二酮acc抑制剂的固体形式及其制备方法 |
WO2019233443A1 (zh) * | 2018-06-05 | 2019-12-12 | 南京明德新药研发有限公司 | 噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8501750B2 (en) * | 2007-05-21 | 2013-08-06 | Takeda Pharmaceutical Company Limited | Heterocyclic compound and use thereof |
CA2855372C (en) | 2011-11-11 | 2022-03-22 | Nimbus Apollo, Inc. | 2,4-dioxo-thieno[2,3-d]pyrimidinyl derivatives and pharmaceutical compositions thereof used as acc inhibitors |
AU2018227588B2 (en) * | 2017-03-03 | 2021-01-21 | Gilead Sciences, Inc. | Processes for preparing ACC inhibitors and solid forms thereof |
-
2020
- 2020-12-04 US US17/781,839 patent/US11578081B1/en active Active
- 2020-12-04 ES ES20896844T patent/ES2965380T3/es active Active
- 2020-12-04 EP EP20896844.6A patent/EP4071154B1/en active Active
- 2020-12-04 JP JP2022534284A patent/JP7265681B2/ja active Active
- 2020-12-04 WO PCT/CN2020/133892 patent/WO2021110135A1/zh unknown
- 2020-12-04 CN CN202080084236.1A patent/CN114746426B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105358154A (zh) * | 2013-05-10 | 2016-02-24 | 尼普斯阿波罗有限公司 | Acc抑制剂和其用途 |
CN105358152A (zh) * | 2013-05-10 | 2016-02-24 | 尼普斯阿波罗有限公司 | Acc抑制剂和其用途 |
CN108368125A (zh) * | 2015-10-26 | 2018-08-03 | 吉利德阿波罗公司 | Acc抑制剂及其用途 |
WO2017147161A1 (en) * | 2016-02-23 | 2017-08-31 | Raju Mohan | Treatment of dermatological disorders or conditions |
CN108699078A (zh) * | 2016-03-02 | 2018-10-23 | 吉利德阿波罗公司 | 噻吩并嘧啶二酮acc抑制剂的固体形式及其制备方法 |
WO2019233443A1 (zh) * | 2018-06-05 | 2019-12-12 | 南京明德新药研发有限公司 | 噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用 |
CN112218871A (zh) * | 2018-06-05 | 2021-01-12 | 南京明德新药研发有限公司 | 噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
US20230034132A1 (en) | 2023-02-02 |
JP7265681B2 (ja) | 2023-04-26 |
ES2965380T3 (es) | 2024-04-15 |
EP4071154A1 (en) | 2022-10-12 |
WO2021110135A1 (zh) | 2021-06-10 |
EP4071154B1 (en) | 2023-08-23 |
US11578081B1 (en) | 2023-02-14 |
JP2022551014A (ja) | 2022-12-06 |
CN114746426A (zh) | 2022-07-12 |
EP4071154A4 (en) | 2022-10-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR20190026827A (ko) | 방향족 아세틸렌 또는 방향족 에틸렌계 화합물, 그의 중간체, 제조 방법, 약물 조성물 및 용도 | |
CN109053731B (zh) | 一种对氯取代含哒嗪酮结构的螺[吲哚嗪-吡唑啉]衍生物及其制备方法与应用 | |
CN118119624A (zh) | 具有病毒增殖抑制作用的核苷衍生物及其前药 | |
KR102394934B1 (ko) | Akt 억제제로서의 염 형태 및 이의 결정 형태 | |
CN112110897B (zh) | 一种氘代克里唑蒂尼及其衍生物的制备方法 | |
CN111182896A (zh) | 脂肪性肝病的治疗剂以及肥胖症的治疗剂 | |
CN112500293A (zh) | 1,1′-联苯-2,6-二酚类化合物及其应用 | |
CN114746426B (zh) | 作为acc1和acc2抑制剂的晶型及其制备方法和应用 | |
WO2021001650A1 (en) | Pi3k inhibitor for use in the therapy of b cell lymphoma | |
CN114787166B (zh) | 噻吩并[2,3-c]哒嗪-4(1H)-酮类化合物的晶型及其制备方法和应用 | |
CN113278012A (zh) | 用作激酶抑制剂的化合物及其应用 | |
CN116284018A (zh) | 一种呋喃并[2,3-b]喹啉衍生物的制备方法及其应用 | |
CN107739381B (zh) | 莪术醇衍生物及其在制备抗肿瘤药物中的应用 | |
CN104650109A (zh) | 紫杉烷类化合物 | |
CN110128359B (zh) | 一种尿酸转运体1抑制剂的晶体及其制备方法和用途 | |
JP2022507558A (ja) | チエノピリドン誘導体のカリウム塩一水和物及びその調製方法 | |
CN111116551A (zh) | 1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物 | |
CN114940696B (zh) | 一种川楝素衍生物及其在乳腺癌治疗中的应用 | |
AU2021407012B2 (en) | CRYSTAL FORM OF CASEIN KINASE 1ε INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF | |
CN113387934B (zh) | 一种多芳基取代咪唑衍生物及其制备方法与应用 | |
CN115010642B (zh) | β-榄香烯酰亚胺类衍生物及其应用 | |
CN109232571B (zh) | 一种对甲巯基取代含哒嗪酮结构的螺[吲哚嗪-吡唑啉]衍生物及其制备方法与应用 | |
CN109180676B (zh) | 3,4,5-三甲氧基取代含哒嗪酮结构的螺[吲哚嗪-吡唑啉]衍生物及制备方法 | |
CN117946165A (zh) | 一种新型结构化合物axl抑制剂及其应用 | |
CN111732590A (zh) | 一种2,9-二取代嘌呤类衍生物及其制备方法和在抗肿瘤药物中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |