CN114195786A - Preparation and application of novel FXR (FXR) small molecule agonist - Google Patents
Preparation and application of novel FXR (FXR) small molecule agonist Download PDFInfo
- Publication number
- CN114195786A CN114195786A CN202010988285.XA CN202010988285A CN114195786A CN 114195786 A CN114195786 A CN 114195786A CN 202010988285 A CN202010988285 A CN 202010988285A CN 114195786 A CN114195786 A CN 114195786A
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- formula
- unsubstituted
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000556 agonist Substances 0.000 title abstract description 5
- 150000003384 small molecules Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 102100038495 Bile acid receptor Human genes 0.000 claims abstract description 37
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 claims abstract description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 230000009471 action Effects 0.000 claims description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 20
- 229910052805 deuterium Inorganic materials 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 229910052757 nitrogen Chemical group 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003613 bile acid Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 230000004060 metabolic process Effects 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 230000023852 carbohydrate metabolic process Effects 0.000 claims description 3
- 235000021256 carbohydrate metabolism Nutrition 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 230000037356 lipid metabolism Effects 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 26
- 238000003786 synthesis reaction Methods 0.000 abstract description 26
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000001270 agonistic effect Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 241000700721 Hepatitis B virus Species 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 16
- -1 2, 5-dichlorophenyl group Chemical group 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000013612 plasmid Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 8
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 6
- 239000012414 tert-butyl nitrite Substances 0.000 description 6
- RSHBFZCIFFBTEW-UHFFFAOYSA-M tetrabutylazanium;thiocyanate Chemical compound [S-]C#N.CCCC[N+](CCCC)(CCCC)CCCC RSHBFZCIFFBTEW-UHFFFAOYSA-M 0.000 description 6
- 101710142246 External core antigen Proteins 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 229960003280 cupric chloride Drugs 0.000 description 4
- 229940045803 cuprous chloride Drugs 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 210000005228 liver tissue Anatomy 0.000 description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 4
- 229960001601 obeticholic acid Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical group NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 3
- 108091036055 CccDNA Proteins 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- RIJWDPRXCXJDPK-UHFFFAOYSA-N methyl 3-cyclopropyl-3-oxopropanoate Chemical compound COC(=O)CC(=O)C1CC1 RIJWDPRXCXJDPK-UHFFFAOYSA-N 0.000 description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 101100328884 Caenorhabditis elegans sqt-3 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 108010052090 Renilla Luciferases Proteins 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000006274 endogenous ligand Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 208000010157 sclerosing cholangitis Diseases 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RGHJWZADAWEIFE-UHFFFAOYSA-N 4-amino-2-methylbenzonitrile Chemical compound CC1=CC(N)=CC=C1C#N RGHJWZADAWEIFE-UHFFFAOYSA-N 0.000 description 1
- OREVCMGFYSUYPX-UHFFFAOYSA-N 4-amino-3-chlorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1Cl OREVCMGFYSUYPX-UHFFFAOYSA-N 0.000 description 1
- RLMBRRQWBTWGMB-UHFFFAOYSA-N 4-amino-3-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1F RLMBRRQWBTWGMB-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108070000005 Bile acid receptors Proteins 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VYLOOGHLKSNNEK-PIIMJCKOSA-N OC(=O)c1cc(F)c2nc(sc2c1)N1[C@H]2CC[C@@H]1C[C@@H](C2)OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 Chemical compound OC(=O)c1cc(F)c2nc(sc2c1)N1[C@H]2CC[C@@H]1C[C@@H](C2)OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 VYLOOGHLKSNNEK-PIIMJCKOSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 125000003716 cholic acid group Chemical group 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000003021 clonogenic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000003228 intrahepatic bile duct Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- VOLSRTAMKIBBTQ-UHFFFAOYSA-N methyl 3-cyclobutyl-3-oxopropanoate Chemical compound COC(=O)CC(=O)C1CCC1 VOLSRTAMKIBBTQ-UHFFFAOYSA-N 0.000 description 1
- DOMJYWCXCVFKCA-UHFFFAOYSA-N methyl 4-amino-3-fluorobenzoate Chemical compound COC(=O)C1=CC=C(N)C(F)=C1 DOMJYWCXCVFKCA-UHFFFAOYSA-N 0.000 description 1
- HNNFDXWDCFCVDM-UHFFFAOYSA-N methyl 4-methyl-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)C HNNFDXWDCFCVDM-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000013326 plasmid cotransfection Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an FXR (farnesoid X receptor) micromolecule agonist and a preparation method thereof, and the structure of the FXR micromolecule agonist is shown as a formula I. Wherein, the definition of each substituent is described in the specification. The compound has the advantages of high FXR agonistic activity, simple synthesis, easily obtained raw materials and the likeCan be used for treating FXR related diseases.
Description
Technical Field
The invention belongs to the field of medicines, and relates to preparation and application of non-steroidal compounds serving as FXR agonists. In particular to a preparation method of organic small molecular compounds capable of being used as FXR agonists, enantiomers, diastereomers, tautomers, racemates, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, and application thereof in preparing drugs for treating FXR related diseases.
Background
Farnesoid X receptor (Farnesoid X receptor) is a member of the nuclear receptor superfamily, belongs to ligand-dependent nuclear transcription factors, and is mainly expressed in systems such as liver, intestinal tract, kidney, bile duct and the like; FXR is also called bile acid receptor because it can be activated by endogenous ligand bile acid and participates in important links such as bile acid metabolism and cholesterol metabolism. FXR may be directly involved in regulating the expression of over 300 genes including lipid metabolism, carbohydrate metabolism, inflammation, fibrosis, liver regeneration, cell differentiation and proliferation, etc. In natural environment, the ligand comprises primary bile acid chenodeoxycholic acid, secondary cholic acid lithocholic acid, deoxycholic acid and the like. For example, FXR activated by endogenous ligand bile acid plays an important role in Triglyceride (TG) metabolism, and can regulate and control key enzymes, lipoproteins, and corresponding receptors involved in TG metabolism, thereby achieving steady-state equilibrium of TG content in liver and circulating blood. Therefore, up to now, many FXR synthetic ligand molecules have been applied to metabolic diseases such as liver.
FXR agonist molecules have shown superior clinical efficacy in the treatment of liver diseases such as Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC) and nonalcoholic steatohepatitis (NASH). To date, the FXR agonist molecule obeticholic acid (OCA), which will be the first approved molecule to market, has been shown to significantly improve various metabolic symptoms, such as lowering liver fat content, reducing inflammatory response, and inhibiting liver fibrosis. However, OCA is increasingly showing a number of clinical short plates, such as causing itching, decreasing high-density lipoprotein (HDLc), increasing low-density lipoprotein (LDLc), etc. Therefore, in the aspect of clinical requirements, new FXR agonist molecules with good clinical effect and low toxic and side effects are urgently needed to appear.
In addition, research has confirmed that FXR is closely related to the development and development of tumors. FXR plays a role as an oncogene suppressor in a variety of tumors. For example, in hepatocellular carcinoma and rectal cancer, FXR is in a low-expression state, and after FXR is activated, the progress of liver cancer or rectal cancer is remarkably inhibited by inhibiting the activity of beta-catenin. Recent studies have shown that, in bile duct cancer, OCA, which is an agonist of FXR, can significantly inhibit proliferation, migration, clonogenic and the like of intrahepatic bile duct cells.
Furthermore, FXR agonists serve as a new antiviral drug candidate and studies have shown that FXR ligands can serve as a new therapeutic strategy for the inhibition of Hepatitis B Virus (HBV) replication. FXR agonists inhibit HBV surface antigen synthesis, inhibit replication of HBV DNA and RNA, and most importantly, inhibit HBV cccDNA production. In the case of Hepatitis C Virus (HCV), the FXR agonist GW4064 may inhibit HCV entry into hepatic tissue cells in an indirect manner. Therefore, the FXR agonist molecules also have great prospects in development of antiviral drugs.
In conclusion, a novel FXR agonist molecule which is simple in preparation method and good in inhibition effect is not available in the field.
Disclosure of Invention
The invention aims to provide a novel FXR agonist molecule which is simple in preparation method and good in inhibition effect.
In a first aspect of the present invention, there is provided a compound represented by formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
Wherein,
ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R1selected from: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted 5-9 membered heterocyclic ring (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R21、R22、R23each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6An alkoxy group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
y is selected from the group consisting of: o, NH, CH2Or CHR3Wherein R is3Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
wherein said substitution means that one or more hydrogen atoms on the group are each independently replaced by a substituent selected from the group consisting of: deuterium, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C3-C6Cycloalkoxy, cyano or nitro.
In another preferred embodiment, Ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring wherein the aryl or heteroaryl substituents are selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, R21、R22、R23Each independently selected from the group consisting of: hydrogen, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkoxy group.
In another preferred embodiment, R is1Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
In another preferred embodiment, R is21、R22、R23Each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, Ar is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen).
In another preferred embodiment, Ar is selected from the group consisting of substituted or unsubstituted groups selected from: a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a furan ring, a thiophene ring, a pyrrole ring, a thiazole ring, or an imidazole ring.
In another preferred embodiment, R is1Selected from the group consisting of: substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted cyclopropyl.
In another preferred embodiment, Ar is a substituted or unsubstituted benzene ring.
In another preferred embodiment, Ar is selected from the group consisting of: 2, 5-dichlorophenyl group, 2-methylphenyl group, 2-trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group.
In another preferred embodiment, said X is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group; the Y is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group.
In another preferred embodiment, the compound is selected from the group consisting of:
in another preferred embodiment, the compound of formula (I) has the structure shown below:
in a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, said process comprising: preparing a compound of formula I by a process selected from the group consisting of those described in scheme one, scheme two or scheme three:
route one:
(a') reacting a compound of formula VIII with a compound of formula XI under basic conditions to form a compound of formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I,
wherein, X is NH,y is O, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention;
and a second route:
(a') reacting the compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form a compound of formula I;
wherein X is O, Y is NH, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention;
and a third route:
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I,
wherein X is NH and Y is CH2,R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention.
In another preferred embodiment, the compound of formula VIII is prepared by the following steps:
(a) reacting a compound shown as a general formula II of substituted benzaldehyde serving as an initial raw material with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and chlorinating the intermediate by using N-chlorosuccinimide (NCS) to obtain a compound shown as a general formula III;
(b) then reacting the compound shown in the general formula III with corresponding 3-oxo-propionic ester to obtain a compound shown in a general formula IV;
(c) reducing ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, brominating to generate a compound shown in V,
(d) reacting the compound shown in the general formula V with the compound shown in the formula VI under a basic condition to obtain a compound shown in the general formula VII;
(e) reacting the compound shown in the general formula VII under the action of trifluoroacetic acid to obtain a compound shown in a general formula VIII;
in the formulae, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention.
In another preferred embodiment, the compound of formula XI is prepared by the following steps:
(f) reacting the compound shown in the general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) and (3) reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain the compound shown in the general formula XI.
In the formulae, R21、R22、R23Is as defined in the first aspect of the invention.
The compounds of formula XIV are prepared by the following steps:
(h) reacting the compound shown in the general formula XII with sodium thiocyanate under the action of liquid bromine or tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula XIII;
(i) and (3) reacting the compound shown in the general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain the compound shown in the general formula XIV.
In the formulae, R21、R22、R23Is as defined in the first aspect of the invention.
In another preferred embodiment, when the product has optical isomers, the product is prepared by using the raw materials with corresponding optical configurations.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the present invention, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a use of a compound represented by general formula I according to the first aspect of the present invention, or an enantiomer, a diastereomer, a tautomer, a racemate, a hydrate, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition for treating a disease or disorder associated with FXR activity or expression.
In another preferred embodiment, said FXR related disease is selected from the group consisting of: bile acid metabolism, carbohydrate metabolism, lipid metabolism, inflammation, and/or diseases associated with liver fibrosis processes.
In another preferred example, the FXR-related disease is nonalcoholic fatty liver disease (NASH), Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), gallstones, nonalcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.
In another preferred embodiment, the pharmaceutical composition is used as an FXR agonist.
In another preferred embodiment, the pharmaceutical composition is used for reducing serum levels of ALP, ALT, AST, TBA.
In another preferred embodiment, the pharmaceutical composition is used for reducing the content of hydroxyproline in liver tissues.
In another preferred embodiment, the pharmaceutical composition is used for down-regulating the expression of alpha-SMA and Col1 alpha 1mRNA in liver tissue.
In another preferred embodiment, the pharmaceutical composition is used for inhibiting the synthesis of HBV surface antigens, inhibiting the replication of HBV DNA and RNA, and inhibiting the production of HBV cccDNA.
In another preferred embodiment, the pharmaceutical composition is used for reducing the collagen content in the liver.
In another preferred embodiment, the pharmaceutical composition is prepared by the following method: the compound of the formula I is mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules, syrups and the like for oral administration.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the application researches extensively and deeply and develops a class of non-steroidal compounds capable of being used as FXR agonists, and the non-steroidal compounds have the exciting ability on FXR at a molecular level and a cell level, and the research shows that the compounds can reduce the levels of ALP, ALT, AST and TBA in serum, reduce the content of hydroxyproline in liver tissues, regulate the expression of a-SMA and Col1 a 1mRNA in the liver tissues, reduce the content of collagen in the liver, inhibit the synthesis of HBV surface antigen, inhibit the replication of HBV DNA and RNA and inhibit the generation of HBV cccDNA. The compound has the advantages of high FXR agonistic activity, simplicity in synthesis, easiness in obtaining raw materials and the like, and can be used for preparing medicines for treating FXR related diseases. On the basis of this, the present invention has been completed.
Term(s) for
In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.
In the present invention, the halogen is F, Cl, Br or I.
In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5, or 6 carbon atoms, "C3-C6" means having 3, 4, 5, or 6 carbon atoms, and so on.
In the present invention, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" denotes the group-O- (C1-C6 alkyl). For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
In the present invention, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
In the present invention, the term "cycloalkoxy" denotes cycloalkyl-O-, cycloalkyl being as defined above.
In the present invention, the term "aryl" denotes a hydrocarbyl moiety comprising one or more aromatic rings. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, fluorenyl, anthracenyl, and phenanthrenyl.
In the present invention, the term "heteroaryl" denotes a moiety comprising one or more aromatic rings having at least one heteroatom (e.g. N, O or S). Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, indolyl and the like.
Unless otherwise specified, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C20Cycloalkyl radical, C3-C20Cycloalkenyl radical, C1-C20Heterocycloalkyl radical, C1-C20Heterocycloalkenyl, C1-C6Alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10Alkylamino radical, C1-C20Dialkylamino, arylamino, diarylamino, C1-C10Alkylsulfamoyl, arylsulfamoyl, C1-C10Alkylimino radical, C1-C10Alkylsulfimidyl, arylsulfimidyl, mercapto, C1-C10Alkylthio radical, C1-C10Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. In another aspect, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused to each other.
In the invention, the substitution is mono-substitution or multi-substitution, and the multi-substitution is di-substitution, tri-substitution, tetra-substitution or penta-substitution. By disubstituted is meant having two substituents and so on.
The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound in the general formula I and organic base.
In another preferred embodiment, in the compound, Ar and R1、R21、R22、R23Any of, W, V, X, Y, and Z are each independently the corresponding group in the specific compound described in the examples.
The compounds of the present invention have asymmetric centers, chiral axes and chiral planes, and can exist in the form of racemates, R-isomers or S-isomers. The person skilled in the art is able to obtain the R-isomer and/or the S-isomer by resolution of the racemate by means of customary technical measures.
Preparation method
The preparation method of the compound shown in the general formula I comprises the following synthetic route:
route one:
the preparation method comprises the following steps:
(a) reacting a compound shown as a general formula II of aryl formaldehyde with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and chlorinating the intermediate by using N-chlorosuccinimide (NCS) to obtain a compound shown as a general formula III;
(b) then reacting the compound shown in the general formula III with corresponding 3-oxo-propionic ester under the action of alkali to obtain a compound shown in a general formula IV;
(c) reducing ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, and then carrying out bromination to generate a compound shown in V;
(d) reacting the compound shown in the general formula V with the compound shown in the general formula VI under the action of alkali to obtain a compound shown in the general formula VII;
(e) reacting the compound shown in the general formula VII under the action of trifluoroacetic acid to obtain a compound shown in a general formula VIII;
(a') reacting a compound represented by the general formula VIII with a compound represented by the general formula XI under the action of a base to obtain a compound represented by the general formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride under the action of a base to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I.
Wherein the compound of formula XI is prepared by the following steps:
(f) reacting the compound shown in the general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) then reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XI;
line 2
The compounds of formula VIII can also be prepared by reference to line 1, and further comprising the following steps:
(h) reacting the compound shown in the general formula XII with sodium thiocyanate under the action of liquid bromine or tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula XIII;
(i) then reacting the compound shown in the general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XIV;
(a') reacting the compound of formula VIII with a compound of formula XIV under the action of a base to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form the compound of formula I
Line 3
The compounds of the general formula XVII can also be prepared with reference to line 2, which comprises the following steps:
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I.
Wherein R is1、R21、R22、R23Ar, W, V, U, X and Y are as defined above.
Pharmaceutical compositions and therapeutic uses thereof
The compound provided by the invention can be used alone, or can be mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to be prepared into tablets, capsules, granules, syrups and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional method in pharmacy. The pharmaceutical composition of the present invention comprises the active ingredient in a safe and effective amount range, and a pharmaceutically acceptable carrier.
The active ingredient refers to the compound of the formula I.
The active ingredient and the pharmaceutical composition are used for preparing the medicine for treating FXR related diseases. The invention
The "active ingredient" and pharmaceutical compositions are useful as FXR agonists. In another preferred embodiment, said active ingredient can be used for the preparation of a medicament for the prevention and/or treatment of diseases modulated by FXR agonists.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like)) Gelatin, talc, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as propylene glycol, glycerin, mannitol, sorbitol, etc.)) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include 5 (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other therapeutic agents, such as hypolipidemic agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The instruments used and the main experimental materials were as follows:
the reagents and anhydrous solvents used were purchased from commercial companies in China and used as received unless otherwise specified;1h and13c NMR was performed using a BrukeraM-400 and Varian Mercury plus-400 NMR spectrometer using an Agilent6230 mass spectrometer, and 200-mesh 300-mesh column chromatography silica gel (Qingdao Seisakusho), HSGF254 TLC plate (Nicoti Seisakusho chemical research institute).
The compounds of the present invention are prepared according to any method selected from the following scheme 1, scheme 2 and scheme 3, using suitable starting materials:
line 1
Line 2
Line 3
Synthesis of intermediate VIII-1:
aqueous potassium carbonate (3N, 182mmol) was added dropwise to a stirring solution of hydroxylamine hydrochloride (182mmol) in ethanol (100mL) at 0 deg.C, 2, 6-dichlorobenzaldehyde II-1(20g, 114mmol) was dissolved in 100mL of ethanol and then added to the hydroxylamine solution, the temperature was raised to 90 deg.C, and the reaction was carried out for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. Water/ethanol (1000mL/100mL) solution was added and the solid was broken up by stirring, filtered and dried overnight under vacuum at 50 ℃ to give the intermediate compound (18.4 g). This intermediate was dissolved in N, N-dimethylformamide (50mL), and a solution of N-chlorosuccinimide (97mmol) in N, N-dimethylformamide (100mL) was added dropwise at 0 ℃ and stirred overnight. The reaction solution was poured into ice water at 0 ℃ and then extracted with methyl t-butyl ether (200 mL each time, 3 times in total), the organic phases were washed with saturated brine, and the combined organic phases were concentrated to give a crude product. To a flask containing the crude product was added n-hexane (600mL), stirred with a magneton, filtered, and the solid was dried under vacuum (30 ℃ C.) to give intermediate III-1(18.3g, 73% yield).1H NMR(400MHz,CDCl3)δ7.43–7.39(m,2H),7.39–7.33(m,1H)。
Triethylamine (8.2g)Was added to methyl 3-cyclopropyl-3-oxopropanoate (82mmol), and the mixture was stirred for 30 minutes. Then, it was cooled to 10 ℃ and a solution of III-1(18.3g, 82mmol) in anhydrous ethanol (80mL) was added dropwise thereto (inner temperature not exceeding 30 ℃ C.), and the reaction was allowed to proceed overnight at room temperature. The reaction was diluted with ethyl acetate (100mL), washed with water, and the aqueous phase was extracted with ethyl acetate (100mL each, 3 times). The organic phases were mixed, washed with saturated brine, the combined organic phases were concentrated. To the concentrate was added 100mL of ether and stirred, and the solvent was removed in vacuo to give the product IV-1 as a solid (21.6g, 84% yield).1H NMR(400MHz,CDCl3)δ7.43–7.39(m,2H),7.39–7.33(m,1H),3.72(s,3H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H);MS(ESI,m/z):312[M+H]+。
IV-1(21.6g, 69mmol) was dissolved in tetrahydrofuran (140mL), cooled to 0 deg.C, a toluene solution of diisobutylaluminum hydride (1.5M,102mL) was slowly added dropwise to the solution, and the reaction was stirred at room temperature for 6 h. Slowly pouring the reaction liquid into ice water, adding 1M hydrochloric acid aqueous solution to adjust the pH to be about 2, extracting with ethyl acetate (100mL each time, three times), combining organic phases, concentrating, and performing column chromatography to obtain intermediate alcohol; this intermediate and triphenylphosphine (59mmol) were dissolved in dichloromethane (60mL), cooled to 0 deg.C, and a solution of carbon tetrabromide (62mmol) in dichloromethane (60mL) was added dropwise under nitrogen, and reacted at room temperature for 4 h. The solvent was removed from the reaction mixture to give an oil, which was subjected to column chromatography to give intermediate V-1(15.3g, 96% yield).1H NMR(400MHz,CDCl3)δ7.49–7.44(m,2H),7.43–7.37(m,1H),4.25(d,J=1.3Hz,2H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H);MS(ESI,m/z):346[M+H]+。
At 0 ℃ inward-N-BOC-3-hydroxy-8-azabicyclo [3.2.1 ]]To a solution of octane VI-1(1.48g, 6.5mmol) in dry tetrahydrofuran (20mL) was added potassium tert-butoxide (6.5mmol), and the mixture was stirred for 30 minutes, then a solution of V-1(4.3mmol) in dry tetrahydrofuran (5mL) was added dropwise and reacted for 8 hours. Water (20mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL each time for 3 times), and the organic phase was washed with saturated brine, and the organic phases were combined, concentrated, and subjected to column chromatography to give intermediate VII-1(1.44 g). Intermediate VII-1(1.44g,2.9mmol) was dissolved in dichloromethane (8mL), cooled to 0 deg.C, trifluoroacetic acid (8mL) was added dropwise and stirred at room temperature for 3 h. The solvent was removed under vacuum, and ethyl acetate (20mL) was added to dissolve, and the solution was washed with 2N sodium hydroxide solution and saturated brine, and the solvent was removed to give intermediate VIII-1(638mg, yield 56%).1H NMR(400MHz,CDCl3)δ7.42–7.39(m,2H),7.36–7.31(m,1H),4.27–4.18(m,2H),4.10–3.96(m,2H),3.53(t,J=4.8Hz,1H),2.16–2.07(m,1H),1.91–1.69(m,6H),1.64(d,J=14.4Hz,2H),1.26–1.22(m,2H),1.14–1.08(m,2H);MS(ESI,m/z):393[M+H]+。
Example 1 synthesis:
intermediate IX-1(16.8g, 142.3mmol), tetrabutylammonium thiocyanate (142.3mmol), benzyltrimethylammonium bromide (142.3mmol) were added to a round bottom flask and dichloromethane (140mL) was added under nitrogen and allowed to react at room temperature for three days. And adding water into the reaction liquid for quenching, adding a saturated sodium bicarbonate solution to adjust the reaction system to be neutral, extracting by ethyl acetate, combining organic phases, concentrating, and performing column chromatography to obtain an intermediate X-1(2.5g, yield 10%). MS (ESI, m/z): 176[ M + H]+。
X-1(2.5g, 14.3mmol), cuprous bromide (22mmol) and acetonitrile (50mL) were added to a three-necked round bottom flask and stirred, tert-butyl nitrite (2.9mmol) was slowly added dropwise under nitrogen, and the mixture was heated to 30 ℃ for reaction for 48 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XI-1(2.12g, 62% yield). MS (ESI, m/z): 239[ M + H]+。
Intermediate VIII-1(0.43g, 1.09mmol), intermediate XI-1(1.09mmol), cesium carbonate (1.6mmol) were added to a round bottom flask, N-dimethylacetamide (5mL) was added under nitrogen, and the mixture was heated to 60 ℃ for 12 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XV-1(0.55g, 91% yield). MS (ESI, m/z): 551[ M + H ]]+。
Intermediate XV-1(0.55g, 1mmol), hydroxylamine hydrochloride (2.6mmol) and absolute ethanol (10mL) were added to a three-necked round bottom flask and stirred, triethylamine (2.6mmol) was slowly added dropwise under nitrogen protection, and the mixture was heated to 90 ℃ for 12 hours. The reaction solution was cooled to room temperature, quenched with water, evaporated to remove ethanol, extracted with ethyl acetate, the combined organic phases concentrated, and subjected to column chromatography to give intermediate XVI-1(0.58g, yield 99%). MS (ESI, m/z): 584[ M + H ]]+。
Intermediate XVI-1(0.58g, 0.99mmol), N, N' -carbonyldiimidazole (1.2mmol), 1, 4-dioxane (5mL) was charged to a round-bottomed flask, followed by 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (1.2mmol) was heated to 100 ℃ for 4 hours. The reaction was cooled to room temperature, diluted with water (5mL), adjusted to pH 2 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, the combined organic phases concentrated to give the crude product, which was then subjected to column chromatography to give the final product 1 as a white solid (0.28g yield 64%).1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.28(s,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H);MS(ESI,m/z):610[M+H]+。
Synthesis of example 2:
the preparation of example 2 proceeds from compound XII-1 via scheme 2, which follows:
intermediate XII-1(6g, 35.6mmol), tetrabutylammonium thiocyanate (35.6mmol), benzyltrimethylammonium bromide (35.6mmol) were added to a round bottom flask, dichloromethane (50mL) was added under nitrogen and allowed to react at room temperature for three days. Adding water to the reaction solution for quenching, and adding saturated waterThe reaction system was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate, the combined organic phases were concentrated and subjected to column chromatography to give intermediate XIII-1(2.62g, yield 32%). MS (ESI, m/z): 227[ M + H ]]+。
XIII-1(2.62g, 11.6mmol), cuprous bromide (17.9mmol) and acetonitrile (30mL) were added to a three-necked round-bottomed flask and stirred, tert-butyl nitrite (2.32mmol) was slowly added dropwise under nitrogen, and the mixture was heated to 30 ℃ for reaction for 48 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XIV-1(2.35g, yield 70%). MS (ESI, m/z): 290[ M + H ]]+。
Intermediate VIII-1(0.34g, 0.86mmol), intermediate XIV-1(0.86mmol), and cesium carbonate (1.3mmol) were added to a round-bottomed flask, N-dimethylacetamide (5mL) was added under nitrogen, and the mixture was heated to 60 ℃ for 12 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XVII-1(0.5g, 96% yield). MS (ESI, m/z): 602[ M + H]+。
Intermediate XVII-1(0.5g, 0.83mmol), hydrazine hydrate (20.6mmol), and absolute ethanol (10mL) were added to a three-necked round-bottomed flask, stirred, and heated to 90 ℃ under nitrogen for 48 hours. The reaction mixture was cooled to room temperature, quenched with water, evaporated to remove ethanol, extracted with ethyl acetate, the combined organic phases concentrated, and subjected to column chromatography to give intermediate XVIII-1(0.28g, yield 56%). MS (ESI, m/z): 602[ M + H]+。
Intermediate XVIII-1(0.21g, 0.35mmol), N, N' -carbonyldiimidazole (0.42mmol), 1, 4-dioxane (2mL) was charged into a round-bottomed flask, and 1, 8-diazabicyclo [5.4.0 ] was added under nitrogen]Undec-7-ene (0.42mmol) was heated to 100 ℃ for 4 hours. The reaction was cooled to room temperature, diluted with water (5mL), adjusted to pH 2 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, the combined organic phases concentrated and the crude product obtained was chromatographed to give the final product 2 as a white solid (0.18g yield 82%).1H NMR(400MHz,d-DMSO)δ7.77(s,1H),7.64–7.62(m,2H),7.59–7.52(m,1H),7.31–7.28(m,1H),4.25(s,2H),4.15(s,2H),3.49(s,1H),1.97–1.93(m,2H),1.77–1.67(m,6H),1.57(s,2H),1.18–1.02(m,4H);MS(ESI,m/z):628[M+H]+。
Synthesis of example 3:
preparation of example 3 starting from 4-amino-3-fluorobenzoic acid methyl ester XII-2 the intermediate XVII-1 of reference example 2 was prepared to give intermediate XVII-2, which was then prepared via scheme 3, as follows:
intermediate XVII-2(0.57g, 0.95mmol), toluene (5mL) was added to a round-bottomed flask, then N, N-dimethylformamide (0.02mL) and thionyl chloride (1mL) were added under nitrogen, and the mixture was heated to 110 ℃ for 1 hour. The reaction mixture was concentrated, and the resulting crude product, intermediate XIX-2(0.3g), was used directly in the next reaction. MS (ESI, m/z): 606[ M + H]+。
Crude intermediate XVII-2 (0.3g), glycinamide (64mg, 0.58mmol) and acetonitrile (5mL) were added to a round bottom flask, followed by triethylamine (0.58mmol) under nitrogen and heated to 40 ℃ for 2 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XX-2(0.25g, 81% yield). MS (ESI, m/z): 644[ M + H ]]+。
Intermediate XX-2(0.25g, 0.48mmol), 1, 4-dioxane (5mL) was added to a round bottom flask, then phosphorus oxychloride (1mL) was added under nitrogen, and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give the final product, white solid 3(0.04g, yield 13%).1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),4.16(s,br,2H),3.55–3.50(m,1H),2.39–2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H);MS(ESI,m/z):626[M+H]+。
Synthesis of example 4:
the synthetic route of example 4 is as follows:
starting from a raw material III-1, synthesizing a compound VIII-2 by replacing 3-cyclopropyl-3-oxopropanoic acid methyl ester with methyl isobutyrylacetate according to a synthetic method for synthesizing an intermediate VIII-1, and then preparing 4 through a route 1, wherein:
the yield of the white solid is 21 percent,1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.65–7.63(m,3H),7.59–7.52(m,2H),4.20(s,4H),3.47(s,1H),3.38(t,J=6.8Hz,1H),1.96-1.91(m,2H),1.82(s,4H),1.69(d,J=14.8Hz,2H),1.32(d,J=7.2Hz,6H).;MS(ESI,m/z):612[M+H]+。
synthesis of example 5:
the synthetic route of example 5 is as follows:
starting from a raw material III-1, synthesizing a compound VIII-3 by replacing 3-cyclopropyl-3-oxopropanoic acid methyl ester with 3-cyclobutyl-3-oxopropanoic acid methyl ester according to the synthesis method for synthesizing an intermediate VIII-1, and then preparing 5 through a scheme 1, wherein:
the yield of the white solid 5 percent is 19 percent,1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.67-7.65(m,3H),7.60–7.53(m,2H),4.30(s,1H),4.21–4.15(m,2H),3.63–3.61(m,2H),2.26–1.83(m,11H),1.80–1.76(m,3H),1.65(d,J=14.8Hz,1H).MS(ESI,m/z):624[M+H]+。
synthesis of example 6:
the synthetic route of example 6 is as follows:
compound XI-2 was synthesized starting from starting material IX-2 following the synthetic procedure for the synthesis of intermediate XI-1, substituting 4-aminobenzonitrile with 4-amino-2-methylbenzonitrile, followed by preparation of 6 via scheme 1, wherein:
the yield of the white solid 5 percent is 20 percent,1H NMR(400MHz,DMSO-d6)δ7.69–7.61(m,2H),7.61–7.53(m,1H),7.51–7.39(m,2H),4.28(s,2H),4.22(br,s,1H),3.50–3.42(m,1H),3.28–3.21(m,2H),2.55(s,3H),2.38–2.31(m,1H),2.02–1.91(m,2H),1.87–1.78(m,4H),1.76–1.67(m,2H),1.19–1.06(m,4H).MS(ESI,m/z):625[M+H]+。
synthesis of example 7:
the synthetic route of example 7 is as follows:
compound XI-3 is synthesized starting from raw material IX-3 according to the synthesis of synthesis intermediate XI-1, replacing 4-aminobenzonitrile with 4-amino-3-chlorobenzonitrile, followed by scheme 1 to afford 7, wherein:
the yield of the white solid 7 is 21 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.75(s,1H),7.69–7.62(m,2H),7.61–7.55(m,1H),4.28(s,2H),4.19(s,br,2H),3.55-3.49(m,1H),2.38–2.32(m,1H),1.99–1.92(m,2H),1.89–1.72(m,6H),1.19–1.05(m,4H);MS(ESI,m/z):644[M+H]+。
synthesis of example 8:
the synthetic route of example 8 is as follows:
compound XI-4 is synthesized starting from starting material IX-4 by the synthetic method for the synthesis of intermediate XI-1, replacing 4-aminobenzonitrile with 4-amino-3-fluorobenzonitrile, followed by scheme 1 to afford 8, wherein:
the yield of the white solid is 8 percent and 24 percent,1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),3.55–3.50(m,1H),2.39-2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H);MS(ESI,m/z):628[M+H]+。
synthesis of example 9:
the synthetic route for example 9 is as follows:
preparation of 9 via scheme 1 starting from starting material III-2, wherein:
the yield of the white solid is 9 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.74–7.62(m,2H),7.57–7.46(m,1H),7.33–7.24(m,2H),4.31(s,2H),4.19(s,br,2H),3.56–3.50(m,1H),2.35–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H);MS(ESI,m/z):578[M+H]+。
synthesis of example 10:
the synthetic route of example 10 is as follows:
starting from starting material III-3, preparation via scheme 1 yields 10, where:
the yield of the white solid is 10 percent and 28 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.73–7.62(m,1H),7.59–7.48(m,3H),7.44–7.29(m,2H),4.35(s,2H),4.21(s,br,2H),3.58–3.53(m,1H),2.36–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H);
MS(ESI,m/z):560[M+H]+。
synthesis of example 11:
the synthetic route for example 11 is as follows:
preparation of 11 via scheme 1 starting from starting material III-4, wherein:
the yield of the white solid is 11 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.92–7.89(m,1H),7.85–7.71(m,2H),7.69-7.52(m,3H),4.25(s,2H),4.21(s,br,2H),3.55–3.46(m,1H),2.38–2.24(m,1H),2.02–1.90(m,2H),1.89–1.68(m,6H),1.19-1.04(m,4H).
MS(ESI,m/z):610[M+H]+。
synthesis of example 12:
the synthetic route for example 12 is as follows:
preparation of 12 via scheme 1 starting from starting material III-5, wherein:
the yield of the white solid is 12 percent and 19 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.80–7.59(m,3H),7.58–7.50(m,3H),4.35(s,2H),4.21(s,br,2H),3.60–3.48(m,1H),2.38–2.24(m,1H),2.05–1.92(m,2H),1.91–1.65(m,6H),1.18–1.02(m,4H).
MS(ESI,m/z):626[M+H]+。
synthesis of example 13:
the synthetic route for example 13 is as follows:
prepared by route 1 starting from starting material III-6 to 13, wherein:
the yield of the white solid is 13 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.63(m,1H),7.58–7.51(m,1H),7.45–7.24(m,4H),4.35–4.10(m,4H),3.58–3.49(m,1H),2.37–2.25(m,1H),2.21(s,3H),2.05–1.94(m,2H),1.92–1.73(m,6H),1.19–1.03(m,4H).
MS(ESI,m/z):556[M+H]+。
synthesis of example 14:
the synthetic route for example 14 is as follows:
prepared by route 1 starting from starting material III-7 to 14, wherein:
the yield of the white solid is 14 percent,1H NMR(400MHz,d-DMSO)δ8.74(d,J=5.2Hz,2H),8.20(s,1H),7.72(d,J=5.2Hz,2H),7.66(d,J=8.4Hz,1H),7.55(d,J=8.4Hz,1H),4.51(s,2H),4.29(s,2H),3.72(s,1H),2.38–2.34(m,1H),2.11–2.06(m,2H),2.01–1.91(m,6H),1.13–1.11(m,2H),1.06–1.05(m,2H).
MS(ESI,m/z):543[M+H]+。
synthesis of example 15:
the synthetic route for example 15 is as follows:
starting from a raw material III-1, replacing diisobutyl aluminum hydride synthetic compound intermediate VIII-10 with deuterated lithium aluminum hydride according to the synthetic method of the synthetic intermediate VIII-1, and then preparing 15 through a route 1, wherein:
white solid 15 (yield 58%).1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H);MS(ESI,m/z):612[M+H]+。
Synthesis of example 16:
the synthetic route for example 16 is as follows:
preparation of intermediate VIII-1 starting from V-1 gives VIII-11, which is prepared by scheme 1 to give 16, wherein:
white solid 16 (yield 21%),1H NMR(400MHz,d-DMSO)δ.8.18(s,1H),7.72–7.60(m,3H),7.59–7.51(m,2H),4.20–3.85(m,2H),3.66–3.20(m,2H),2.95–2.48(m,1H),2.29–2.03(m,1H),2.02–1.88(m,2H),1.78–1.69(m,4H),1.66–1.43(m,2H),1.19–1.03(m,4H)
MS(ESI,m/z):609[M+H]+。
pharmacological test example:
a method for detecting FXR agonistic activity of a compound based on a reporter gene activity assay:
1.1 construction and preparation of plasmids pGAL4-FXR-LBD and pG5-Luc
pGAL4-FXR-LBD and pG5-Luc plasmids used by a reporter gene detection system are constructed according to a conventional molecular cloning method. The method mainly comprises the following steps: inserting the FXR (NM-001206979.2) cDNA sequence corresponding to the FXR-LBD (212-476AA) amino acid sequence into BamHI and NotI enzyme cutting sites of pGAL4 vector by using PCR technology to obtain pGAL 4-FXR-LBD; pG5-Luc and phRL-TK plasmids were given to Shanghai pharmaceutical research institute of Chinese academy of sciences; by using CaCl2The plasmid was transformed into DH 5. alpha. E.coli, further cultured and amplified, and then purified with a plasmid extraction kit (TIANGEN, # D107) to obtain the corresponding plasmid DNA.
1.2 plasmid cotransfection of HEK293T cells and Compound treatment
HEK293T cells were transfected at 1X 10 the day before plasmid transfection4Density of/well was seeded in 96-well plates. According to the transfection reagent FuHD (Promega, # E2311) instructions for cell transfection. The main steps areComprises the following steps: using one well as an example, the plasmids pGAL4-FXR-LBD, pG5-Luc and phRL-TK were added to 10uL of Opti-MEM in a ratio of 20ng, 50ng and 5ngTMMix well in I medium (Gibco, # 11058021); then add 0.25uL of FuHD, standing for 5min at room temperature after uniformly mixing; this 10uL mixture was then added to the wells containing 100uL of medium. 6h after cell cotransfection, the compound was diluted in 3-fold gradient with 1uM as the highest concentration, and added to the cell culture medium in 10 concentrations for 24h, and 2 multiple wells in total, with LJN452 compound as the positive control.
1.3Dual-Glo Luciferase assay
Cells were treated with compound for 24h, followed by Dual-The Luciferase Assay System (Promega, # E2940) was used for the Assay. The method mainly comprises the following steps: 50uL of culture medium was aspirated from each well, and 50uL of Dual-Shaking Luciferase reagent at room temperature for 10 min; taking 80uL of the lysis reaction solution to a white opaque optiPlate-96 pore plate, and detecting the luminescence signal value (Firefly-Luc) of Firefly luciferase (Firefly luciferase) by using an MD i3x multifunctional microplate reader; then adding 40uL Dual-Stop&Shaking the reagent at room temperature for 10 min; the luminescence signal value (Renilla-Luc) of Renilla luciferase (Renilla luciferase) was detected using an MD i3x multi-functional microplate reader. The ratio of Firefly-Luc/Renilla-Luc was used as the FXR activating activity of the compound, the ratio of the solvent DMSO group was used for normalization, a dose-response curve was fitted with four parameters using GraphPad prism6.0 software, and EC was calculated50The value is obtained.
2. Results
The experimental data show that the compounds all have certain FXR agonistic activity, wherein the EC of the examples 1, 2, 4, 7, 8 and 1650All values are less than 10nM, in particular EC of example 850Values of less than 5nM, very strong FXR agonistic activity. The FXR agonist activity data for each example are shown in table 1.
FXR agonistic Activity of the Compounds of Table 1
Test sample | FXR cellular level Activity EC50(nM) |
Example 1 | *** |
Example 2 | *** |
Example 3 | ** |
Example 4 | *** |
Example 5 | * |
Example 6 | ** |
Example 7 | *** |
Example 8 | **** |
Example 9 | ** |
Example 10 | ** |
Example 11 | ** |
Example 12 | ** |
Example 13 | * |
Example 14 | * |
Example 15 | *** |
Example 16 | *** |
LJN452 | *** |
****:EC50(nM)<5;***:5<EC50(nM)<10;**:10<EC50(nM)<50;
*:50<EC50(nM)
Pharmacological experiment example two:
in vitro anti-HBV activity of compound detected based on human primary hepatocyte (PHH) in vitro infection model
1. Method of producing a composite material
1.1HBV Virus infects human primary hepatocytes to establish HBV in vitro infection model and compound treatment
After culturing hepg2.2.15 cells in DMEM containing 10% FBS for 72h, D-type HBV was collected and concentrated in the culture broth and its viral titer was determined by quantitative PCR. Human primary hepatocytes (purchased from Reid liver disease research Co., Ltd.) frozen in liquid nitrogen were thawed, and the cell density was adjusted to 6X 105Cells/ml, and plated in 48-well plates at 220uL per well (approximately 1.3X 10)5Individual cell), placed in 5% CO2Incubated overnight at 37 ℃. Day 2, D-type HBV was added to PHH cells at a ratio of 800 genome equivalents/cell; on day 3, compound treatment was started, compound at 10uM concentration, 3 replicates, and treatment continued for 8 days, with compound-containing medium changed every 2 days, with DMSO as negative control.
1.2 collecting cell culture supernatant to detect HBV DNA, hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg)
Cell culture supernatants were collected after day 8 of compound treatment and tested for HBV DNA, HBeAg and HBsAg, respectively. DNA was extracted from 100ul of cell culture supernatant according to the QIAamp 96DNA Blood Kit (QIAGEN, #51161) instructions; and (3) qPCR (quantitative polymerase chain reaction) quantitative detection of the content of the HBV DNA by taking the HBV plasmid DNA as a standard substance. HBsAg and HBsAg were detected according to the ELISA kit instructions. The method is briefly described as follows: the samples were first diluted 8-fold (15ul cell supernatant +105ul PBS); then respectively taking 50ul of standard substance, adding the sample and the reference substance into a detection plate, then adding 50ul of enzyme conjugate into each hole, and incubating for 60 minutes at 37 ℃; washing the plate with washing liquor, then sucking to dry, then adding 50ul of premixed luminescent substrate, incubating for 10 minutes at room temperature in a dark place, and finally measuring the luminescent value by an enzyme-linked immunosorbent assay.
1.3CCK-8 test of the Effect of Compounds on cell viability
Cell viability was determined according to the CCK-8 kit instructions, the procedure is briefly as follows: after the compound treatment day 8, after the cell culture supernatant was collected, 180ul of fresh medium and 20ul of CCK-8 were added to each well, mixed well, incubated at 37 ℃ for 2.5 hours, and the absorbance (450nm/650nm) was measured with an enzyme reader.
1.4 data processing
The calculation is carried out according to the following formulas respectively:
HBV DNA inhibition rate ═ (1-compound HBV DNA copy number/DMSO control HBV DNA copy number) × 100%;
HBsAg inhibition rate ═ 1-HBsAg (IU/ml for sample)/HBsAg (IU/ml) for DMSO control) × 100%;
HBeAg inhibition ═ 100% (1-HBeAg (PEIU/ml for sample)/DMSO control HBeAg (PEIU/ml)) ×;
cell viability ═ 100% (signal value for sample-signal value for media control)/(signal value for DMSO control-signal value for media control).
2. Results
The specific experimental results of the HBV DNA inhibition rate, HBsAg inhibition rate, HBeAg inhibition rate and cell viability of the compounds in an in vitro model of primary hepatocytes (PHH) infected with HBV are shown in the following table.
Inhibition% < 50; inhibition% 50; a: the concentration of the compound was 0.5uM
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound of formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug, or a pharmaceutically acceptable salt thereof:
wherein,
ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R1selected from: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted 5-9 membered heterocyclic ring (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R21、R22、R23each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6An alkoxy group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
y is selected from the group consisting of: o, NH, CH2Or CHR3Wherein R is3Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
wherein said substitution means that one or more hydrogen atoms on the group are each independently replaced by a substituent selected from the group consisting of: deuterium, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radicals、C3-C6Cycloalkoxy, cyano or nitro.
2. The compound of claim 1, wherein Ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring wherein the aryl or heteroaryl substituents are selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
3. A compound of claim 1 wherein R is1Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
4. A compound of claim 1 wherein R is21、R22、R23Each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
5. The compound of claim 1, wherein X is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group; the Y is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group.
7. a process for the preparation of a compound according to claim 1, which comprises: preparing a compound of formula I by a process selected from the group consisting of those described in scheme one, scheme two or scheme three:
route one:
(a') reacting a compound of formula VIII with a compound of formula XI under basic conditions to form a compound of formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I,
wherein X is NH, Y is O, R1、R21、R22、R23Ar, W, V and U are defined as in claim 1;
and a second route:
(a') reacting the compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form a compound of formula I;
wherein X is O, Y is NH, R1、R21、R22、R23Ar, W, V, U are as defined in claim 1;
And a third route:
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I,
wherein X is NH and Y is CH2,R1、R21、R22、R23Ar, W, V and U are defined as in claim 1.
8. A pharmaceutical composition comprising a compound of formula I according to claim 1, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
9. Use of a compound of formula I according to claim 1, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease or condition associated with FXR activity or expression.
10. The use according to claim 9, wherein the FXR related disease is selected from the group consisting of: bile acid metabolism, carbohydrate metabolism, lipid metabolism, inflammation, and/or diseases associated with liver fibrosis processes.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010988285.XA CN114195786B (en) | 2020-09-18 | 2020-09-18 | Preparation and application of novel FXR small molecule agonist |
PCT/CN2021/116794 WO2022057672A1 (en) | 2020-09-18 | 2021-09-06 | Preparation of novel fxr small molecule agonist and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010988285.XA CN114195786B (en) | 2020-09-18 | 2020-09-18 | Preparation and application of novel FXR small molecule agonist |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114195786A true CN114195786A (en) | 2022-03-18 |
CN114195786B CN114195786B (en) | 2023-08-22 |
Family
ID=80645144
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010988285.XA Active CN114195786B (en) | 2020-09-18 | 2020-09-18 | Preparation and application of novel FXR small molecule agonist |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114195786B (en) |
WO (1) | WO2022057672A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7450951B2 (en) * | 2022-02-17 | 2024-03-18 | カスケード ファーマシューティカルズ、インコーポレーテッド | Production of new FXR small molecule agonists and their use |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4608079A (en) * | 1983-08-02 | 1986-08-26 | American Cyanamid Company | Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
CN1956984A (en) * | 2004-04-01 | 2007-05-02 | 安万特药物公司 | 1,3,4-oxadiazol-2-ones as PPAR-delta modulators |
CN106146483A (en) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | Heterocyclic method Buddhist nun's ester derivant X receptor modulators |
CN108064223A (en) * | 2014-12-17 | 2018-05-22 | 吉利德科学公司 | FXR (NR1H4) modulating compound of hydroxyl |
CN109906223A (en) * | 2016-10-04 | 2019-06-18 | 英安塔制药有限公司 | Isoxazole analog is as FXR agonist and its application method |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110452235B (en) * | 2018-05-08 | 2023-02-17 | 中国科学院上海药物研究所 | Fluorine-containing isoxazole compound and preparation method, pharmaceutical composition and application thereof |
-
2020
- 2020-09-18 CN CN202010988285.XA patent/CN114195786B/en active Active
-
2021
- 2021-09-06 WO PCT/CN2021/116794 patent/WO2022057672A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4608079A (en) * | 1983-08-02 | 1986-08-26 | American Cyanamid Company | Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
CN1956984A (en) * | 2004-04-01 | 2007-05-02 | 安万特药物公司 | 1,3,4-oxadiazol-2-ones as PPAR-delta modulators |
CN108064223A (en) * | 2014-12-17 | 2018-05-22 | 吉利德科学公司 | FXR (NR1H4) modulating compound of hydroxyl |
CN106146483A (en) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | Heterocyclic method Buddhist nun's ester derivant X receptor modulators |
CN109906223A (en) * | 2016-10-04 | 2019-06-18 | 英安塔制药有限公司 | Isoxazole analog is as FXR agonist and its application method |
Also Published As
Publication number | Publication date |
---|---|
WO2022057672A1 (en) | 2022-03-24 |
CN114195786B (en) | 2023-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6957522B2 (en) | Xanthone derivatives for the treatment and prevention of hepatitis B viral disease | |
CN108250122B (en) | Sulfonamide-aryl amide compounds and pharmaceutical use thereof for treating hepatitis B | |
WO2020211872A1 (en) | Fxr small molecule agonist and preparation method therefor and use thereof | |
CN107501257B (en) | Dihydropyrimidine-triazole derivative and preparation method and application thereof | |
US20060223783A1 (en) | 3,4-Disubstituted coumarin and quinolone compounds | |
CN114195777B (en) | Preparation and application of novel FXR small molecule agonist | |
CN108137589B (en) | Carboline derivatives as bromodomain inhibitors | |
JP7209723B2 (en) | Nucleoside Cyclic Phosphate Ester Compounds and Applications of Gemcitabine Prodrugs Based on Hepatic Delivery | |
CN111018938A (en) | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof | |
WO2007133211A1 (en) | 3,4-disubstituted coumarin and quinolone compounds | |
CN114195786B (en) | Preparation and application of novel FXR small molecule agonist | |
WO2006080406A1 (en) | Tricyclic compounds | |
WO2022063128A1 (en) | Aromatic ring or arylheterocyclic pyridone compound, pharmaceutical compositions, and use thereof | |
CN114195776B (en) | Preparation and application of novel FXR small molecule agonist | |
CN111825667B (en) | FXR small molecule agonist and preparation method and application thereof | |
CN112979661B (en) | Heterocyclic compound, preparation method and application thereof in medicine | |
JP7450951B2 (en) | Production of new FXR small molecule agonists and their use | |
JP7012822B2 (en) | Phtaladinone compounds, methods for producing them, pharmaceutical compositions and their uses | |
WO2021254389A1 (en) | Pyrazolo[3,4-d]pyrimidine-3-ketone derivative as wee-1 inhibitor | |
CN112209896A (en) | Thiazolidinedione derivatives and pharmaceutical compositions containing the same | |
CN114315830A (en) | FXR small molecule agonist and preparation method and application thereof | |
EP4245365A1 (en) | A fxr small molecule agonist, the preparation and use thereof | |
US20230295141A1 (en) | Fxr small molecule agonist, the preparation and use thereof | |
WO2020140894A1 (en) | Fluorine-containing substituted benzothiophene compound, and pharmaceutical composition and application thereof | |
CN109134600B (en) | Alkyl and heterocyclic compounds as hepatitis C inhibitors and application thereof in medicines |
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 |