CN115894220A - 一类作用于acly的长链类化合物、其制备方法及其用途 - Google Patents
一类作用于acly的长链类化合物、其制备方法及其用途 Download PDFInfo
- Publication number
- CN115894220A CN115894220A CN202111116425.5A CN202111116425A CN115894220A CN 115894220 A CN115894220 A CN 115894220A CN 202111116425 A CN202111116425 A CN 202111116425A CN 115894220 A CN115894220 A CN 115894220A
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- membered ring
- pharmaceutically acceptable
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 142
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 102100035623 ATP-citrate synthase Human genes 0.000 title claims abstract description 5
- 101000782969 Homo sapiens ATP-citrate synthase Proteins 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title description 8
- 230000008569 process Effects 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 18
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 7
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims abstract description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 4
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims abstract description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims abstract description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 4
- 201000002313 intestinal cancer Diseases 0.000 claims abstract description 4
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 18
- 239000003112 inhibitor Substances 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 7
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 28
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 19
- 150000002632 lipids Chemical class 0.000 abstract description 14
- 230000006195 histone acetylation Effects 0.000 abstract description 8
- 210000003494 hepatocyte Anatomy 0.000 abstract description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- 230000009702 cancer cell proliferation Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 102000004146 ATP citrate synthases Human genes 0.000 description 36
- 108090000662 ATP citrate synthases Proteins 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000004698 Polyethylene Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- -1 methoxy, ethoxy, adamantyl Chemical group 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
- 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 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000006555 catalytic reaction Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000009987 spinning Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- YSTSHUWHIDBZAK-UHFFFAOYSA-N methyl 3-chloro-5-[(2,4-difluoro-5-phenylphenyl)sulfamoyl]-4-hydroxybenzoate Chemical compound COC(=O)c1cc(Cl)c(O)c(c1)S(=O)(=O)Nc1cc(c(F)cc1F)-c1ccccc1 YSTSHUWHIDBZAK-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 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
- 238000001816 cooling Methods 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000006718 epigenetic regulation Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 2
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 2
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 2
- 238000006677 Appel reaction Methods 0.000 description 2
- 108010018763 Biotin carboxylase Proteins 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 2
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000035823 Non-specific autoimmune cerebellar ataxia without characteristic antibodies Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 description 2
- 229940100228 acetyl coenzyme a Drugs 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 239000003795 chemical substances by application 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
- 210000003483 chromatin Anatomy 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000004136 fatty acid synthesis Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 210000001700 mitochondrial membrane Anatomy 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940078494 nickel acetate Drugs 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000771 poly (alkylcyanoacrylate) Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102100030381 Acetyl-coenzyme A synthetase 2-like, mitochondrial Human genes 0.000 description 1
- 101710179225 Acetyl-coenzyme A synthetase 2-like, mitochondrial Proteins 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 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
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000015303 Fatty Acid Synthases Human genes 0.000 description 1
- 108010039731 Fatty Acid Synthases Proteins 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- MZHJJOMWLPIVFA-UHFFFAOYSA-N [Na].C#C Chemical group [Na].C#C MZHJJOMWLPIVFA-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 1
- 229950002974 bempedoic acid Drugs 0.000 description 1
- 150000008331 benzenesulfonamides Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 108010075600 citrate-binding transport protein Proteins 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940050411 fumarate Drugs 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
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000002796 luminescence method Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 description 1
- LTYOQGRJFJAKNA-VFLPNFFSSA-N malonyl-coa Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-VFLPNFFSSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- SYKXNRFLNZUGAJ-UHFFFAOYSA-N platinum;triphenylphosphane Chemical compound [Pt].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 SYKXNRFLNZUGAJ-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007651 self-proliferation Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/26—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings
- C07C55/28—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings monocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/16—Unsaturated compounds
- C07C61/35—Unsaturated compounds having unsaturation outside the rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Biochemistry (AREA)
- Vascular Medicine (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类长链类化合物、其制备方法及其用途，结构如式I所示，式中，各取代基的定义如说明书和权利要求书中所述。本发明的化合物，能够直接抑制ACLY，抑制原代肝细胞脂质合成，且在H358等多种癌细胞中抑制脂质从头合成、组蛋白乙酰化，并可抑制癌细胞增殖，可应用于制备治疗高血脂症、动脉粥样硬化等代谢性疾病，或者肺癌、胰腺癌、乳腺癌、卵巢癌、肝癌、肠癌、脑癌、急性髓系白血病等多种癌症的药物。
Description
技术领域
本发明属于药物化学领域，涉及一类新型ACLY抑制剂或其在药学上可接受的盐及其制备方法，以及包含该类抑制剂的药物组合物，该类抑制剂能直接抑制ACLY，并且在原代肝细胞中抑制脂质合成，在H358等多种癌细胞中抑制脂质从头合成、组蛋白乙酰化，并可抑制其增殖，可应用于制备高血脂症、动脉粥样硬化、非酒精性脂肪肝炎等代谢性疾病，或肺癌、胰腺癌、乳腺癌、卵巢癌、肝癌、肠癌、脑癌、急性髓系白血病等多种癌症疾病的药物。
背景技术
ATP柠檬酸裂解酶(ACLY)处在糖脂代谢的关键位置。在线粒体中产生的乙酰辅酶A(Ac-CoA)并不能直接穿过线粒体膜到达胞质中，但AC-CoA可进入三羧酸循环，三羧酸循环产生的柠檬酸通过线粒体膜上的柠檬酸转运蛋白转运至胞质中，在胞质中柠檬酸和辅酶A(CoA)可被ACLY催化产生乙酰辅酶A和草酰乙酸，同时消耗一分子ATP。乙酰辅酶A在体内的生物功能可概括为三个：在脂肪酸合成途径中，它可经乙酰辅酶A羧化酶(ACC)的羧化作用形成丙二酰辅酶A，再经相关脂肪酸合成酶最终生成脂肪酸；乙酰辅酶A也同样是甲羟戊酸途径的前体，这一途径可以合成焦磷酸法尼酯(FPP)，FPP参与胆固醇的合成；另外，乙酰辅酶A也为乙酰化反应提供原料，参与了包括组蛋白在内的多种蛋白质乙酰化。ACLY通过调控体内乙酰辅酶A从而参与了体内的脂质合成和表观遗传调控。
高血脂症、动脉粥样硬化以及非酒精脂肪肝等多种代谢性疾病都与自身脂质合成水平提高有关，ACLY作为产生胞质中Ac-CoA的主要酶，为脂质合成提供原料，是脂质合成中的关键一环，作用于ACLY的药物Bempedoic acid能明显降低肝脏脂质合成水平。此外，苯磺酰胺类等ACLY抑制剂的降脂作用也在细胞水平上被验证。
代谢重组是癌细胞最常见和最主要的特征，这是由于癌细胞的快速增长需要大量的能量和大分子物质，而为了满足癌细胞的这种“需求”，其代谢将发生很大的改变。由于癌组织经常发展成一些不规则形状的肿块，导致癌细胞从周围血管中获取脂质变得异常困难，其自身脂质从头合成通常处于较高水平，是其增殖所需脂质的主要来源。表观遗传调控异常是癌细胞另外一个主要特征，作为表观遗传调控的关键一环，组蛋白的乙酰化有着十分重要的作用，组蛋白乙酰化水平升高时，染色质结构松弛，此时处于转录激活状态；反之，组蛋白乙酰化水平低，染色质结构紧密，此时处在转录抑制状态。研究表明许多癌症的发生都与组蛋白乙酰化水平的升高有着密切联系。ACLY所催化产生的乙酰辅酶A既是脂质合成的原料，又参与组蛋白乙酰化。研究表明，包括非小细胞肺癌、乳腺癌、肝癌等多种癌症中ACLY均高表达，ACLY的高表达与相关癌症的不良预后密切相关。
综上所述，ACLY抑制剂的研发有望用于代谢性疾病和癌症的临床治疗。
发明内容
本发明的目的在于提供一类新型的具有ACLY抑制活性的化合物或其在药学上可接受的盐，“药学上可接受的盐”包括但不限于所述化合物中羧酸基团形成的的钠盐、钾盐、镁盐、钙盐，或当该系列化合物含有氮时所形成的无机酸盐。
本发明的第一方面，提供一种通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，
式中，
表示双键或单键；
R1、R2各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基或C6-C10芳基；或者，R1和R2与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
R3、R4各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基；或者，R3和R4与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
R5、R6各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基；或者，R5和R6与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
m、n和q各自独立地为0、1、2、3、4、5或6；
Z为-OH、-COOH、-COOR7、-SO3H或-CONHR7，其中R7为C1-C4烷基；
X为-CO-、-O-、-NH-、-S-、-CH2-、
-CONH-、
-NHOC-、
-CH2CO-或-COCH2-；
Y为H、C6-C10芳基、C1-C4烷基或金刚烷基(Ad-)；或者Y为：
其中linker为C1-C20的亚烷基或聚乙二醇，或无该linker；
上述各C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基或C6-C10芳基为未取代的或取代的，其中，所述取代是指被选自下组的1、2、3、4或5个取代基取代：卤素、C1-C4烷基、C1-C4烷氧基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基。
在另一优选例中，
表示双键，双键构型为顺式或反式。
在另一优选例中，所述化合物具有式II所示的结构：
在另一优选例中，所述化合物具有式III所示的结构：
在另一优选例中，所述化合物具有式IV所示的结构：
W为不存在、-O-、-NH-、-S-或-CH2-。
在另一优选例中，R1、R2各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R1和R2与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环。
在另一优选例中，R3、R4各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R3和R4与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环。
在另一优选例中，R5、R6各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R5和R6与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环。
在另一优选例中，m、n各自独立地为1、2、3、4或5。
在另一优选例中，q为0、1、2、3或4。
在另一优选例中，R1和R2与连接的碳一起形成饱和的四元环、饱和的五元环、饱和的六元环、含有一个不饱和双键的四元环、含有一个不饱和双键的五元环或含有一个不饱和双键的六元环。
在另一优选例中，R3和R3与连接的碳一起形成饱和的四元环、饱和的五元环、饱和的六元环、含有一个不饱和双键的四元环、含有一个不饱和双键的五元环或含有一个不饱和双键的六元环。
在另一优选例中，R5和R6与连接的碳一起形成饱和的四元环、饱和的五元环、饱和的六元环、含有一个不饱和双键的四元环、含有一个不饱和双键的五元环或含有一个不饱和双键的六元环。
在另一优选例中，Y为H、甲基、乙基、丙基、苯环、萘环、甲氧基、乙氧基、金刚烷基，或带有p个卤素取代的芳香环(苯环或萘环)，其中p为1、2、3、4、5，优选为1或2，上述卤素为F或Cl或Br或I；或Y为具有乙酰辅酶A合成酶2(ACSS2)抑制活性的结构片段：
或Y为具有如下组蛋白甲基转移酶EZH2抑制活性的结构片段，此时化合物同时具有ACLY和EZH2抑制活性：
或Y为含有E3连接酶配体的结构：
在另一优选例中，所述化合物选自下组：M1-M35。
本发明的第二方面，提供具有ACLY活性的化合物药物组合物，该组合物包含第一方面所述的通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐；和药学上可接受的载体。
本发明所述的药物组合的剂型可以是多样的，包括但不限于：片剂、胶囊、颗粒、糖浆、溶液、悬浮液或气雾剂。
本发明的第三方面，提供第一方面所述的通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或第二方面所述的药物组合物的用途，用作ACLY抑制剂；用于制备ACLY抑制剂；或制备预防和/或治疗代谢性疾病或癌症的药物。
在另一优选例中，所述代谢性疾病选自下组：高血脂症、动脉粥样硬化、非酒精性脂肪肝、糖尿病。
在另一优选例中，所述癌症选自下组：肺癌、胰腺癌、乳腺癌、卵巢癌、肝癌、肠癌、脑癌、急性髓系白血病。
本发明的第四方面，提供具有ACLY抑制活性的化合物与其他抗癌药物(疗法)组合使用的治疗方法。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
具体实施方式
本申请的发明人经过广泛而深入地研究，研发出一种长链化合物，该系列化合物具有ACLY抑制活性，在A549、H358、ASPC-1、MIA-PACA、MCF-7等多种癌细胞中显示了非常好的ACLY抑制活性，降低组蛋白乙酰化水平，抑制癌细胞自身增殖，作为癌症或代谢性疾病的治疗药物具有较好的开发潜力。在此基础上，完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C4”是指具有1、2、3或4个碳原子。术语“C3-C7”是指具有3、4、5、6或7个碳原子。以此类推。
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C4烷基”是指具有1至4个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
在本发明中，术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C2-C4烯基”是指具有2至4个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基。
在本发明中，术语“炔基”是指含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基等。
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C3-C7环烷基”是指在环上具有3至7个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基等。
在本发明中，术语“环烯基”表示包含至少一个双键的环状烃基部分，例如术语“C3-C7环烯基”是指在环上具有3至7个碳原子的环状烷基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基等。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
制备方法
本发明所述具有通式I、II、III、IV的化合物可通过如下路线制备合成。
路线一
(1)1-炔基醇化合物A1与过量的3,4-二氢-2H-吡喃(DHP)在对甲基苯磺酸(TsOH)催化下生成中间体A3；1-羟基溴化物与过量3,4-二氢-2H-吡喃(DHP)在对甲基苯磺酸(TsOH)催化下生成中间体A4。
(2)A3和A4在正丁基锂(n-BuLi)和六甲基磷酰三胺(HMPA)条件下生成中间体A5。
(3)中间体A5在TsOH催化下在甲醇中脱去保护基生成中间体A6。
(4)中间体A6与四溴化碳和三苯基磷(PPh3)发生Appel反应生成中间体A7。
(5)A7用醋酸镍、硼氢化钠和乙二胺在氢气条件下转化为A8。
(6)A8与α位具有活泼氢的酯在二异丙基氨基锂(LDA)条件下生成A9。
(7)A9在氢氧化钾存在下发生水解，进一步酸化得到A10。
R3、R4、R5、R6、m、n如通式I所述，R7、R8各自独立的为甲基或乙基。
路线二
(1)中间体A15在180℃被四氢铝锂(LiAlH4)还原为含反式双键的中间体A11。
(2)中间体A11在TsOH催化下在甲醇中脱去保护基生成中间体A12。
(3)中间体A12与四溴化碳和三苯基磷(PPh3)发生Appel反应生成中间体A13。
(4)中间体A13与α位具有活泼氢的酯在二异丙基氨基锂条件下生成A14。
(5)A14在氢氧化钾存在下发生水解，进一步酸化得到A15。
路线三
(1)中间体A15在140℃被四氢铝锂(LiAlH4)还原为含反式双键的中间体A11。
(2)化合物A10与化合物A16在二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)条件下发生缩合反应，生成化合物A17，或在缩合剂N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)条件下发生缩合反应，生成化合物A17,或A10经草酰氯转化为酰氯再与A16转化为A17，或A10与A16在碳酸钾做碱生成A17；化合物A15与化合物A16在在二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)条件下发生缩合反应，生成化合物A18，或在缩合剂N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)条件下发生缩合反应，生成化合物A18,或A15经草酰氯转化为酰氯再与A16转化为A18，或A15与A16在碳酸钾做碱生成A18。
R3、R4、R5、R6、m、n、Y、W均同通式IV中所述，R7、R8各自独立的为甲基或乙基，此外，A16中的Z为羟基或者卤素。
路线四
(1)中间体A117在与α位具有活泼氢的酯在二异丙基氨基锂(LDA)条件下生成中间体A19。
(2)A19在四三苯基磷铂催化下与联硼酸频那醇酯反应生成A20。
(3)A20在四三苯基磷钯的催化下与R1L1或R2L2发生偶联反应得到化合物A21。
(4)A21在碱性条件下发生水解，经酸化得到化合物A22
R3、R4、R5、R6、m、n、均同通式I中所述，R7、R8各自独立的为甲基或乙基，L1、L2各自独立的为卤素，即F、Cl、Br或I。
路线一中的中间体A7同样可用如下路线五合成。
路线五
(1)悬浮在二甲苯中的乙炔钠和二卤代物A34在DMF中反应生成中间体A35。
(2)A35在六甲基磷酰三胺(HMPA)存在下，在溶剂四氢呋喃(THF)中经正丁基锂拔氢再与二卤代物A36反应，生成二氯代物A37。
(3)中间体A37与溴化锂在有机溶剂中回流，生成A7。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
在本发明所述的实施例中，NMR采用布鲁克400M仪器测定，NMR定标：δH7.26ppm(CDC13),2.50ppm(DMSO-d6),2.05ppm(Acetone-d6)，质谱采用Agilent 1200QuadrupoleLC/MS液质联用仪)；TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产，型号HSGF254；化合物纯化使用的正相柱层析硅胶为山东青岛海洋化工厂分厂生产，型号zcx-11,200-300目，其他常规使用的商品化试剂均由上海试剂公司提供。
实施例1M1的合成
(1)化合物B3和B4的制备
氮气保护下，将4.6g化合物B1(36.0mmol)溶于40ml二氯甲烷(DCM)中，加入1.2g对甲基苯磺酸TSOH(7.2mmol)，冰水浴冷却，滴加6.1g 3,4-二氢-2H-吡喃，室温反应过夜。TLC监测反应完全，加DCM 80ml稀释，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝50:1过柱，得产物B3 7.1g，产率95％。
氮气保护下，将5.0g化合物B2(27.6mmol)溶于40ml二氯甲烷中，加入951mg对甲基苯磺酸TSOH(5.5mmol)，冰水浴冷却，滴加4.6g 3,4-二氢-2H-吡喃，室温反应过夜。TLC监测反应完全，加DCM 80ml稀释，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝50:1过柱，得产物B4 5.9g，无色油状物，产率69％。
(2)化合物B5的制备
将化合物2.0g B3(9.4mmol)溶于20ml干燥四氢呋喃中(THF)，氮气保护，换气三次，-78℃冷却，滴加正丁基锂4.7ml(2.4M 11.3mmol)，加六甲基磷酰三胺(HMPA)4.0ml，-78℃反应30min，将3.0g化合物B4(11.3mmol)溶于8ml干燥四氢呋喃后，滴加到上述反应瓶中，-78℃到室温反应过夜，TLC监测反应完全，加入饱和氯化铵溶液80ml，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝10:1过柱，得产物B53.2g，无色油状物，产率84％。
(3)化合物B6的制备
将3.2g化合物B5(7.9mmol)溶于30ml甲醇中，加入对甲基苯磺酸TsOH 136mg(0.79mmol)，室温反应4小时，TLC监测反应完全，旋去甲醇，加入60ml乙酸乙酯，水洗三次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝3:1过柱得产物B6 1.3g，白色固体，产率73％。
(4)化合物B7的制备
将1.9g B6(8.4mmol)和5.6g四溴化碳(16.8mmol)溶于20ml干燥氯甲烷中，氮气保护，0℃冷却，将4.4g三苯基膦(16.8mmol)溶于干燥二氯甲烷中，滴加到上述反应瓶中，升至室温反应2h，TLC监测反应完全，旋去大部分溶剂，慢慢滴加80ml乙醚，有大量固体析出，硅藻土过滤除去固体，乙醚洗涤固体，浓缩滤液，PE:EA＝50:1过柱，得到产物B7 2.8g，无色油状，产率95％。
(5)化合物B8的制备
将477mg醋酸镍(1.9mmol)悬浮于10ml乙醇中，加入硼氢化钠72mg(1.9mmol)，溶液有淡绿色变黑，加氢气球，换气多次，加乙二胺0.58ml，滴加1.4g B7的乙醇溶液，常温反应3小时，TLC监测反应完全，加乙酸乙酯40ml稀释，硅藻土过滤出去固体，滤液浓缩，PE:EA＝50:1过柱，得到产物900mg，无色油状，产率67％。
(6)化合物B10的制备
将150mg B8(0.4mmol)和453mg B9(2.5mmol)溶于8ml干燥四氢呋喃，氮气保护，换气，-78℃冷却，滴加二异丙基氨基锂LDA 1.3ml(2.0M 2.6mmol)，溶液由无色变为橙黄色，-78℃到常温反应过夜，TLC监测反应完全，加入饱和氯化铵溶液40ml，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝20:1过柱，得产物B10200mg，无色油状，产率77％。
(7)化合物M1的制备
将180mg B10(0.28mmol)溶于8ml乙醇中，将180mg氢氧化钾溶于2ml水，加入上述反应瓶中，回流反应过夜，TLC监测反应完全，旋去乙醇，加水16ml稀释，1M盐酸调pH到2左右，有固体析出，乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，浓缩，PE：EA＝2:1过柱，得到产物M1 110mg，微黄固体，产率80％。1H NMR(400MHz,CDCl3)δ7.42–7.28(m,8H),7.27–7.19(m,2H),5.41–5.25(m,2H),2.21–2.05(m,2H),2.05–1.95(m,4H),1.92–1.80(m,2H),1.54(s,3H),1.51(s,3H),1.42–1.02(m,16H).
替换不同底物，采用与M1相类似的合成路线，得到下列化合物。
化合物M2：1H NMR(400MHz,CDCl3)δ5.63–5.58(m,4H),5.36–5.30(m,2H),2.92(d,J＝15.1Hz,4H),2.29(d,J＝15.1Hz,4H),2.06–1.96(m,4H),1.75–1.65(m,4H),1.31–1.21(m,16H).
化合物M3：1H NMR(400MHz,CDCl3)δ5.66–5.55(m,4H),5.39–5.26(m,2H),2.91(d,J＝16.1Hz,4H),2.30(d,J＝16.1Hz,4H),2.08–1.93(m,4H),1.75–1.64(m,4H),1.35–1.22(m,18H).
化合物M4：1H NMR(400MHz,CDCl3)δ5.40–5.25(m,2H),2.22–2.07(m,4H),2.07–1.95(m,4H),1.70–1.53(m,13H),1.51–1.41(m,4H),1.37–1.14(m,17H).
化合物M5：1H NMR(400MHz,CDCl3)δ5.85–5.78(m,2H),5.77–5.70(m,2H),5.39–5.27(m,2H),2.46–2.30(m,6H),2.07–1.95(m,4H),1.76(dt,J＝17.4,6.1Hz,4H),1.64–1.47(m,2H),1.29(d,J＝21.1Hz,16H).
化合物M6：1H NMR(400MHz,CDCl3)δ5.73–5.55(m,4H),5.39–5.21(m,2H),2.54(d,J＝16.9Hz,2H),2.21–2.09(m,2H),2.09–1.95(m,8H),1.95–1.85(m,2H),1.68–1.55(m,4H),1.54–1.45(m,2H),1.37–1.28(m,4H),1.28–1.15(m,12H).
化合物M7：1H NMR(400MHz,CDCl3)δ6.14–6.01(m,2H),5.39–5.28(m,2H),5.18–5.08(m,4H),2.08–1.94(m,4H),1.84–1.68(m,2H),1.58–1.44(m,2H),1.39–1.11(m,22H).
化合物M8：1H NMR(400MHz,CDCl3)δ5.70–5.58(m,4H),5.37–5.27(m,2H),2.54(d,J＝16.9Hz,2H),2.23–2.09(m,2H),2.08–1.95(m,8H),1.94–1.84(m,2H),1.71–1.54(m,4H),1.54–1.43(m,2H),1.38–1.13(m,17H).
化合物M9：1H NMR(400MHz,CDCl3)δ7.39–7.31(m,10H),5.44–5.31(m,2H),2.14–1.89(m,8H),1.55–1.50(m,6H),1.40–1.15(m,10H).
化合物M10：1H NMR(400MHz,CDCl3)δ6.10–5.97(m,2H),5.41–5.27(m,2H),5.12(d,J＝13.9Hz,4H),2.07–1.92(m,4H),1.80–1.66(m,2H),1.64–1.49(m,2H),1.35–1.23(m,24H).
化合物M11：1H NMR(400MHz,CDCl3)δ7.40–7.31(m,8H),7.27–7.21(m,2H),5.41–5.23(m,2H),2.10–1.85(m,8H),1.55(s,6H),1.33–1.18(m,18H).
化合物M12：1H NMR(400MHz,CDCl3)δ5.75–5.56(m,4H),5.41–5.24(m,2H),2.53(d,J＝17.3Hz,2H),2.21–2.08(m,2H),2.05–1.97(m,6H),1.95–1.87(m,2H),1.67–1.48(m,6H),1.33–1.23(m,22H).
化合物M13：1H NMR(400MHz,CDCl3)δ5.85–5.78(m,2H),5.78–5.69(m,2H),5.40–5.24(m,2H),2.48–2.29(m,6H),2.09–1.89(m,5H),1.87–1.67(m,4H),1.66–1.52(m,2H),1.43–1.13(m,18H).
化合物M14：1H NMR(400MHz,CDCl3)δ5.86–5.78(m,2H),5.77–5.69(m,2H),5.39–5.28(m,2H),2.46–2.32(m,6H),2.06–1.93(m,4H),1.83–1.71(m,4H),1.64–1.55(m,2H),1.32–1.24(m,14H).
实施例2化合物M15的合成
(1)化合物B13和B14的制备
氮气保护下，将4.1g化合物B11(41.2mmol)溶于30ml二氯甲烷(DCM)中，加入1.5g对甲基苯磺酸TSOH(8.2mmol)，冰水浴冷却，滴加7.4ml 3,4-二氢-2H-吡喃，室温反应过夜。TLC监测反应完全，加DCM 80ml稀释，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝50:1过柱，得产物B13 5.5g，无色油状，收率39％。
氮气保护下，将3.5g化合物B12(20.9mmol)溶于30ml二氯甲烷中，加入794mg对甲基苯磺酸TSOH(4.2mmol)，冰水浴冷却，滴加3.9ml 3,4-二氢-2H-吡喃，室温反应过夜。TLC监测反应完全，加DCM 80ml稀释，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝50:1过柱，得产物B14 6.3g，无色油状物，产率75％。
(2)化合物B15的制备
将化合物1.8g B13(9.9mmol)溶于20ml干燥四氢呋喃中(THF)，氮气保护，换气三次，-78℃冷却，滴加正丁基锂7.4ml(1.6M 11.9mmol)，加六甲基磷酰三胺(HMPA)3.0ml，-78℃反应30min，2.5g化合物B14(11.3mmol)溶于6ml干燥四氢呋喃后，滴加到上述反应瓶中，-78℃到室温反应过夜，TLC监测反应完全，加入饱和氯化铵溶液50ml，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝10:1过柱，得产物B15 1.9g，无色油状，产率55％。
(3)化合物B16的制备
氮气保护下，将726mg四氢铝锂(18.2mmol)溶于10ml二乙二醇二甲醚，将800mgB15(2.3mmol)溶于4ml二乙二醇二甲醚，滴加如上述反应液，140℃反应28小时，TLC监测反应完全，加40ml乙醚稀释，冰水浴冷却条件下，分批次加入十水硫酸钠至不冒泡为止，硅藻土过滤除去固体，无水乙醚洗涤，无水硫酸钠干燥，浓缩，PE：EA＝20：1过柱，得产物B16487mg，无色液体，产率61％。
(4)化合物B17的制备
将1g B16(2.8mmol)溶于20ml甲醇，加入100mg对甲基苯磺酸，常温搅拌3小时，TLC监测反应完全，旋去甲醇，加水80ml，乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，浓缩,PE:EA＝3:1过柱得产物B17 470mg，无色油状，产率90％。
(5)化合物B18的制备
氮气保护下，将470mg B18(2.5mmol)和2.5g四溴化碳(7.5mmol)溶于10ml干燥二氯甲烷，0℃冷却，将1.9g三苯基膦(7.5mmol)溶于干燥二氯甲烷中，滴加到上述反应瓶中，升至室温反应2h，TLC监测反应完全，慢慢滴加40ml乙醚，有大量固体析出，硅藻土过滤除去固体，乙醚洗涤固体，浓缩滤液，PE:EA＝50:1过柱，得产品740mg，无色油状，产率95％。
(6)化合物B19的制备
氮气保护下，将150mg B18(0.48mmol)和510mg B9(2.9mmol)溶于干燥四氢呋喃，氮气换气，-78℃冷却，缓慢滴加1.5ml二异丙基氨基锂LDA 1.5ml(2.0M 3.0mmol)，溶液由无色变为橙黄色，-78℃到常温反应过夜，TLC监测反应完全，加入饱和氯化铵溶液40ml，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，PE:EA＝20:1过柱，得产物B19 130mg，黄色油状物，产率54％。
(7)化合物M15的制备
将130mg B19(0.26mmol)溶于8ml乙醇，将130mg氢氧化钾溶于2ml水，加入反应瓶，回流反应过夜，TLC监测反应完全，旋去乙醇，加水20ml稀释，1M HCl调节pH至2，有固体析出，加乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，PE：EA＝2:1过柱，得到产物M23 80mg，黄色油状，产率69％。1H NMR(400MHz,CDCl3)δ7.39–7.30(m,8H),7.25–7.20(m,2H),5.36–5.27(m,2H),2.08–2.02(m,2H),2.00–1.87(m,6H),1.55(s,6H),1.33–1.18(m,10H).
采用同M15的合成路线，换不同底物可得下列化合物。
化合物M16：1H NMR(400MHz,CDCl3)δ7.42–7.28(m,8H),7.26–7.23(m,2H),5.42–5.23(m,2H),2.31–2.16(m,2H),2.08–1.71(m,6H),1.52(s,3H),1.46(s,3H),1.34–1.24(m,16H).
化合物M17：1H NMR(400MHz,CDCl3)δ5.66–5.55(m,4H),5.33–5.23(m,2H),2.93(d,J＝15.7Hz,4H),2.29(d,J＝15.7Hz,4H),2.03–1.91(m,4H),1.76–1.64(m,4H),1.33–1.19(m,16H).
化合物M18：1H NMR(400MHz,CDCl3)δ5.34–5.21(m,2H),2.15–2.03(m,4H),2.02–1.90(m,4H),1.64–1.53(m,6H),1.51–1.44(m,4H),1.45–1.34(m,4H),1.34–1.11(m,22H).
实施例3化合物M19的合成
氮气保护下，将190mg化合物M5(0.46mmol)溶于6ml DMF中，加入107mg B20(0.46mmol)、126mg碳酸钾(0.92mmol)后常温反应过夜，TLC监测有新点产生，旋去溶剂，加水50ml稀释，1M HCl调pH到2，乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，DCM：MeOH＝20:1过柱，得产物100mg，微黄色油状物，产率37％。1H NMR(400MHz,CDCl3)δ7.38(s,1H),7.17(d,J＝1.0Hz,2H),5.86–5.80(m,1H),5.80–5.74(m,1H),5.73–5.69(m,1H),5.67–5.61(m,1H),5.40–5.28(m,2H),4.29(t,J＝6.2Hz,2H),3.05(t,J＝6.6Hz,2H),2.49–2.24(m,6H),2.07–1.94(m,4H),1.74–1.59(m,6H),1.34–1.16(m,16H).
换不同的B20类似物，采用M19类似的合成方法，可得下列化合物。
化合物M20：1H NMR(400MHz,CDCl3)δ5.86–5.81(m,1H),5.81–5.76(m,1H),5.74–5.68(m,2H),5.38–5.29(m,2H),4.13(t,J＝7.1,3.0Hz,2H),2.46–2.29(m,7H),2.07–1.93(m,4H),1.77–1.60(m,6H),1.28–1.24(m,16H).
化合物M21：1H NMR(400MHz,CDCl3)δ5.85–5.77(m,2H),5.75–5.67(m,2H),5.38–5.30(m,2H),3.67(s,3H),2.48–2.30(m,6H),2.05–1.93(m,4H),1.81–1.55(m,6H),1.34–1.23(m,16H).
化合物M22：1H NMR(400MHz,CDCl3)δ5.87–5.80(m,1H),5.80–5.74(m,1H),5.73–5.65(m,2H),5.39–5.26(m,2H),4.12(td,J＝7.4,1.7Hz,2H),2.46–2.30(m,6H),2.02–1.93(m,6H),1.84–1.56(m,12H),1.52(d,J＝2.0Hz,6H),1.41(t,J＝7.2Hz,2H),1.27(d,J＝10.4Hz,16H).
化合物M23：1H NMR(400MHz,CDCl3)δ7.24–7.16(m,2H),7.09–6.98(m,2H),5.86–5.80(m,1H),5.78–5.73(m,1H),5.73–5.68(m,1H),5.66–5.61(m,1H),5.39–5.28(m,2H),4.29(td,J＝6.7,1.8Hz,2H),2.98(t,J＝6.7Hz,2H),2.48–2.26(m,6H),2.05–1.93(m,4H),1.82–1.47(m,6H),1.32–1.10(m,16H).
化合物M24：1H NMR(400MHz,CDCl3)δ7.40(d,J＝1.9Hz,1H),7.33(d,J＝8.3Hz,1H),7.24(dd,J＝8.3,1.9Hz,1H),5.85–5.77(m,2H),5.75–5.66(m,2H),5.39–5.26(m,2H),5.16(d,J＝2.7Hz,2H),2.50–2.27(m,7H),2.04–1.95(m,4H),1.84–1.70(m,5H),1.63–1.55(m,2H),1.30–1.19(m,16H).
化合物M25：1H NMR(400MHz,CDCl3)δ7.21–7.12(m,2H),7.03–6.91(m,2H),5.87–5.80(m,1H),5.80–5.73(m,1H),5.73–5.67(m,1H),5.67–5.61(m,1H),5.40–5.28(m,2H),4.26(t,J＝6.4Hz,2H),2.90(t,J＝6.5Hz,2H),2.48–2.25(m,6H),2.06–1.93(m,4H),1.84–1.46(m,6H),1.32–1.18(m,16H).
化合物M26：1H NMR(400MHz,CDCl3)δ7.34(d,J＝7.8Hz,2H),7.25–7.17(m,1H),5.86–5.80(m,1H),5.79–5.73(m,1H),5.73–5.66(m,2H),5.40–5.26(m,4H),2.47–2.29(m,6H),2.03–1.91(m,4H),1.81–1.66(m,4H),1.65–1.50(m,3H),1.32–1.22(m,16H).
化合物M27：1H NMR(400MHz,CDCl3)δ7.33–7.26(m,2H),7.25–7.18(m,3H),5.85–5.80(m,1H),5.79–5.74(m,1H),5.73–5.68(m,1H),5.68–5.63(m,1H),5.39–5.28(m,2H),4.29(td,J＝6.9,2.9Hz,2H),2.93(t,J＝6.9Hz,2H),2.50–2.26(m,6H),2.07–1.92(m,4H),1.80–1.50(m,6H),1.32–1.19(m,16H).
化合物M28：1H NMR(400MHz,CDCl3)δ7.36(d,J＝1.9Hz,1H),7.20–7.10(m,2H),5.86–5.77(m,2H),5.74–5.67(m,2H),5.38–5.27(m,2H),4.10(t,J＝6.2Hz,2H),2.82–2.72(m,2H),2.49–2.31(m,6H),2.05–1.89(m,6H),1.84–1.68(m,4H),1.60(dd,J＝11.9,3.5Hz,2H),1.32–1.23(m,16H).
化合物M29：1H NMR(400MHz,CDCl3)δ7.83–7.74(m,3H),7.65(s,1H),7.48–7.40(m,2H),7.35(dd,J＝8.4,1.5Hz,1H),5.84–5.79(m,1H),5.78–5.73(m,1H),5.73–5.68(m,1H),5.67–5.63(m,1H),5.36–5.27(m,2H),4.44–4.31(m,2H),3.09(t,J＝6.8Hz,2H),2.43–2.28(m,6H),2.04–1.91(m,5H),1.81–1.66(m,4H),1.62–1.49(m,2H),1.29–1.11(m,16H).
化合物M30：1H NMR(400MHz,CDCl3)δ7.25(d,J＝5.2Hz,2H),7.14(d,J＝8.3Hz,2H),5.87–5.80(m,1H),5.80–5.75(m,1H),5.73–5.68(m,1H),5.66–5.61(m,1H),5.38–5.28(m,2H),4.30–4.19(m,2H),2.90(t,J＝6.7Hz,2H),2.46–2.24(m,6H),2.06–1.94(m,4H),1.80–1.52(m,6H),1.32–1.19(m,16H).
化合物M31：1H NMR(400MHz,CDCl3)δ7.37–7.33(m,1H),7.25–7.22(m,1H),7.21–7.14(m,2H),5.86–5.80(m,1H),5.79–5.74(m,1H),5.73–5.68(m,1H),5.67–5.62(m,1H),5.38–5.28(m,2H),4.31(td,J＝6.8,2.1Hz,2H),3.08(t,J＝6.8Hz,2H),2.44–2.29(m,6H),2.04–1.94(m,4H),1.79–1.51(m,6H),1.31–1.22(m,16H).
化合物M32：1H NMR(400MHz,CDCl3)δ7.13(d,J＝8.6Hz,2H),6.83(d,J＝8.6Hz,2H),5.85–5.80(m,1H),5.79–5.75(m,1H),5.73–5.68(m,1H),5.68–5.64(m,1H),5.38–5.28(m,2H),4.24(td,J＝7.0,2.7Hz,2H),3.78(s,3H),2.87(t,J＝6.9Hz,2H),2.44–2.26(m,6H),2.05–1.94(m,4H),1.80–1.53(m,6H),1.32–1.18(m,16H).
实施例4化合物M33的合成
(1)化合物B23的制备
氮气保护下，将600mg化合物B21(1.1mmol)和599mg化合物B22(1.7mmol)溶于26ml干燥DMF(N，N-二甲基甲酰胺)中，加入646mg N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲HATU(1.7mmol),N,N-二异丙基乙胺DIPEA 4.8ml,常温反应过夜，TCL监测反应完全，旋去DMF，加乙酸乙酯60ml，水洗三次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩，DCM：MeOH＝20:1过柱，得产物B23 900mg，橙色粉末状固体，产率94％。
(2)化合物B24的制备
氮气保护下，将900mg B23溶于8ml二氯甲烷中，加入2.0ml三氟乙酸，常温反应1小时，TLC监测反应完全，加饱和碳酸氢钠50ml淬灭反应，二氯甲烷萃取多次，浓缩，DCM：MeOH＝10:1过柱，得产物B24 513mg，白色固体，产率82％。
(3)化合物M33的制备
氮气保护下，将512mg B24(0.8mmol)和514mg M18(1.5mmol)溶于16ml干燥二氯甲烷中，零度冷却，加入309mg DCC(1.5mmol)和98mg(0.8mmol)DMAP，零度到室温反应过夜，TLC监测反应完全，过滤除去固体，加水80ml，DCM萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，DCM：MeOH＝20:1过柱得318mg，白色粉末状固体，产率42％。1H NMR(400MHz,CDCl3)δ8.47(d,J＝2.4Hz,1H),7.80(dd,J＝7.7,5.6Hz,1H),7.47(s,1H),7.02(s,1H),6.96(d,J＝5.5Hz,1H),6.76–6.68(m,1H),6.15(d,J＝7.2Hz,1H),5.35–5.26(m,3H),4.60(d,J＝2.5Hz,2H),4.39(dd,J＝13.2,6.5Hz,1H),3.77(d,J＝3.1Hz,2H),0.83(dd,J＝8.2,6.3Hz,3H).
上述化合物B22可通过常规化学方法合成
换不同的底物，采用和上述类似及路线三种提到的合成方法，合成下列化合物。
化合物M34：1H NMR(400MHz,CDCl3)δ8.70(d,J＝4.3Hz,1H),8.67(s,1H),8.40(d,J＝8.2Hz,1H),7.41–7.35(m,4H),6.28(d,J＝7.8Hz,1H),5.32(d,J＝16.1Hz,2H),5.11–5.03(m,1H),4.75(t,J＝7.9Hz,1H),4.50(d,J＝7.4Hz,2H),4.22(d,J＝11.1Hz,1H),3.55(d,J＝9.6Hz,1H),2.53(s,3H),2.07–1.97(m,4H),1.86–1.80(m,2H),1.63–1.61(m,5H),1.51–1.49(m,6H),1.49–1.46(m,4H),1.39–1.36(m,4H),1.28–1.23(m,6H),1.18–1.15(m,6H),1.06–1.01(m,9H).
实施例5化合物M35的合成
(1)化合物B26的制备
氮气保护下，3.0g B7(8.5mmol)溶于30ml干燥四氢呋喃中，加入六甲基磷酰三胺HMPA5.9ml(34mmol)，-78℃冷却，氮气换气多次，缓慢滴加17ml二异丙基氨基锂LDA(2.0M34mmol)，溶液由无色变为橙黄色，30min后滴加入4.3gB25(34.0mmol)，-78℃到常温反应过夜，TLC监测反应完全，加入饱和氯化铵80ml，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，PE：EA＝10:1过柱，得产物2.3g，无色油状物，产率61％。
(2)化合物B27的制备
将400mg B26(0.93mmol)和474mg连硼酸频那醇酯(1.8mmo)溶于6ml二氧六环，加入催化剂四三苯基膦铂111mg(0.09mmol)，110℃微波反应一小时，溶液由黄色变为褐红色，TLC监测反应完全，过滤除去固体，旋干溶剂，PE：EA＝10:1过柱，得产物338mg，无色油状，产率52％。
(3)化合物B28的制备
将338mg B27(0.48mmol)，228mg溴苯(1.45mmol)和402mg碳酸钾(2.91mmol)溶于12ml甲苯和1.5ml水中，氮气换多次，加入催化剂四三苯基膦钯58mg(0.05mmol)，90℃反应过夜，溶液由黄色变为浅绿色，TLC监测反应完全，过滤除去固体，加水60ml稀释，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩过柱得产物188mg，无色油状，产率66％。
(4)化合物M35的制备
将142mg B28(0.24mmol)溶于16ml乙醇和2ml水中，加入氢氧化钾284mg，60℃反应过夜，TLC监测反应完全，旋去乙醇，加30ml水稀释，1M HCl调至酸性，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗，无水硫酸啊干燥，浓缩过柱得产物69mg，微黄粉末状固体，产率51％。1H NMR(400MHz,CDCl3)δ7.07–6.90(m,10H),5.86–5.78(m,2H),5.77–5.70(m,2H),2.56–2.46(m,4H),2.46–2.30(m,7H),1.81–1.69(m,4H),1.64–1.52(m,2H),1.35–1.25(m,16H).
实施例6生物实验测试
6.1ACLY酶活测试
仪器：Envision(PerkinElmer,USA)
材料：Acl----人ACLY/acly/ATP柠檬酸裂解酶蛋白(His标签)从Sino Biological公司购买；激酶检测试剂盒ADP-GLO(promega公司#V9102)。
实验原理：本实验中ATP依赖的柠檬酸裂解酶ACL能将柠檬酸催化转变为乙酰辅酶A，进而产生脂肪酸合成的前体分子－丙二酸单酰辅酶A，该反应伴随ATP的消耗，因此可以使用ADP-Glo Kinase Assay(#V9102)；激酶检测试剂盒检测ATP的变化，来间接反应化合物对ACL的酶活的抑制作用。该激酶检测试剂盒可以定量测定由ACLY酶活力所催化产生的ADP量。(首先，将化合物、酶与底物37度共孵育半小时，加入ADP-Glo&#V9102；试剂孵育半小时，以终止反应，并消耗完剩余的ATP；再加入激酶检测试剂(使ADP转化成ATP的同时，还使用偶联的萤光素酶/萤光素反应来检测新合成的ATP)孵育半小时用Envision读值)。
实验方法：使用ADP-Glo发光方法进行测定。它通过定量检测ADP的量来反应ACLY酶的活力，ACLY所催化的酶促反应与发光信号检测到的ADP的量成比例。首先，将化合物稀释10％DMSO中，再将1ul的化合物稀释液加到5ul的反应体系中，使最终的反应体系中，DMSO的含量为2％。ACLY所催化的酶促反应在37℃反应30min，5ul的反应混合物包含如下成分(40mM Tris,pH 8.0,10mM MgCl2,5mM DTT,ATP,CoA,柠檬酸钠和ACLY)。酶促反应之后，将2.5ul ADP-Glo试剂添加到每个反应体系中，并在室温下孵育1小时。之后，加入5ul的激酶检测试剂并在室温下孵育30分钟。发光信号使用Envision(PerkinElmer,USA)进行检测。
数据处理：对于化合物测试活性剂量依赖关系，IC50值，通过样品活性对样品浓度进行非线性拟和得到，计算所用软件为Graphpad Prism 7，拟合所使用的模型为sigmoidaldose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。一般情况下，每个样品在测试中均设置复孔(n≥2)，在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。
实验结果如下表1所示。NDI-091143为已报道的ACLY抑制剂，作为阳性对照。
表1实施例中化合物对ACLY抑制活性
NDI-091143为已报道的ACLY抑制剂，作为阳性对照，结构如下：
6.2MTS实验
实验仪器：Molecular Device VersaMax
实验材料：NCI-H358细胞(H358，人非小细胞肺癌细胞)购自中国科学院细胞库/干细胞库；培养基RPMI-1640(GIBCO,货号3180002),人源肿瘤细胞人非小细胞肺癌细胞A549，为中科院上海药物研究所李佳研究员课题组馈赠。CellTiter
AQueous One SolutionCell Proliferation Assay(MTS)购自promega#G3581。
实验原理：用CellTiter
AQueous One Solution Cell Proliferation Assay(MTS)比色法检测细胞增殖。该分析方法以四唑化合物[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,内盐；MTS]为基础。黄色的MTS到蓝紫色水溶性甲臜的转化由脱氢酶催化，而脱氢酶存在于有代谢活性的活细胞中；死细胞不能完成MTS到甲臜的转化。由490nm处吸光度确定的甲臜(Formazan)的量与培养中活细胞的数量直接成正比。
实验方法：
样品处理:样品用DMSO溶解，低温保存。DMSO在最终体系中的浓度控制在不影响检测活性的范围内。
用MTS法检测细胞存活率，即将生长在对数生长期的细胞，贴壁细胞经0.025％的胰酶消化，计数；A549细胞以3000/well，H358 5000/well(均以1％FBS条件培养铺板)的密度接种到96孔板中80ul,置于5％CO2 37℃培养箱过夜生长。测试化合物每个以三倍浓度梯度进行稀释，测试八个浓度，每个浓度设置三复孔；稀释后的化合物分别取20ul加到对应的细胞孔中，贴壁细胞A549、H358在5％CO2 37℃培养箱中培养72小时；分别加入20ul的MTS，在5％CO2 37℃培养箱中孵育2小时。使用Molecular Device VersaMax测试490nm(L1)的光吸收值，参考波长690nm(L2)，将(L1-L2)值对抑制剂不同浓度作图，经公式拟合得到IC50。
数据处理：
将实验结果利用Graphpad Prism 7进行IC50的拟合，拟合所用的模型为log(inhibitor)vs.Response---variable slop，每次检测结果均设有三复孔以保证实验的精准性，在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。
同理，化合物对胰腺癌细胞系ASPC-1、人胰腺癌细胞MIA-PACA以及乳腺癌细胞MCF-7抗增殖实验基本同上。
实验结果：
化合物M5、M19、M25和M29对各癌细胞增殖抑制活性如下表2所示，其中※表示尚未测试，NDI-091143为已报道的ACLY抑制剂，作为阳性对照。
表2代表性化合物对各癌细胞体外增殖抑制活性
本发明所述的化合物对ACLY具有抑制活性，细胞活性优于NDI-091143。这是由于本发明的化合物具有疏水性长链，其膜通透性优于苯磺酰胺类抑制剂NDI-091143。本发明所述化合物具有优异的类药性，更有潜力成为靶向ACLY的抑制剂，用于制备应用于代谢性疾病或癌症的药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，
式中，
表示双键或单键；
R1、R2各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基或C6-C10芳基；或者，R1和R2与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
R3、R4各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基；或者，R3和R4与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
R5、R6各自独立为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基；或者，R5和R6与连接的碳一起形成饱和的3-7元环，或含有不饱和双键的3-7元环；
m、n和q各自独立地为0、1、2、3、4、5或6；
Z为-OH、-COOH、-COOR7、-SO3H或-CONHR7，其中R7为C1-C4烷基；
X为-CO-、-O-、-NH-、-S-、-CH2-、
-CONH-、
-NHOC-、
-CH2CO-或-COCH2-；
Y为H、C6-C10芳基、C1-C4烷基或金刚烷基(Ad-)；或者Y为：
其中linker为C1-C20的亚烷基或聚乙二醇，或无该linker；
上述各C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基或C6-C10芳基为未取代的或取代的，其中，所述取代是指被选自下组的1、2、3、4或5个取代基取代：卤素、C1-C4烷基、C1-C4烷氧基、C3-C7环烷基、C3-C7环烯基、C6-C10芳基。
2.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物具有式II所示的结构：
3.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物具有式III所示的结构：
4.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物具有式IV所示的结构：
W为不存在、-O-、-NH-、-S-或-CH2-。
5.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，R1、R2各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R1和R2与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环；
R3、R4各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R3和R4与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环；
R5、R6各自独立为H、甲基、乙基、丙基、乙烯基、丙烯基、乙炔基、丙炔基、C3-C6环烷基、C3-C6环烯基或C6-C10芳基；或者，R5和R6与连接的碳一起形成饱和的3-6元环，或含有一个不饱和双键的3-6元环。
6.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，m、n各自独立地为1、2、3、4或5；和/或q为0、1、2、3或4。
7.如权利要求1所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物选自下组：
8.一种药物组合物，其特征在于，包含：
如权利要求1-7任一项所述的通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐；和药学上可接受的载体。
9.如权利要求1-7任一项所述的通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或权利要求8所述的药物组合物用途，其特征在于，用于制备ACLY抑制剂；或用于制备预防和/或治疗代谢性疾病或癌症的药物。
10.如权利要求9所述的用途，其特征在于，所述代谢性疾病选自下组：高血脂症、动脉粥样硬化、非酒精性脂肪肝、糖尿病；
所述癌症选自下组：肺癌、胰腺癌、乳腺癌、卵巢癌、肝癌、肠癌、脑癌、急性髓系白血病。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111116425.5A CN115894220A (zh) | 2021-09-23 | 2021-09-23 | 一类作用于acly的长链类化合物、其制备方法及其用途 |
| PCT/CN2022/120328 WO2023045986A1 (zh) | 2021-09-23 | 2022-09-21 | 一类作用于acly的长链类化合物、其制备方法及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111116425.5A CN115894220A (zh) | 2021-09-23 | 2021-09-23 | 一类作用于acly的长链类化合物、其制备方法及其用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115894220A true CN115894220A (zh) | 2023-04-04 |
Family
ID=85720091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111116425.5A Pending CN115894220A (zh) | 2021-09-23 | 2021-09-23 | 一类作用于acly的长链类化合物、其制备方法及其用途 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115894220A (zh) |
| WO (1) | WO2023045986A1 (zh) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL64542A0 (en) * | 1981-12-15 | 1982-03-31 | Yissum Res Dev Co | Long-chain alpha,omega-dicarboxylic acids and derivatives thereof and pharmaceutical compositions containing them |
| DE3423166A1 (de) * | 1984-06-22 | 1986-01-02 | Epis S.A., Zug | Alpha-, omega-dicarbonsaeuren, verfahren zu ihrer herstellung und arzneimittel, die diese verbindungen enthalten |
| US5026461A (en) * | 1990-01-19 | 1991-06-25 | E. I. Du Pont De Nemours And Company | Process for the preparation of dodecanedioic acid |
| CN107118098B (zh) * | 2016-02-25 | 2020-07-14 | 中国科学院上海药物研究所 | 一类脂肪酸类化合物、其制备方法及其用途 |
-
2021
- 2021-09-23 CN CN202111116425.5A patent/CN115894220A/zh active Pending
-
2022
- 2022-09-21 WO PCT/CN2022/120328 patent/WO2023045986A1/zh active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023045986A1 (zh) | 2023-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106795155A (zh) | 制备(4s)‑4‑(4‑氰基‑2‑甲氧基苯基)‑5‑乙氧基‑2，8‑二甲基‑1，4‑二氢‑1，6‑萘啶‑3‑甲酰胺的方法及其纯化以用作活性药物活性成分 | |
| BR112021005044A2 (pt) | compostos antibacterianos | |
| CN102942567A (zh) | 吡咯并喹啉醌的二钠盐结晶 | |
| CN112047973B (zh) | 一种大麻素类化合物，其制备方法、组合物和用途 | |
| CN102260190B (zh) | 具有抗肿瘤作用的n-苯基-n’-(末端羧酸取代酰氧基)辛二酰胺类化合物及其药用盐 | |
| CN107674083A (zh) | 一种含哒嗪酮结构的l‑亮氨酸取代去甲斑蝥素衍生物的制备方法及其应用 | |
| CN108752365A (zh) | 一种含吡唑结构的螺[吲哚嗪-异噁唑啉]衍生物及其制备方法与应用 | |
| EP4074699A1 (en) | Compound as cyclin-dependent kinase 9 inhibitor and use thereof | |
| CN108473428B (zh) | 一种吡啶衍生物类化合物的制备方法及其中间体和晶型 | |
| WO2008103382A1 (en) | Method for assembling high-purity chemical libraries, compounds suppressing acetyl coenzyme a carboxylase activities discovered by same | |
| CN115894220A (zh) | 一类作用于acly的长链类化合物、其制备方法及其用途 | |
| CN114605340B (zh) | 一种邻香兰素-吡嗪酰胺共晶及其制备方法 | |
| MX2007009007A (es) | Derivados de acido aminobutanoico que inhiben carnitina palmitoil transferasa. | |
| TW202024013A (zh) | 用於製備α-酮戊二酸鈣之方法 | |
| CN111196791B (zh) | 一种手性γ-丁内酯衍生物及其合成方法和应用 | |
| CN105949180B (zh) | 治疗中枢神经系统退行性疾病的化合物及其应用 | |
| CN108689983B (zh) | 5,7,8-三氯-1,3-二羟基氧杂蒽酮化合物、制备方法及应用 | |
| CN108997300B (zh) | 7,8-二氟-1,3-二羟基氧杂蒽酮及其制备方法和应用 | |
| CN101104609B (zh) | 茄呢基多胺衍生物、制备及其应用 | |
| CN108752306B (zh) | 6-氟-1,3-二羟基氧杂蒽酮及其制备方法和应用 | |
| CN111892486B (zh) | 一种羟基取代的二苯甲酮类化合物及其制备方法和应用 | |
| CN115010642B (zh) | β-榄香烯酰亚胺类衍生物及其应用 | |
| CN107955004A (zh) | 一类苦参碱-2(5h)-呋喃酮衍生物及其制法与在制备抗肝癌药物中的应用 | |
| CN108484639B (zh) | 一种对氟取代含吡唑结构的螺[吲哚嗪-异噁唑啉]衍生物及其制备方法与应用 | |
| CN114746426B (zh) | 作为acc1和acc2抑制剂的晶型及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |