CN117777049A - 一种噻唑烷二酮类hdac抑制剂、制备方法及应用 - Google Patents
一种噻唑烷二酮类hdac抑制剂、制备方法及应用 Download PDFInfo
- Publication number
- CN117777049A CN117777049A CN202410218999.0A CN202410218999A CN117777049A CN 117777049 A CN117777049 A CN 117777049A CN 202410218999 A CN202410218999 A CN 202410218999A CN 117777049 A CN117777049 A CN 117777049A
- Authority
- CN
- China
- Prior art keywords
- hydroxyheptanamide
- dioxathiazolidin
- carbon atoms
- thiazolidinedione
- methoxybenzylidene
- 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
- 229940123464 Thiazolidinedione Drugs 0.000 title claims abstract description 39
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims abstract description 35
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 11
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 10
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- -1 hydroxy, mercapto Chemical class 0.000 claims description 248
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 51
- 239000000543 intermediate Substances 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 36
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 34
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 229940000635 beta-alanine Drugs 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 8
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- OOBFNDGMAGSNKA-UHFFFAOYSA-N ethyl 7-bromoheptanoate Chemical compound CCOC(=O)CCCCCCBr OOBFNDGMAGSNKA-UHFFFAOYSA-N 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 6
- 150000003935 benzaldehydes Chemical class 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- KIWUVOGUEXMXSV-UHFFFAOYSA-N rhodanine Chemical compound O=C1CSC(=S)N1 KIWUVOGUEXMXSV-UHFFFAOYSA-N 0.000 claims description 3
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 239000004593 Epoxy Substances 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims 1
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 0.000 claims 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 1
- 206010029260 Neuroblastoma Diseases 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 1
- 206010057644 Testis cancer Diseases 0.000 claims 1
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- 201000010175 gallbladder cancer Diseases 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 208000007538 neurilemmoma Diseases 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 206010039667 schwannoma Diseases 0.000 claims 1
- 208000017520 skin disease Diseases 0.000 claims 1
- 201000003120 testicular cancer Diseases 0.000 claims 1
- 150000001467 thiazolidinediones Chemical class 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000005918 in vitro anti-tumor Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 84
- 239000007787 solid Substances 0.000 description 56
- 239000000203 mixture Substances 0.000 description 47
- 239000012634 fragment Substances 0.000 description 41
- 238000001308 synthesis method Methods 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012295 chemical reaction liquid Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 239000012046 mixed solvent Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 238000010828 elution Methods 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 9
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 9
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 230000021736 acetylation Effects 0.000 description 6
- 238000006640 acetylation reaction Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 230000004481 post-translational protein modification Effects 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 6
- 229960000237 vorinostat Drugs 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000002512 chemotherapy 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
- 229940088598 enzyme Drugs 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- SGIZECXZFLAGBW-VURMDHGXSA-N (5z)-5-benzylidene-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)\C1=C\C1=CC=CC=C1 SGIZECXZFLAGBW-VURMDHGXSA-N 0.000 description 2
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical compound O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 description 2
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 2
- 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 2
- 108010077544 Chromatin Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000003893 Histone acetyltransferases Human genes 0.000 description 2
- 108090000246 Histone acetyltransferases Proteins 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- SZMJVTADHFNAIS-BJMVGYQFSA-N chidamide Chemical compound NC1=CC(F)=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)\C=C\C1=CC=CN=C1 SZMJVTADHFNAIS-BJMVGYQFSA-N 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000006718 epigenetic regulation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- TVQGDYNRXLTQAP-UHFFFAOYSA-N heptanoic acid ethyl ester Natural products CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 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
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000001356 surgical procedure Methods 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
- 125000002053 thietanyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229950001415 tucidinostat Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- OHZAHWOAMVVGEL-UHFFFAOYSA-N 2,2'-bithiophene Chemical group C1=CSC(C=2SC=CC=2)=C1 OHZAHWOAMVVGEL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate 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)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA 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
- 206010059866 Drug resistance Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 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
- 101150037263 PIP2 gene Proteins 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101100262439 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UBA2 gene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-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
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical group [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 150000004653 carbonic acids Chemical class 0.000 description 1
- 125000005111 carboxyalkoxy group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000003446 ligand Substances 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000014616 translation Effects 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种噻唑烷二酮类HDAC抑制剂、制备方法及应用,属于医药技术领域。本发明的一种噻唑烷二酮类HDAC抑制剂,结构新颖、作为HDAC的高效抑制剂,其有益效果是:具有高效优异的HDAC酶抑制活性,且具备优异体外抗肿瘤活性,为HDAC抑制剂在实体瘤中的应用/或治疗与组蛋白去乙酰化酶活性失控有关的疾病提供新颖有效的化合物实体。
Description
技术领域
本发明涉及一种噻唑烷二酮类HDAC抑制剂、制备方法及应用,属于医药技术领域。
背景技术
传统的恶性肿瘤治疗方法主要包括手术治疗、化学治疗、放射治疗。手术治疗虽然是一种较好的方法,但如果不继续进行其他的辅助治疗,对于延长患者生命的效果并不理想;化学治疗可能会有耐药性的产生,产生药物的副作用,常见的有对骨髓的抑制,对肠道功能的抑制等;放射治疗是一种局部治疗,放疗可以抑制肿瘤的生长,但另一方面也会对周围组织产生影响以及造成损伤。分子靶向治疗因特异性强和毒性低等特点成为治疗癌症的新方法。在不影响DNA序列的情况下,通过对DNA等遗传物质的甲基化修饰、乙酰化修饰、染色质构象改变等改变个体发育并遗传给后代,研究这种机制的学科即为表观遗传学。表观遗传调控在许多生物过程中起到至关重要的作用,并与癌症等各种人类疾病的发生和进展息息相关。人类基因组包含20000至25000个基因,仅由DNA序列的5 %编码,然而,并非是一个基因对应着一蛋白质,因为信使核糖核酸在编译等过程后会导致转录组比基因数量高出数倍,其中就包括在蛋白质合成后,通过氨基酸侧链的翻译后修饰(posttranslationalmodification,PTM)发生的进一步的扩增。大多数 PTM本质上是动态的,能使单个蛋白质能够以多种功能状态存在,并以可逆的方式从一种状态变化到另一种状态。其中,特别是赖氨酸的ε-氨基侧链,可以通过烷基化或酰化等多种 PTM产生各种修饰后的蛋白质。例如,烷基化增加了赖氨酸侧链的长度,同时在生理pH下保持其带正电的性质,而酰化则会产生中性甚至带负电荷的侧链,酰化的范围从甲酰化到蛋白质如泛素的结合。在这些PTM中,乙酰化和甲基化,常发生在富含赖氨酸的组蛋白 N 末端,在染色质结构的表观遗传调控和基因转录过程中配体的募集中发挥核心作用,因此,参与到赖氨酸乙酰化、甲基化以及去除乙酰或甲基化的酶已成为小分子药物发现的重要靶点。而赖氨酸乙酰化在20世纪60年代初首次在组蛋白中观察到,其可以显著地改变蛋白质的生物学特性,例如改变蛋白结合、改变蛋白稳定性、降低相关酶的催化活性等。在此后不久,发现了催化乙酰化反应和脱乙酰化反应的酶,并将其分别命名为组蛋白乙酰转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶。恶性肿瘤目前是人类的最大威胁之一,人类积极的在各领域寻找缓治以及解决该疾病的方法,而在化学治疗方面,抑制组蛋白去乙酰化酶已经经过大量研究证明对许多癌症都有相当好的治疗效果。但尽管经过了三十多年的研究,现有的临床候选HDAC抑制剂仍旧存在药代动力学性质不佳、药效一般、适应症有限等问题,没有完全发挥HDAC靶点的联用优势,并且已上市的HDAC抑制剂种类较少,所以该靶点仍具有很高的研究价值以及研究空间。
发明内容
本发明的目的是针对现有技术存在的缺陷,提出一种噻唑烷二酮类HDAC抑制剂、制备方法及应用,筛选出高活性HDAC抑制剂用于抑制肿瘤的药物制备,为抗肿瘤药物的开发提供良好的前景。
本发明通过以下技术方案解决技术问题:本发明首先提供一种噻唑烷二酮类HDAC抑制剂,其包括具有通式的取代噻唑烷二酮类化合物,或其立体异构体、水合物或药学上可接受的盐,所述通式结构如下:
其中,式中W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地可任选被R2取代,R2可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、芳基或Het;
Q选自长度为1-9个碳原子的饱和或不饱和直链或支链烃基,芳基或Het;
R1选自羟基、可任选被一个或多个R3取代的2-氨基苯基;
R3可以是氢、烷基、氰基、卤素、卤代烷基、羟基基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、芳基或Het;
烷基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
烷氧基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-9个碳原子的环状饱和烃基;或为连接具有1-9个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
烷氨基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-9个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被NH原子团取代;
烷氧基烷基如上定义的烷氧基与烷基连接;
烯基、炔基为具有1-9个碳原子的直链或支链的含有双键或三键的不饱和烃基;
芳基为选自苯基、萘基、苊基或四氢萘基的碳环,其各自任选被1、2或3个取代基取代,各取代基独立地选自氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
芳烷基、二芳基烷基为如上定义的芳基与烷基连接;
Het为选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环;或选自3-6个碳原子的单环饱和烃基、6-12个碳原子的双环饱和烃基,其中环上的碳原子独立任选地被1-4个O、S、N或NH取代;各单环或双环任选被1、2或3个取代基取代,各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基。
卤素为选自氟、氯、溴或碘的取代基;
卤代烷基为具有1-9个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代。
优选的,本发明进一步选择以下化合物作为噻唑烷二酮类HDAC抑制剂:式中W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地任选被R2取代,R2是氢、烷基、氰基、卤素、卤代烷基、烷氧基、烷硫基、烷氧基烷基;
Q是选自长度为1-9个碳原子的饱和或不饱和直链或支链烃基、芳基;
R1选自羟基、任选被一个或多个R3取代的2-氨基苯基;
R3是氢、烷基、氰基、卤素、卤代烷基、芳基或Het。
优选的,本发明进一步选择以下化合物作为噻唑烷二酮类HDAC抑制剂:式中W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地任选被R2取代,R2是氢、烷基、卤素、烷氧基;
Q是选自长度为3-9个碳原子的饱和或不饱和直链或支链烃基、芳基;
R1选自羟基、任选被一个或多个R3取代的2-氨基苯基;
R3是氢、烷基、氰基、卤素、卤代烷基、芳基或Het。
进一步地,所述通式中与碳相连的氢可以被替换为氢的同位素氘;例如,烷基可被氘代烷基替代,烷氧基可被氘代环氧基替代,苯环被氘代苯环替代,芳环可被氘代芳环替代。
药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式。药学上可接受的盐包括,但不仅限于,碱性基团例如胺(氨)基的无机或有机酸盐类。本发明药学上可接受的盐可以由母体化合物合成,即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remington’s Pharmaceutical Sciences ,17th ed .,MackPublishing Company ,Easton ,Pa .,1985 ,p .1418和Journal of Pharmaceutical Science ,66 ,2 (1977) 中。
本发明中化合物碱性基团可与酸成盐,这些酸成盐的例子包括:与无机酸,尤其氢卤酸(如氢氯酸、氢溴酸、氢碘酸)、硝酸、硫酸、磷酸、碳酸等形成的盐;低级烷基磺酸,如甲磺酸,三氟甲磺酸形成的盐;与芳基磺酸,如苯磺酸或对甲苯磺酸形成的盐;与有机酸,如乙酸、富马酸、酒石酸、草酸、柠檬酸、马来酸、苹果酸或琥珀酸形成的盐;与氨基酸,如天冬氨酸或谷氨酸形成的盐。
本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。一般来说,溶剂化物或水合物的形式与非溶剂化的或非水合的形式等同,并涵盖在本发明的范围内。本发明中的某些化合物有可能存在多晶体或无定形的形式。总的来说,所有的物理形式具有同等的用途,并且涵盖在本发明的范围内。
另外,除非其它方面表明,本发明的噻唑烷二酮类HDAC抑制剂中化合物的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本申请所涉及的术语“烷基”为包括1-20个碳原子饱和直链或支链的单价烃基,其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是,烷基基团含有1-10个碳原子,另外一些实施例是,烷基基团含有1-8个碳原子,另外一些实施例是,烷基基团含有1-6个碳原子,另外一些实施例是,烷基基团含有1-4个碳原子。烷基基团更进一步的实例包括,但并不限于甲基(Me,-CH3)、乙基(Et,-CH2CH3)、正丙基(n-Pr,-CH2CH2CH3)、异丙基(i-Pr,-CH(CH3)2)、正丁基(n-Bu,-CH2CH2CH2CH3)、异丁基(i-Bu,-CH2CH(CH3)2)、仲丁基(s-Bu,-CH(CH3)CH2CH3)、叔丁基(t-Bu,-C(CH3)3)等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。
术语“烷氧基”涉及到烷基的部分与前述“烷基”的定义相同,其是通过氧原子连接到“烷基”主要的碳链上形成的。
术语“卤代烷基”或“卤代烷氧基”是表示“烷基”或“烷氧基”可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基和烷氧基团具有如本发明前述的含义,这样的实例包括但并不限于三氟甲基、三氟甲氧基等。
术语“羟基烷基”或“羟基烷氧基”是表示“烷基”或“烷氧基”可以被一个或多个羟基所取代的情况。其中“烷基”和“烷氧基”基团具有如本发明前述的含义,这样的实例包括但并不限于羟甲基、1-羟乙基、羟丙基、1, 2-二羟基丙基、羟甲氧基、1-羟乙氧基等。
术语“卤素”、“卤原子”或“卤素原子”包括氟、氯、溴、碘。
术语“杂环基”可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括但并不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、噻噁烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、哌啶基、高哌啶基、环氧丙基、氮杂环庚基、氧杂环庚基、硫杂环庚基、N-吗啉基、2-吗啉基、3-吗啉基、硫代吗啉基、N-哌嗪基、2-哌嗪基、3-哌嗪基、高哌嗪基、4-甲氧基-哌啶-1-基、1,2,3,6-四氢吡啶-1-基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡咯啉-1-基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,6-噻二嗪烷、1,1-二氧-2-基、喹嗪基和N-吡啶基尿素。并且所述杂环基可以是取代或非取代的,其中取代基可以是但并不限于氧代(=O)、羟基、氨基、卤素、氰基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(=O)、烷基-C(=O)、羧基烷氧基等。
基于上述通式,本发明所述的噻唑烷二酮类HDAC抑制剂包含以下其中之一的结构:
(1)(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)-N-羟基庚酰胺;
(2)(Z)-7-(5-(2-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(3)(Z)-7-(5-(3-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(4)(Z)-7-(5-(4-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(5)(Z)-7-(5-(2-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(6)(Z)-7-(5-(3-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(7)(Z)-7-(5-(4-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(8)(Z)-7-(5-(4-氟亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(9)(Z)-N-羟基-7-(5-(3-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(10)(Z)-N-羟基-7-(5-(4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(11)(Z)-3-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯;
(12)(Z)-4-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯;
(13)(Z)-7-(5-(4-氨基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(14)(Z)-7-(5-(2-乙氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(15)(Z)-N-羟基-7-(5-(4-异丙基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(16)(Z)-7-(5-(4-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(17)(Z)-7-(5-(5-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(18)(Z)-7-(5-(3-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(19)(Z)-7-(5-(2-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(20)(Z)-7-(5-(3-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(21)(Z)-7-(5-(3-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(22)(Z)-7-(5-(4-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(23)(Z)-7-(5-(5-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(24)(Z)-7-(5-(6-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(25)(Z)-N-羟基-7-(5-(2-甲氧基-4-甲基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(26)(Z)-7-(5-(4-氟-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(27)(Z)-7-(5-(2,4-二甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(28)(Z)-N-羟基-7-(5-(萘-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(29)(Z)-7-(2,4-二氧代-5-(喹啉-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(30)(Z)-7-(2,4-二氧代-5-(喹啉-7-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(31)(Z)-7-(2,4-二氧代-5-(喹啉-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(32)(Z)-7-(2,4-二氧基-5-(喹啉-6-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(33)(Z)-7-(5-((2,3-二氢苯并呋喃-5-基)亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(34)(Z)-7-(5-(苯并[d][1,3]二氧唑-5-基亚甲基)-2,4-二氧杂噻唑啉-3-基)-N-羟基庚酰胺;
(35)(Z)-7-(2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(36)(Z)-7-(2,4-二氧代-5-(喹啉-8-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(37)(Z)-7-(2,4-二氧代-5-(噻吩-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(38)(Z)-7-(5-(呋喃-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(39)(Z)-N-羟基-7-(5-(4-甲氧基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺;
(40)(Z)-7-(5-(4-氯亚苄基)-4-氧代-2-硫杂噻唑烷-3-基)-N-羟基庚酰胺;
(41)(Z)-N-羟基-7-(5-(4-甲基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺;
(42)(Z)-7-(5-(4-乙基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)-N-羟基庚酰胺;
(43)(Z) -N-(2-氨基-4-氟苯基)-4-((2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)甲基)苯甲酰胺。
本发明进一步提供上述抑制剂的制备方法,其中所述噻唑烷二酮类HDAC抑制剂(1-15)的制备方法包括以取代苯甲醛(1a-1o)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(2a-2o);中间体(2a-2o)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(3a-3o);中间体(3a-3o)在酸性条件下发生水解反应得到中间体(4a-4o);中间体(4a-4o)与盐酸羟胺缩合反应得到目标化合物(1-15),具体是先称取5mmol噻唑烷酮、5 mmol化合物1a-1o、6 mmol β-丙氨酸于 10mL 冰醋酸中,回流搅拌约 5h,TLC 确认原料噻唑烷酮消失后加水淬灭、过滤,收集滤饼,干燥得到化合物2a-2o。收率80.1 %。然后取4 mmol化合物2a-2o于圆底烧瓶中,加入DMF 10 mL作为溶剂,再加入1.5 eq碳酸钾(6 mmol),冰浴预搅拌30 min,移除冰浴待反应升温至室温,加入2 eq溴代酸酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为3:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到化合物3a-3o透明油状液体收率为35-56.2%。再取2 mmol化合物3a-3o,加入3 mL冰醋酸、0.5 mL浓盐酸(10 M),加热至 90℃搅拌反应,用 TLC 监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤3遍滤饼,干燥得到粗品4a-4o。最后,直接取上一步得到的4a-4o,用5 mL四氢呋喃溶解,搅拌中分批加入CDI(N,N-碳基二咪唑)3 mmol,预搅拌1 h,TLC确认原料完全消失后加入6 mmol盐酸羟胺,搅拌反应过夜12 h,将反应液浓缩,经以二氯甲烷:甲醇体积比为25:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到5a-5o,产率为11 %到20.2 %。制备路线如下:
。
所述噻唑烷二酮类HDAC抑制剂(16-27)的制备方法包括以多取代苯甲醛(6a-6I)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(7a-7I);中间体(7a-7I)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(8a-8I);中间体(8a-8I)在酸性条件下发生水解反应得到中间体(9a-9I);中间体(9a-9I)与盐酸羟胺缩合反应得到目标化合物(16-27),具体是:先称取5 mmol噻唑烷酮、5 mmol化合物6a-6l、6mmol β-丙氨酸于 10mL冰醋酸中,回流搅拌约5 h,TLC确认原料噻唑烷酮消失后加水淬灭、过滤,收集滤饼,干燥得到化合物7a-7l。收率80.1 %。然后取4 mmol化合物7a-7l于圆底烧瓶中,加入DMF 10 mL作为溶剂,再加入1.5 eq 碳酸钾(6 mmol),冰浴预搅拌30 min,移除冰浴待反应升温至室温,加入2 eq溴代酸酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为3:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到化合物8a-8l透明油状液体收率为35-56.2 %。再取2 mmol化合物8a-8l,加入3 mL冰醋酸、0.5 mL浓盐酸(10 M),加热至90 ℃搅拌反应,用TLC监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤3遍滤饼,干燥得到粗品9a-9l。最后,直接取上一步得到的9a-9l,用5 mL四氢呋喃溶解,搅拌中分批加入CDI(N,N-碳基二咪唑)3 mmol,预搅拌1 h,TLC 确认原料完全消失后加入6 mmol盐酸羟胺,搅拌反应过夜12 h,将反应液浓缩,经以二氯甲烷:甲醇体积比为25:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到10a-10l,产率为11%到20.2 %。制备路线如下:
。
所述噻唑烷二酮类HDAC抑制剂(28-38)的制备方法包括以芳香醛(11a-11k)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(12a-12k);中间体(12a-12k)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(13a-13k);中间体(13a-13k)在酸性条件下发生水解反应得到中间体(14a-14k);中间体(14a-14k)与盐酸羟胺缩合反应得到目标化合物(28-38),具体是:先称取5 mmol噻唑烷酮、5 mmol化合物11a-11k、6 mmol β-丙氨酸于10mL冰醋酸中,回流搅拌约5 h,TLC 确认原料噻唑烷酮消失后加水淬灭、过滤,收集滤饼,干燥得到化合物12a-12k。收率80.1 %。然后取4 mmol化合物12a-12k于圆底烧瓶中,加入DMF 10 mL 作为溶剂,再加入1.5 eq碳酸钾(6 mmol),冰浴预搅拌30 min,移除冰浴待反应升温至室温,加入2 eq溴代酸酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为3:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到化合物13a-13k透明油状液体收率为35-56.2 %。再取2 mmol化合物13a-13k,加入3 mL冰醋酸、0.5 mL浓盐酸(10 M),加热至90 ℃搅拌反应,用TLC监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤3遍滤饼,干燥得到粗品14a-14k。最后,直接取上一步得到的14a-14k,用5 mL四氢呋喃溶解,搅拌中分批加CDI(N,N-碳基二咪唑)3 mmol,预搅拌1 h,TLC确认原料完全消失后加入6 mmol盐酸羟胺,搅拌反应过夜12 h,将反应液浓缩,经以二氯甲烷:甲醇体积比为25:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到15a-15k,产率为11 %到20.2 %。制备路线如下:
所述噻唑烷二酮类HDAC抑制剂(39-42)的制备方法包括对位取代苯甲醛(16a-16d)和罗丹宁为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(17a-17d);中间体(17a-17d)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(18a-18d);中间体(18a-18d)在酸性条件下发生水解反应得到中间体(19a-19d);中间体(19a-19k)与盐酸羟胺缩合反应得到目标化合物(39-42),具体是:先称取 5 mmol 罗丹宁、5 mmol 化合物16a-16d、6 mmol β-丙氨酸于 10mL 冰醋酸中,回流搅拌约 5 h,TLC 确认原料噻唑烷酮消失后加水淬灭、过滤,收集滤饼,干燥得到化合物 17a-17d。收率 80.1%。然后取 4 mmol化合物17a-17d于圆底烧瓶中,加入 DMF 10 mL 作为溶剂,再加入 1.5 eq 碳酸钾(6mmol),冰浴预搅拌 30 min,移除冰浴待反应升温至室温,加入 2 eq 溴代酸酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为 3:1 的混合溶剂作为洗脱剂柱层析洗脱,分离得到化合物18a-18d透明油状液体收率为 35-56.2%。再取 2 mmol 化合物 18a-18d,加入 3 mL 冰醋酸、0.5 mL浓盐酸(10 M),加热至 90℃搅拌反应,用 TLC 监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤 3 遍滤饼,干燥得到粗品 19a-19d。最后,直接取上一步得到的19a-19d,用 5 mL 四氢呋喃溶解,搅拌中分批加入 CDI(N,N-碳基二咪唑)3 mmol,预搅拌 1 h,TLC 确认原料完全消失后加入 6 mmol 盐酸羟胺,搅拌反应过夜 12 h,将反应液浓缩,经以二氯甲烷:甲醇体积比为 25:1 的混合溶剂作为洗脱剂柱层析洗脱,分离得到 20a-20d,产率为 11%到 20.2%。制备路线如下:
。
本发明再进一步提供一种前述的噻唑烷二酮类HDAC抑制剂或前述的药物组合物或前述的药物组合物在制备用于体外抑制癌症细胞生长的药物中的应用。
本发明的化合物结构新颖、作为HDAC的高效抑制剂,其有益效果是:具有高效优异的HDAC酶抑制活性,且具备成本低、抗肿瘤活性显著,使用剂量小,疗效佳、毒性小的特点,且在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本。可用于相关肿瘤药物的研究,具有积极且可预见的抗肿瘤药物的临床应用价值,并具有很好的开发前景。
具体实施方式
下面结合具体的实施方式来对本发明的技术方案做进一步的限定,但要求保护的范围不仅局限于所作的描述。下面所描述的实施例中除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如安徽泽升科技有限公司、百灵威科技有限公司、阿拉丁试剂有限公司、北京偶合科技有限公司等,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从西陇化工股份有限公司、南京化学试剂股份有限公司、国药集团化学试剂有限公司和青岛海洋化工有限公司等购买得到。
下面所描述的实施例中色谱柱使用硅胶柱,硅胶(200-300目)购于青岛海洋化工有限公司。核磁共振光谱以CDCl3或DMSO-d 6为溶剂(以ppm为单位),用TMS(0 ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),m(multiplet,多重峰),br(broadened,宽峰),dd (doublet ofdoublets,双双重峰),dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
下面描述的实施例为了便于表述,部分原料会以其简称进行描述,这些简称与其全称对照说明如下:DCM为CH2Cl2,即二氯甲烷;CDC13为氘代氯仿;PE为石油醚;EtOAc与EA均为乙酸乙酯;MeOH与CH3OH均为甲醇;ClSO3H为氯磺酸;TEA与Et3N为三乙胺;DMSO-d 6 为六氘代二甲亚砜;THF为四氢呋喃;NaCl为氯化钠;Na2SO4为硫酸钠;CDI为N,N-羰基二咪唑。
实施例1
(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)-N-羟基庚酰胺的合成,合成步骤如下:
步骤1:(Z) -5-亚苄基噻唑烷-2,4-二酮的合成,结构式如下:按顺序在 100 mL 圆底烧瓶中加入噻唑烷酮(5mmol,585.6 mg)、醋酸(10 mL)、苯甲醛(5 mmol,530.6mg),120 ℃回流搅拌反应 8h。冷却至室温,有固体析出,抽滤烘干滤饼,为白色固体820 mg,收率 80.1%。
步骤2:(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸乙酯的合成,结构式如下:取4 mmol(Z)-5-亚苄基噻唑烷-2,4-二酮于圆底烧瓶中,加入DMF 10 mL作为溶剂,再加入1.5 eq碳酸钾(6 mmol),冰浴预搅拌30 min,移除冰浴待反应升温至室温,加入2 eq溴代酸酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为3:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到化合物(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸乙酯 透明油状液体收率为35-56.2%。
步骤3:(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸的合成,结构式如下:取2 mmol化合物(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸乙酯,加入3 mL冰醋酸、0.5 mL浓盐酸(10 M),加热至90 ℃搅拌反应,用TLC监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤3遍滤饼,干燥得到粗品(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸。
步骤4:(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)-N-羟基庚酰胺的合成,结构式如下:取上一步得到的(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸,用5 mL四氢呋喃溶解,搅拌中分批加入CDI(N,N-碳基二咪唑)3 mmol,预搅拌1 h,TLC确认原料完全消失后加入6 mmol盐酸羟胺,搅拌反应过夜12 h,将反应液浓缩,经以二氯甲烷:甲醇体积比为25:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)-N-羟基庚酰胺,产率为11 %到20.2 %。1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.63 (d, J = 7.0Hz, 2H), 7.53 (dt, J = 13.0, 6.8 Hz, 3H), 3.64 (t, J = 7.2 Hz, 2H), 1.93 (t,J = 7.3 Hz, 2H), 1.57 (t, J = 6.8 Hz, 2H), 1.48 (s, 2H), 1.54 – 1.42 (m, 1H),1.30 – 1.21 (m, 4H). 13C NMR (101 MHz, DMSO-d 6) δ 169.51, 167.80, 166.13,133.45, 133.30, 131.08, 130.57, 129.84, 121.83, 41.98, 32.61, 28.55, 27.44,26.30, 25.41.
实施例2
(Z)-7-(5-(2-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺的合成,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:17 %。1H NMR (300 MHz,DMSO-d 6) δ 10.36 (s, 1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.66 (dt, J = 7.8, 2.9Hz, 1H), 7.66 – 7.46 (m, 3H), 3.64 (t, J = 7.2 Hz, 2H), 2.02 – 1.88 (m, 2H),1.52 (dt, J = 28.4, 6.9 Hz, 2H), 1.32 – 1.12 (m, 4H)./>
实施例3
(Z) -7-(5-(3-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:14 %。1H NMR (400 MHz, DMSO-d 6)δ 10.33 (s, 1H), 8.65 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.57 (s, 3H), 3.64(t, J = 7.2 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.4 Hz, 2H), 1.57 (p, J = 6.8Hz, 2H), 1.47 (q, J = 7.0 Hz, 2H), 1.30 – 1.21 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.48, 167.46, 165.92, 135.64, 134.44, 131.65, 130.64, 130.50, 128.26,123.67, 42.08, 32.61, 28.55, 27.41, 26.30, 25.41.
实施例4
(Z) -7-(5-(4-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z) -7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z) -7-(5-(4-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:15 %。1H NMR (400 MHz,DMSO-d 6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.63 (q, J = 8.5 Hz,4H), 3.64 (t, J = 7.2 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.4 Hz, 2H), 1.57(p, J = 6.9 Hz, 2H), 1.47 (t, J = 7.2 Hz, 2H), 1.26 (qd, J = 7.6, 4.9, 3.7Hz, 4H), 0.78 (s, 0H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.55, 166.03,135.66, 132.37, 132.20, 131.96, 129.91, 122.62, 42.04, 32.61, 28.55, 27.42,26.29, 25.40.
实施例5
(Z)-7-(5-(2-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:14 %。1H NMR (400 MHz, DMSO-d 6) δ10.34 (s, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.59 (q,J = 3.8, 2.9 Hz, 2H), 7.43 (ddd, J = 8.5, 5.9, 3.1 Hz, 1H), 3.68 – 3.58 (m,2H), 2.26 (s, 0H), 1.94 (t, J = 7.4 Hz, 2H), 1.70 (p, J = 6.8 Hz, 0H), 1.58(d, J = 14.5 Hz, 0H), 1.58 (s, 2H), 1.48 (t, J = 7.2 Hz, 2H), 1.43 – 1.32 (m,0H), 1.27 (p, J = 3.5 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.63,165.74, 134.11, 133.19, 132.62, 130.94, 129.57, 129.14, 125.76, 125.64,42.14, 32.62, 28.55, 27.40, 26.31, 25.40.
实施例6
(Z)-7-(5-(3-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:21 %。1H NMR (400 MHz, DMSO-d 6) δ10.33 (s, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.69(dt, J = 8.0, 1.3 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H),3.64 (t, J = 7.2 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.4 Hz, 2H), 1.52 (dt, J= 36.6, 7.2 Hz, 5H), 1.25 (td, J = 8.2, 7.7, 4.0 Hz, 5H), 0.79 (s, 0H). 13CNMR (101 MHz, DMSO-d 6) δ 169.49, 167.45, 165.90, 135.89, 133.52, 133.39,131.85, 131.61, 128.59, 123.63, 122.95, 42.08, 32.61, 28.55, 27.41, 26.30,25.41.
实施例7
(Z)-7-(5-(4-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:18 %。1H NMR (400 MHz, DMSO-d 6) δ10.33 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 8.4 Hz,2H), 7.57 (d, J = 8.3 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 2.25 (s, 0H), 1.93(t, J = 7.4 Hz, 2H), 1.56 (t, J = 7.0 Hz, 2H), 1.47 (s, 2H), 1.53 – 1.41 (m,1H), 1.32 – 1.21 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.53, 166.03,132.83, 132.68, 132.34, 132.05, 124.59, 122.69, 42.05, 32.61, 28.55, 27.42,26.30, 25.41.
实施例8
(Z)-7-(5-(4-氟亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-氟亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:19 %.1H NMR (300 MHz, DMSO-d 6) δ10.38 – 10.31 (m, 1H), 8.68 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.78 – 7.64(m, 2H), 7.40 (t, J = 8.8 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 2.24 (d, J = 7.7Hz, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.52 (dt, J = 26.6, 7.0 Hz, 5H), 1.33 –1.19 (m, 4H). 13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.68, 166.09, 164.67,162.17, 133.11, 133.02, 132.23, 130.15, 130.12, 121.54, 121.52, 117.13,116.91, 41.99, 32.61, 28.55, 27.44, 26.30, 25.41.
实施例9
(Z)-7-(5-(3-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.34 (s, 1H), 8.67 (d, J = 1.3 Hz, 1H), 7.90 (s, 1H), 7.47 (t, J= 8.2 Hz, 1H), 7.22 – 7.16 (m, 2H), 7.08 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H),3.63 (t, J = 7.2 Hz, 2H), 3.35 (s, 2H), 2.25 (t, J = 7.5 Hz, 0H), 2.02 – 1.89(m, 2H), 1.56 (p, J = 7.0 Hz, 2H), 1.47 (s, 2H), 1.54 – 1.41 (m, 1H), 1.33 –1.13 (m, 5H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.74, 166.07, 160.10,134.81, 133.26, 130.94, 122.39, 122.17, 116.94, 115.90, 60.23, 55.76, 41.97,32.61, 28.55, 27.44, 26.30, 25.42, 21.23, 14.55.
实施例10
(Z)-7-(5-(4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300 MHz,DMSO-d 6) δ 10.34 (s, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.66 – 7.54 (m, 2H),7.18 – 7.06 (m, 2H), 3.84 (s, 3H), 3.63 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.3Hz, 2H), 1.59 – 1.42 (m, 1H), 1.31 – 1.19 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ203.28, 169.49, 167.86, 166.24, 161.61, 133.36, 132.72, 129.32, 125.91,118.49, 115.44, 60.23, 55.98, 41.87, 32.61, 28.55, 27.47, 26.30, 25.41,21.23, 14.55.
实施例11
(Z)-3-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-(甲氧羰基)亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 8.17 (d, J = 1.9 Hz,1H), 8.11 – 7.98 (m, 2H), 7.95 – 7.85 (m, 1H), 7.69 (t, J = 7.8 Hz, 1H).13CNMR (101 MHz, DMSO-d 6) δ 169.49, 167.46, 165.98, 165.94, 134.96, 134.06,132.09, 131.16, 131.05, 130.63, 130.44, 123.30, 55.38, 52.98, 42.07, 32.61,28.56, 27.42, 26.30, 25.41.
实施例12
(Z)-4-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-(甲氧羰基)亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1HNMR (300 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 8.07 (d, J = 8.2 Hz,2H), 7.97 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 3.88 (s, 3H), 3.64 (t, J = 7.2Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.52 (dt, J = 28.8, 7.1 Hz,5H), 1.25 (td, J = 8.1, 7.5, 3.5 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49,167.54, 165.98, 165.96, 163.01, 137.81, 131.71, 131.01, 130.69, 130.36,124.56, 60.22, 52.89, 42.10, 32.61, 28.55, 27.41, 26.29, 25.41, 21.23, 14.55.
实施例13
(Z) -7-(5-(4-氨基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-氨基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %1H NMR (400 MHz, Acetone-d 6) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.27 (s, 1H), 6.91 – 6.83 (m, 2H), 6.26 –6.17 (m, 2H), 5.70 (s, 2H), 3.20 – 3.12 (m, 2H), 2.75 – 2.70 (m, 0H), 1.79(d, J = 8.1 Hz, 0H), 1.57 – 1.44 (m, 2H), 1.05 (dq, J = 29.2, 7.3 Hz, 5H),0.87 – 0.68 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 168.09, 166.39,152.52, 134.83, 133.26, 120.17, 114.37, 112.83, 60.22, 41.63, 32.61, 28.56,27.55, 26.31, 25.42, 21.23, 14.56.
实施例14
(Z)-7-(5-(2-乙氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2-乙氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %1H NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 8.69 – 8.63 (m, 1H), 8.11 (s, 1H), 7.53 – 7.40 (m, 2H),7.19 – 7.05 (m, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.26(s, 0H), 1.94 (t, J = 7.4 Hz, 2H), 1.52 (dt, J = 34.3, 7.0 Hz, 5H), 1.39 (t,J = 6.9 Hz, 3H), 1.32 – 1.20 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49,168.01, 166.20, 157.86, 133.06, 129.12, 128.10, 121.96, 121.65, 121.34,113.21, 64.50, 41.91, 32.62, 28.56, 27.44, 26.32, 25.41, 14.97.
实施例15
(Z)-N-羟基-7-(5-(4-异丙基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-异丙基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.57(d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 2.94(h, J = 6.9 Hz, 1H), 1.93 (t, J = 7.3 Hz, 2H), 1.56 (s, 2H), 1.48 (d, J = 6.7Hz, 0H), 1.23 (t, J = 6.3 Hz, 10H). 13C NMR (400 MHz, DMSO-d 6) δ 170.81,169.48, 167.85, 166.20, 152.00, 133.36, 131.11, 130.81, 127.87, 120.65,60.23, 41.94, 33.90, 32.61, 28.55, 27.46, 26.31, 25.41, 23.97, 21.24, 14.56.
实施例16
(Z)-7-(5-(4-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(400 MHz, DMSO-d 6) δ 10.33 (s, 1H), 8.65 (d, J = 1.3 Hz, 1H), 7.97 (s, 1H),7.41 – 7.27 (m, 3H), 3.93 (s, 3H), 3.62 (t, J = 7.2 Hz, 2H), 2.04 – 1.89 (m,2H), 1.51 (dt, J = 32.8, 7.1 Hz, 5H), 1.29 – 1.14 (m, 6H), 0.80 (s, 0H).13CNMR (101 MHz, DMSO-d 6) δ 169.49, 167.79, 166.12, 158.96, 130.67, 127.04,125.99, 124.50, 122.64, 121.26, 115.80, 56.89, 41.97, 32.61, 28.55, 27.43,26.30, 25.40.
实施例17
(Z)-7-(5-(5-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(5-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.65 (dd, J = 8.9,2.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 3.90 (s,3H), 3.62 (t, J = 7.2 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.52(dt, J = 33.1, 7.1 Hz, 5H), 1.25 (p, J = 3.4 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.62, 165.97, 157.50, 135.15, 131.46, 126.90, 124.14, 123.76,114.76, 112.65, 56.62, 42.00, 32.62, 28.55, 27.42, 26.29, 25.41.
实施例18
(Z)-7-(5-(3-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 8.67 (d, J = 1.4 Hz, 1H), 7.95 (s, 1H),7.80 (dd, J = 8.0, 1.4 Hz, 1H), 7.53 (dd, J = 7.9, 1.4 Hz, 1H), 7.28 (t, J =7.9 Hz, 1H), 3.79 (s, 3H), 3.64 (t, J = 7.2 Hz, 2H), 2.26 (t, J = 7.3 Hz,0H), 2.02 – 1.89 (m, 2H), 1.53 (dt, J = 38.0, 6.8 Hz, 5H), 1.26 (p, J = 3.5Hz, 4H), 1.18 (t, J = 7.1 Hz, 0H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.76,165.99, 156.30, 136.00, 129.06, 129.02, 127.03, 126.91, 124.80, 118.10,62.43, 60.23, 42.07, 32.61, 28.55, 27.42, 26.31, 25.40, 21.23, 14.55.
实施例19
(Z)-7-(5-(2-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 8.66 (s, 1H), 7.98 (s, 1H), 7.51 (d, J =8.8 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.8, 2.6 Hz, 1H), 3.85(s, 3H), 3.63 (t, J = 7.2 Hz, 2H), 2.26 (s, 0H), 1.94 (t, J = 7.3 Hz, 2H),1.58 (q, J = 6.9 Hz, 2H), 1.48 (s, 2H), 1.54 – 1.42 (m, 0H), 1.30 – 1.22 (m,4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.70, 165.96, 161.76, 130.79,130.59, 127.49, 125.13, 122.46, 119.44, 115.30, 60.23, 56.51, 42.04, 32.61,28.55, 27.42, 26.31, 25.40, 21.23, 14.55.
实施例20
(Z)-7-(5-(3-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(400 MHz, DMSO-d 6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.91 – 7.85 (m, 2H), 7.62(dd, J = 8.7, 2.2 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 3.63 (t, J= 7.2 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.56 (t, J = 6.8 Hz,2H), 1.47 (q, J = 7.1 Hz, 2H), 1.25 (p, J = 3.4 Hz, 4H).13C NMR (101 MHz,DMSO-d 6) δ 169.49, 167.55, 166.03, 157.46, 135.54, 131.87, 131.21, 127.43,120.22, 113.74, 111.91, 57.14, 41.97, 32.61, 28.55, 27.45, 26.30, 25.41.
实施例21
(Z)-7-(5-(3-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(3-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(300 MHz, DMSO-d 6) δ 10.35 (d, J = 1.6 Hz, 1H), 8.67 (d, J = 1.5 Hz, 1H),7.96 (s, 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H),7.35 (t, J = 7.9 Hz, 1H), 3.82 (s, 3H), 3.64 (t, J = 7.2 Hz, 2H), 1.94 (t, J= 7.3 Hz, 2H), 1.58 (d, J = 7.4 Hz, 2H), 1.59 – 1.42 (m, 1H), 1.48 (s, 2H),1.26 (td, J = 6.9, 3.0 Hz, 5H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 167.63,165.99, 157.08, 132.27, 128.58, 126.94, 125.10, 123.75, 123.60, 114.29,56.66, 41.99, 32.61, 28.56, 27.43, 26.30, 25.41.
实施例22
(Z)-7-(5-(4-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(400 MHz, DMSO-d 6) δ 10.37 (s, 1H), 8.70 (s, 1H), 7.97 (s, 1H), 7.43 (d, J =8.3 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.3, 1.9 Hz, 1H), 3.92(s, 3H), 3.61 (t, J = 7.1 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.77 (t, J = 7.3Hz, 0H), 1.73 – 1.65 (m, 0H), 1.55 (t, J = 7.0 Hz, 2H), 1.46 (q, J = 6.8 Hz,2H), 1.35 (q, J = 7.0 Hz, 0H), 1.24 (p, J = 4.0, 3.6 Hz, 4H).13C NMR (101 MHz,DMSO-d 6) δ 169.58, 167.83, 166.13, 159.07, 137.29, 130.54, 126.97, 122.53,121.54, 120.91, 112.97, 60.25, 56.87, 41.95, 32.60, 28.53, 27.41, 26.28,25.39, 14.54.
实施例23
(Z)-7-(5-(5-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(5-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400MHz, DMSO-d 6) δ 10.37 – 10.32 (m, 1H), 8.67 (d, J = 1.6 Hz, 1H), 7.94 (s,1H), 7.54 (dd, J = 8.9, 2.6 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.19 (d, J =8.9 Hz, 1H), 3.90 (s, 3H), 3.62 (d, J = 14.4 Hz, 1H), 3.35 (s, 1H), 2.25 (s,0H), 1.93 (t, J = 7.4 Hz, 2H), 1.52 (dt, J = 32.8, 7.1 Hz, 5H), 1.26 (qd, J =7.7, 5.2, 3.8 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 174.78, 171.68, 169.31,155.78, 155.39, 142.45, 134.54, 129.36, 129.01, 128.98, 124.43, 122.74,114.01, 65.39, 56.75, 56.73, 42.81, 42.76, 37.23, 33.65, 32.24, 29.30, 29.09,22.73, 22.03, 18.68, 16.27, 15.64, 13.95.
实施例24
(Z)-7-(5-(6-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(6-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300MHz, DMSO-d 6) δ 10.35 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 7.92 (s,1H), 7.49 (t, J = 8.3 Hz, 1H), 7.25 – 7.11 (m, 2H), 3.91 (s, 3H), 3.61 (t, J= 7.2 Hz, 2H), 2.25 (d, J = 7.9 Hz, 0H), 1.94 (t, J = 7.3 Hz, 2H), 1.51 (dq,J = 21.4, 7.1 Hz, 5H), 1.26 (p, J = 3.7 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ169.49, 167.74, 166.01, 155.26, 132.99, 129.02, 128.35, 126.67, 126.52,124.75, 62.38, 42.08, 32.61, 28.55, 27.42, 26.31, 25.40.
实施例25
(Z)-N-羟基-7-(5-(2-甲氧基-4-甲基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2-甲氧基-4-甲基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1HNMR (400 MHz, DMSO-d 6) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.31 (d,J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 7.9 Hz, 1H), 5.75 (s, 0H), 3.88(s, 3H), 3.61 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.24 (d, J = 8.4 Hz, 0H),1.93 (t, J = 7.3 Hz, 2H), 1.50 (dt, J = 31.3, 7.0 Hz, 4H), 1.28 – 1.20 (m,4H).13C NMR (101 MHz, DMSO-d 6) δ 169.57, 168.10, 166.31, 158.52, 143.98,129.20, 128.25, 122.24, 120.36, 119.09, 113.05, 60.25, 56.19, 41.83, 32.61,28.53, 27.45, 26.29, 25.40, 22.03, 21.22, 14.54.
实施例26
(Z)-7-(5-(4-氟-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-氟-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(300 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 7.99 (s, 1H), 7.47 (dd, J =8.7, 6.6 Hz, 1H), 7.11 (dd, J = 11.3, 2.4 Hz, 1H), 6.96 (td, J = 8.4, 2.4 Hz,1H), 3.92 (s, 3H), 3.62 (t, J = 7.1 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.51(dt, J = 24.1, 7.0 Hz, 4H), 1.31 – 1.19 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ169.49, 167.93, 166.19, 160.30, 160.20, 131.19, 131.07, 127.25, 121.53,118.57, 108.52, 108.30, 101.13, 100.87, 56.93, 41.92, 32.61, 28.55, 27.44,26.30, 25.40.
实施例27
(Z)-7-(5-(2,4-二甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(2,4-二甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR(300 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 8.03 (s, 1H), 7.37 (d, J =8.4 Hz, 1H), 6.71 (d, J = 8.5 Hz, 2H), 3.88 (d, J = 15.3 Hz, 6H), 3.61 (t, J= 7.1 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.51 (dt, J = 22.4, 7.2 Hz, 5H),1.30 – 1.19 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 168.12, 166.38,163.74, 160.33, 130.88, 128.14, 118.18, 114.68, 107.06, 99.15, 56.42, 56.15,41.78, 32.62, 28.56, 27.49, 26.31, 25.41.
实施例28
(Z)-N-羟基-7-(5-(萘-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(萘-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.35 (s, 1H), 8.67 (s, 1H), 8.33 (s, 0H), 8.22 (s, 1H), 8.06 (d,J = 7.6 Hz, 3H), 7.98 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.62 (p,J = 6.6 Hz, 2H), 7.02 (s, 0H), 3.65 (t, J = 7.1 Hz, 2H), 2.26 (s, 0H), 1.94(t, J = 7.3 Hz, 2H), 1.76 (s, 0H), 1.63 – 1.54 (m, 2H), 1.48 (q, J = 7.0 Hz,2H), 1.27 (t, J = 5.4 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.52, 167.85,166.15, 133.80, 133.31, 133.19, 131.56, 131.03, 129.48, 129.22, 128.57,128.18, 127.65, 126.44, 122.04, 42.00, 32.62, 28.56, 27.45, 26.32, 25.42.
实施例29
(Z)-7-(2,4-二氧代-5-(喹啉-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-2-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300 MHz,DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.17 – 8.05(m, 2H), 7.99 (dd, J = 17.3, 8.2 Hz, 2H), 7.85 (t, J = 7.7 Hz, 1H), 7.68 (t,J = 7.5 Hz, 1H), 3.64 (t, J = 7.1 Hz, 2H), 2.26 (s, 0H), 1.94 (t, J = 7.3 Hz,2H), 1.53 (dt, J = 28.2, 7.0 Hz, 4H), 1.27 (d, J = 5.7 Hz, 4H).13C NMR (101MHz, DMSO-d 6) δ 169.50, 167.50, 165.90, 152.07, 147.80, 136.76, 135.59,131.92, 129.93, 129.59, 129.23, 128.16, 127.50, 126.98, 124.16, 42.13, 32.62,28.56, 27.44, 26.32, 25.43./>
实施例30
(Z)-7-(2,4-二氧代-5-(喹啉-7-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-7-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.35 (s, 1H), 9.02 – 8.96 (m, 1H), 8.68 (s, 1H), 8.42 (d, J = 8.3Hz, 1H), 8.26 (s, 1H), 8.16 – 8.09 (m, 2H), 7.82 (dd, J = 8.5, 1.8 Hz, 1H),7.62 (dd, J = 8.3, 4.2 Hz, 1H), 3.66 (t, J = 7.2 Hz, 2H), 2.26 (s, 0H), 1.94(t, J = 7.4 Hz, 2H), 1.60 (q, J = 7.0 Hz, 2H), 1.49 (p, J = 7.1 Hz, 2H), 1.33– 1.23 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.46, 167.61, 166.02, 152.34,147.83, 136.37, 134.50, 132.64, 131.50, 129.79, 129.08, 127.39, 123.65,123.38, 42.09, 32.62, 28.57, 27.45, 26.32, 25.42.
实施例31
(Z)-7-(2,4-二氧代-5-(喹啉-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-3-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400MHz, DMSO-d 6) δ 10.36 (s, 1H), 9.13 (d, J = 2.3 Hz, 1H), 9.02 (s, 1H), 8.62(s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.20 – 8.09 (m, 2H), 8.06 (d, J = 8.4 Hz,1H), 7.87 (ddd, J = 8.4, 6.7, 1.4 Hz, 1H), 7.74 – 7.65 (m, 2H), 7.03 (s, 1H),3.66 (t, J = 7.2 Hz, 2H), 2.26 (t, J = 7.4 Hz, 0H), 1.94 (t, J = 7.4 Hz, 2H),1.54 (dp, J = 41.0, 7.1 Hz, 5H), 1.36 – 1.19 (m, 5H).13C NMR (101 MHz, DMSO-d 6) δ 169.49, 168.01, 166.01, 158.03, 134.85, 133.09, 127.64, 127.35, 122.37,120.07, 111.32, 56.27, 41.92, 32.62, 28.54, 27.48, 26.36, 25.42.
实施例32
(Z)-7-(2,4-二氧基-5-(喹啉-6-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-6-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.35 (s, 1H), 8.98 (d, J = 4.1 Hz, 1H), 8.68 (s, 1H), 8.50 (d, J= 8.3 Hz, 1H), 8.26 (s, 1H), 8.17 – 8.06 (m, 2H), 8.00 – 7.92 (m, 1H), 7.62(dd, J = 8.3, 4.2 Hz, 1H), 3.66 (t, J = 7.2 Hz, 2H), 2.27 (d, J = 8.6 Hz,0H), 1.94 (t, J = 7.3 Hz, 2H), 1.54 (dp, J = 40.8, 7.1 Hz, 5H), 1.31 – 1.13(m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.46, 167.75, 166.08, 152.77, 148.23,137.32, 132.47, 131.61, 131.26, 130.51, 130.39, 128.33, 123.12, 122.98,42.06, 32.61, 28.56, 27.44, 26.32, 25.42.
实施例33
(Z)-7-(5-((2,3-二氢苯并呋喃-5-基)亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-6-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1HNMR (300 MHz, DMSO-d 6) δ 10.35 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H),7.86 (s, 1H), 7.54 – 7.37 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.63 (t, J = 8.7Hz, 2H), 3.62 (t, J = 7.1 Hz, 2H), 3.26 (t, J = 8.7 Hz, 2H), 1.93 (t, J = 7.3Hz, 2H), 1.59 – 1.42 (m, 5H), 1.26 (q, J = 4.1, 3.6 Hz, 5H).13C NMR (101 MHz,DMSO-d 6) δ 169.49, 167.88, 166.29, 162.55, 133.90, 132.42, 129.71, 127.55,125.98, 117.56, 110.41, 72.51, 41.84, 32.61, 29.04, 28.55, 27.48, 26.31,25.41.
实施例34
(Z)-7-(5-(苯并[d][1,3]二氧唑-5-基亚甲基)-2,4-二氧杂噻唑啉-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(苯并[d][1,3]二羟基-5-基亚甲基)-2,4-二氧杂噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 8.48 (d,J = 8.4 Hz, 1H), 8.15 – 8.05 (m, 2H), 7.99 (dd, J = 24.0, 8.2 Hz, 2H), 7.84(t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 3.64 (t, J = 7.2 Hz, 2H), 2.26(s, 0H), 1.94 (t, J = 7.4 Hz, 2H), 1.58 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.2Hz, 2H), 1.27 (dd, J = 6.9, 3.4 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 172.01,169.50, 166.30, 152.24, 147.34, 137.88, 131.18, 128.89, 128.74, 128.51,128.33, 128.06, 127.50, 124.95, 41.21, 32.62, 28.57, 27.55, 26.34, 25.44.
实施例35
(Z)-7-(2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(吡啶-3-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.33 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.68 – 8.61 (m, 2H), 8.03– 7.95 (m, 2H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 3.65 (t, J = 7.2 Hz, 2H),2.28 – 2.21 (m, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.52 (dq, J = 38.6, 6.9 Hz,5H), 1.27 (qd, J = 7.5, 5.0, 3.5 Hz, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.49,167.41, 165.85, 151.81, 151.17, 136.56, 130.00, 129.62, 124.70, 124.12,42.12, 32.61, 28.55, 27.41, 26.29, 25.41.
实施例36
(Z)-7-(2,4-二氧代-5-(喹啉-8-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(喹啉-8-亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.34 (d, J = 1.5 Hz, 1H), 9.08 – 8.97 (m, 2H), 8.66 (d, J = 1.7Hz, 1H), 8.49 (dd, J = 8.3, 1.8 Hz, 1H), 8.16 (dd, J = 8.2, 1.3 Hz, 1H), 7.95(dd, J = 7.4, 1.2 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.69 (dd, J = 8.3, 4.2Hz, 1H), 3.66 (t, J = 7.2 Hz, 2H), 2.27 (s, 0H), 1.94 (t, J = 7.4 Hz, 2H),1.53 (dq, J = 41.5, 7.2, 6.8 Hz, 5H), 1.28 (p, J = 3.6 Hz, 4H).13C NMR (101MHz, DMSO-d 6) δ 169.50, 168.38, 166.30, 151.00, 145.84, 137.45, 131.64,131.26, 130.64, 129.59, 128.63, 127.11, 123.56, 123.00, 60.22, 41.92, 32.63,28.58, 27.49, 26.34, 25.43, 14.55.
实施例37
(Z)-7-(2,4-二氧代-5-(噻吩-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(噻吩-2-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.37 (s, 1H), 8.70 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 4.9 Hz,1H), 7.71 (d, J = 3.6 Hz, 1H), 7.30 (dd, J = 5.0, 3.7 Hz, 1H), 3.61 (t, J =7.2 Hz, 2H), 2.25 (t, J = 7.5 Hz, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.51 (dt, J= 33.6, 7.0 Hz, 4H), 1.30 – 1.20 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.58,167.11, 165.87, 137.56, 135.46, 133.93, 129.49, 126.68, 119.09, 60.25, 42.08,32.60, 28.53, 27.45, 26.28, 25.40, 21.22, 14.54.
实施例38
(Z)-7-(5-(呋喃-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z) -7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(2,4-二氧代-5-(呋喃-2-基亚甲基)噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.07 (d, J = 1.7 Hz, 1H), 7.74 (s,1H), 7.14 (d, J = 3.5 Hz, 1H), 6.76 (dd, J = 3.5, 1.8 Hz, 1H), 3.60 (t, J =7.2 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.50 (dt, J = 30.9, 7.2 Hz, 4H), 1.28– 1.19 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ 169.58, 168.53, 165.92, 149.68,148.20, 119.84, 119.62, 118.43, 114.09, 60.25, 41.78, 32.59, 28.52, 27.46,26.27, 25.40, 21.22, 14.54.
实施例39
(Z)-N-羟基-7-(5-(4-甲氧基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-甲氧基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400MHz, DMSO-d 6) δ 10.37 (s, 1H), 8.70 (s, 1H), 7.84 (s, 0H), 7.76 (s, 1H), 7.60(d, J = 8.4 Hz, 2H), 7.18 (s, 0H), 7.12 (d, J = 8.5 Hz, 2H), 4.00 (t, J = 7.4Hz, 2H), 3.84 (s, 3H), 1.93 (t, J = 7.4 Hz, 2H), 1.61 (p, J = 7.2 Hz, 2H),1.47 (t, J = 7.2 Hz, 2H), 1.30 – 1.22 (m, 4H).13C NMR (101 MHz, DMSO-d 6) δ193.68, 169.58, 167.49, 162.00, 133.67, 133.41, 125.98, 119.47, 115.63,60.25, 56.06, 44.60, 32.59, 28.57, 26.71, 26.36, 25.40, 14.54.
实施例40
(Z)-7-(5-(4-氯亚苄基)-4-氧代-2-硫杂噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-氯亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (400 MHz,DMSO-d 6) δ 10.37 (s, 1H), 8.70 (s, 1H), 7.79 (s, 1H), 7.63 (q, J = 8.4 Hz,4H), 4.00 (t, J = 7.4 Hz, 2H), 2.25 (s, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.61(p, J = 7.9, 7.4 Hz, 2H), 1.47 (t, J = 7.2 Hz, 2H), 1.35 – 1.19 (m, 5H).13CNMR (101 MHz, DMSO-d 6) δ 193.64, 169.57, 167.36, 136.06, 132.69, 132.32,131.93, 130.04, 123.62, 60.25, 44.70, 32.59, 28.57, 26.69, 26.35, 25.39,21.22, 14.54.
实施例41
(Z)-N-羟基-7-(5-(4-甲基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-甲基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300 MHz,DMSO-d 6) δ 10.35 (s, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.54 (d, J = 7.8 Hz,2H), 7.38 (d, J = 7.8 Hz, 2H), 4.01 (t, J = 7.4 Hz, 2H), 2.37 (s, 3H), 2.25(s, 0H), 1.93 (t, J = 7.3 Hz, 2H), 1.61 (q, J = 7.3 Hz, 2H), 1.48 (p, J = 7.4Hz, 2H), 1.28 (s, 5H).
实施例42
(Z)-7-(5-(4-乙基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)-N-羟基庚酰胺,结构式如下:合成方法:将实施例1中步骤4中的片段(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)庚酸改为(Z)-7-(5-(4-乙基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酸,其他步骤及操作同实施例1;白色固体,收率:25 %。1H NMR (300 MHz,DMSO-d 6) δ 10.35 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 1.7 Hz, 1H), 7.79 (s, 1H),7.57 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.08 – 3.95 (m, 2H), 2.67(q, J = 7.6 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.62 (s, 2H), 1.54 – 1.42 (m,2H), 1.32 – 1.14 (m, 8H).13C NMR (101 MHz, DMSO-d 6) δ 193.88, 169.48, 167.46,148.02, 133.56, 131.35, 131.01, 129.47, 121.66, 44.65, 32.60, 28.63, 28.59,26.72, 26.38, 25.41, 15.61.
实施例43
(Z) -N-(2-氨基-4-氟苯基)-4-((2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)甲基)苯甲酰胺,结构式如下:按顺序在 100 mL 圆底烧瓶中加入噻唑烷酮(5mmol,585.6 mg)、醋酸(10 mL)、3-吡啶甲醛(5 mmol, 530.6mg),120 ℃回流搅拌反应 8h。冷却至室温,有固体析出,抽滤烘干滤饼,为白色固体 820 mg,取白色固体于圆底烧瓶中,加入DMF 10 mL作为溶剂,再加入1.5 eq碳酸钾(6 mmol),冰浴预搅拌30min,移除冰浴待反应升温至室温,加入2 eq4-溴甲基苯甲酸甲酯,搅拌反应8 h,后用水以及乙酸乙酯萃取,取有机层浓缩,经以石油醚:乙酸乙酯体积比为3:1的混合溶剂作为洗脱剂柱层析洗脱,分离得到乳白色固体。取2 mmol乳白色固体加入3 mL冰醋酸、0.5 mL浓盐酸(10 M),加热至90 ℃搅拌反应,用TLC监测反应进程,待原料消失,冷却反应液,向其中缓慢滴入饱和氯化钠水溶液,有固体析出,过滤并用水洗涤3遍滤饼,干燥得到白色粗品。将此白色粗品溶于5mlDMF,加入DIPEA(0.15mmol,20mg)、HATU(0.15mmol,57mg)和对氟邻苯二胺(40mg,0.3mmol),室温搅拌6h,将反应液浓缩,经以二氯甲烷:甲醇体积比为25:1的混合溶剂作为洗脱剂柱层析洗脱,得到(Z) -N-(2-氨基-4-氟苯基)-4-((2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)甲基)苯甲酰胺,白色固体,收率32%。1H NMR (400 MHz, DMSO-d 6)δ 9.59 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.66 (dd, J = 4.8, 1.5 Hz, 1H),8.21 – 7.87 (m, 4H), 7.59 (dd, J = 8.0, 4.8 Hz, 1H), 7.45 (dd, J = 8.5, 1.9Hz, 2H), 7.11 (dd, J = 8.7, 6.4 Hz, 1H), 6.54 (dd, J = 11.2, 2.9 Hz, 1H),6.35 (td, J = 8.5, 2.9 Hz, 1H), 5.23 (s, 2H), 4.94 (s, 2H).
通过以下实验来说明本发明通式代表的化合物所具有的有益效果和应用。
针对本发明抑制剂进行HDAC1激酶抑制实验:
本发明化合物的HDAC1激酶的抑制活性使 用ADP-Glo Luminescent KinaseAssay法测试,具体的实验参照参考文献(Eur .J .Med .Chem .,2020 , 204 ,112637 ;Eur .J .Med .Chem .,2022 ,229 ,114055)。激酶反应用到的试剂如下:HEPES (50 mM)pH 7.5 with NaCl (100 mM), EGTA (1.0 mM), MgCl2 (3.0 mM), DTT (2.0 mM)及CHAPS(0.03 %)。反应过程中,每10 mL含不同浓度的受试化合物(0.05 nM-1.0 μM)中加入50 μMPIP2及25 μM ATP。反应体系在室温下孵育1 h,然后加入10 μL试剂ADP-Glo终止酶反应。数据收集使用Envision软件,并使用Graphpad Prism 5分析及拟合化合物的IC50值。
表1 实施例化合物的HDAC1酶抑制活性(IC50,nM)
实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 |
3.2 | 6.1 | 2.5 | 2.1 | 4.0 | 5.0 | 6.7 |
实施例8 | 实施例9 | 实施例10 | 实施例11 | 实施例12 | 实施例13 | 实施例14 |
3.3 | 2.2 | 3.5 | 3.6 | 4.8 | 2.6 | 3.9 |
实施例16 | 实施例17 | 实施例18 | 实施例19 | 实施例20 | 实施例21 | 实施例22 |
1.9 | 2.6 | 2.8 | 4.1 | 2.4 | 3.2 | 4.4 |
实施例23 | 实施例24 | 实施例25 | 实施例26 | 实施例27 | 实施例28 | 实施例29 |
2.3 | 3.4 | 3.6 | 2.4 | 3.0 | 3.4 | 2.5 |
实施例30 | 实施例31 | 实施例32 | 实施例33 | 实施例34 | 实施例35 | 实施例36 |
5.6 | 4.2 | 1.8 | 1.9 | 2.3 | 10 | 1.3 |
实施例37 | 实施例38 | 实施例40 | 实施例41 | 实施例42 | Vorinostat | Tucidinostat |
3.1 | 4.2 | 11 | 8.5 | 31 | 15.0 | 122.1 |
。
全部实施例的HDAC1激酶抑制活性见表1。从表中可看出,大部分化合物对HDAC1激酶具有纳摩尔水平抑制活性,且大部分化合物显著优于阳性对照Vorinostat。特别地,实施例16、32、33、36对HDAC1激酶的抑制活性明显优于阳性对照Vorinostat。由此说明,本发明实施例化合物为高效的HDAC1抑制剂。
该实验采用MTT法测定,具体实施步骤为:取对数生长期的肿瘤细胞,用EDTA-胰酶将细胞消化分散,用PBS洗去胰酶,用培养基制成单细胞悬液后,配成2000个细胞每100 μL培养基,加入96孔板中,每孔100 μL,放入培养箱24 h等待细胞贴壁生长。设立空白组、阴性对照组(DMSO)与给药组,每孔补100 μL培养基并达到对应浓度,再将细胞于培养箱中培养96 h。后于避光条件下每孔加入10 μL MTT溶液(5 mg/mL),在培养箱中继续孵育4 h,用移液器小心移去各孔中上清液,并加入150 μL DMSO,震荡摇匀。用Molecular Devices ID5多功能酶标仪,在 570 nm处的检测各孔吸光度值,结果按照公式计算并使用Graphad Grism拟合IC50,抑制率(%) = [1-(实验组OD值-空白组OD值)/(阴性对照组OD值-空白组OD值)]× 100%。
表2 实施例化合物的肿瘤细胞株增值抑制活性(IC50,μM)
实施例 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 | 实施例8 |
A549 | 3.10 | 5.36 | 6.44 | 4.71 | 4.31 | 3.67 | 1.61 | 3.62 |
DU145 | 0.51 | 1.23 | 0.86 | 0.84 | 1.22 | 1.29 | 1.05 | 1.64 |
实施例 | 实施例9 | 实施例10 | 实施例11 | 实施例12 | 实施例13 | 实施例14 | 实施例15 | 实施例16 |
A549 | 1.34 | 1.37 | 1.60 | 5.37 | 1.52 | 3.36 | 5.64 | 4.00 |
DU145 | 0.50 | 0.29 | 1.09 | 4.19 | 0.29 | 0.50 | 3.81 | 1.05 |
实施例 | 实施例17 | 实施例18 | 实施例19 | 实施例20 | 实施例21 | 实施例22 | 实施例23 | 实施例24 |
A549 | 1.50 | 1.56 | 2.28 | 2.51 | 3.78 | 5.96 | 2.82 | 7.52 |
DU145 | 3.57 | 0.74 | 0.97 | 0.53 | 2.00 | 1.97 | 1.27 | 3.26 |
实施例 | 实施例25 | 实施例26 | 实施例27 | 实施例28 | 实施例29 | 实施例30 | 实施例31 | 实施例32 |
A549 | 2.00 | 2.71 | 0.91 | 2.44 | 0.55 | 1.07 | 3.83 | 10.08 |
DU145 | 1.15 | 0.93 | 0.74 | 1.39 | 6.56 | <0.10 | 2.10 | 2.40 |
实施例 | 实施例33 | 实施例34 | 实施例35 | 实施例36 | 实施例37 | 实施例38 | 实施例39 | 实施例40 |
A549 | 2.08 | 2.47 | 10.91 | 2.69 | 2.32 | 1.26 | 3.09 | 5.65 |
DU145 | 9.18 | 1.06 | 3.18 | 0.22 | 0.33 | 0.16 | 2.46 | 3.62 |
实施例 | 实施例41 | 实施例42 | Vorinostat | Tucidinostat | ||||
A549 | 2.98 | 2.70 | 1.62 | 9.85 | ||||
DU145 | 3.31 | 3.64 | 0.64 | 1.62 |
。
表2为实施例化合物对两种肿瘤细胞株的抗增殖活性。从中可看出,实施例化合物对两种肿瘤细胞株都具有微摩尔水平的增殖抑制活性,特别大部分实施例化合物对人前列腺癌细胞株DU145具有较高的敏感性。其中,实施例1等10个化合物对表2中DU145的抑制活性小于0.64 μM,而实施例27和29,对表2中人非小细胞肺癌细胞株A549表现出亚微摩尔水平抑制活性,这些都优于阳性对照Vorinostat;特别地,实施例30对表2中的DU145,具有纳摩尔水平抑制活性,对其的抑制活性小于100 nM,显著优于阳性对照Vorinostat。由此可见,本发明实施例化合物可潜在用于临床治疗时上述肿瘤药物的研究。
综上,本发明所保护化合物为HDAC1抑制剂,可通过对HDAC1的高效抑制多种实体瘤与血液瘤细胞的增殖,对前列腺癌具有较高的敏感性,可潜在用于其临床治疗。
除上述实施外,本发明还可以有其他实施方式。凡采用等同替换或等效变换形成的技术方案,均落在本发明要求的保护范围。
Claims (13)
1.一种噻唑烷二酮类HDAC抑制剂,包括具有通式的取代噻唑烷二酮类化合物,或其立体异构体、水合物或药学上可接受的盐,所述通式结构如下,其中,W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地可任选被R2取代,R2可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、芳基或Het;
Q选自长度为1-9个碳原子的饱和或不饱和直链或支链烃基,芳基或Het;
R1选自羟基、可任选被一个或多个R3取代的2-氨基苯基;
R3可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、芳基或Het;
烷基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
烷氧基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-9个碳原子的环状饱和烃基;或为连接具有1-9个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
烷氨基为具有1-9个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-9个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被NH原子团取代;
烷氧基烷基如上定义的烷氧基与烷基连接;
烯基、炔基为具有1-9个碳原子的直链或支链的含有双键或三键的不饱和烃基;
芳基为选自苯基、萘基、苊基或四氢萘基的碳环,其各自任选被1、2或3个取代基取代,各取代基独立地选自氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het ;
芳烷基、二芳基烷基为如上定义的芳基与烷基连接;
Het为选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环;或选自3-6个碳原子的单环饱和烃基、6-12个碳原子的双环饱和烃基,其中环上的碳原子独立任选地被1-4个O、S、N或NH取代;各单环或双环任选被1、2或3个取代基取代,各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基;卤素为选自氟、氯、溴或碘的取代基;
卤代烷基为具有1-9个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代。
2.根据权利要求1所述噻唑烷二酮类HDAC抑制剂,其特征在于:
所述通式V中W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地任选被R2取代,R2是氢、烷基、氰基、卤素、卤代烷基、烷氧基、烷硫基、烷氧基烷基;
Q是选自长度为1-9个碳原子的饱和或不饱和直链或支链烃基、芳基;
R1选自羟基、任选被一个或多个R3取代的2-氨基苯基;
R3可以是氢、烷基、氰基、卤素、卤代烷基、羟基基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、芳基或Het。
3.根据权利要求1所述噻唑烷二酮类HDAC抑制剂,其特征在于:
所述通式V中W选自氧原子或硫原子;X、Y、Z、M1、M2各自独立地表示碳或者氮原子,当X、Y、Z、M1、M2为碳原子时,各自独立地任选被R2取代,R2是氢、烷基、卤素、烷氧基;
Q是选自长度为3-9个碳原子的饱和或不饱和直链或支链烃基、芳基;
R1选自羟基、任选被一个或多个R3取代的2-氨基苯基;
R3是氢、烷基、氰基、卤素、卤代烷基、芳基或Het。
4.根据权利要求1所述噻唑烷二酮类HDAC抑制剂,其特征在于:所述通式中与碳相连的氢被替换为氢的同位素氘。
5.根据权利要求2所述噻唑烷二酮类HDAC抑制剂,其特征在于:烷基被氘代烷基替换,烷氧基被氘代环氧基替换,苯环被氘代苯环替换,芳环被氘代芳环替换。
6.根据权利要求1所述噻唑烷二酮类HDAC抑制剂,其特征在于:所述噻唑烷二酮类HDAC抑制剂的结构包含以下结构:
(1)(Z)-7-(5-亚苄基-2,4-二氧代噻唑烷-3-基)-N-羟基庚酰胺;
(2)(Z)-7-(5-(2-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(3)(Z)-7-(5-(3-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(4)(Z)-7-(5-(4-氯亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(5)(Z)-7-(5-(2-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(6)(Z)-7-(5-(3-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(7)(Z)-7-(5-(4-溴亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(8)(Z)-7-(5-(4-氟亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(9)(Z)-N-羟基-7-(5-(3-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(10)(Z)-N-羟基-7-(5-(4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(11)(Z)-3-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯;
(12)(Z)-4-((3-(7-(羟基氨基)-7-氧庚基)-2,4-二氧杂噻唑烷-5-亚基)甲基)苯甲酸甲酯;
(13)(Z)-7-(5-(4-氨基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(14)(Z)-7-(5-(2-乙氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(15)(Z)-N-羟基-7-(5-(4-异丙基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(16)(Z)-7-(5-(4-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(17)(Z)-7-(5-(5-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(18)(Z)-7-(5-(3-溴-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(19)(Z)-7-(5-(2-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(20)(Z)-7-(5-(3-溴-4-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(21)(Z)-7-(5-(3-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(22)(Z)-7-(5-(4-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(23)(Z)-7-(5-(5-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(24)(Z)-7-(5-(6-氯-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(25)(Z)-N-羟基-7-(5-(2-甲氧基-4-甲基亚苄基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(26)(Z)-7-(5-(4-氟-2-甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(27)(Z)-7-(5-(2,4-二甲氧基亚苄基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(28)(Z)-N-羟基-7-(5-(萘-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)庚酰胺;
(29)(Z)-7-(2,4-二氧代-5-(喹啉-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(30)(Z)-7-(2,4-二氧代-5-(喹啉-7-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(31)(Z)-7-(2,4-二氧代-5-(喹啉-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(32)(Z)-7-(2,4-二氧基-5-(喹啉-6-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(33)(Z)-7-(5-((2,3-二氢苯并呋喃-5-基)亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(34)(Z)-7-(5-(苯并[d][1,3]二氧唑-5-基亚甲基)-2,4-二氧杂噻唑啉-3-基)-N-羟基庚酰胺;
(35)(Z)-7-(2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(36)(Z)-7-(2,4-二氧代-5-(喹啉-8-亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(37)(Z)-7-(2,4-二氧代-5-(噻吩-2-基亚甲基)噻唑烷-3-基)-N-羟基庚酰胺;
(38)(Z)-7-(5-(呋喃-2-基亚甲基)-2,4-二氧杂噻唑烷-3-基)-N-羟基庚酰胺;
(39)(Z)-N-羟基-7-(5-(4-甲氧基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺;
(40)(Z)-7-(5-(4-氯亚苄基)-4-氧代-2-硫杂噻唑烷-3-基)-N-羟基庚酰胺;
(41)(Z)-N-羟基-7-(5-(4-甲基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)庚酰胺;
(42)(Z)-7-(5-(4-乙基亚苄基)-4-氧代-2-硫代噻唑烷-3-基)-N-羟基庚酰胺;
(43)(Z) -N-(2-氨基-4-氟苯基)-4-((2,4-二氧基-5-(吡啶-3-基亚甲基)噻唑烷-3-基)甲基)苯甲酰胺。
7.根据权利要求6所述噻唑烷二酮类HDAC抑制剂的制备方法,其特征在于:所述噻唑烷二酮类HDAC抑制剂(1-15)的制备方法包括以取代苯甲醛(1a-1o)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(2a-2o);中间体(2a-2o)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(3a-3o);中间体(3a-3o)在酸性条件下发生水解反应得到中间体(4a-4o);中间体(4a-4o)与盐酸羟胺缩合反应得到目标化合物(1-15),制备路线如下:
。
8.根据权利要求6所述噻唑烷二酮类HDAC抑制剂的制备方法,其特征在于:所述噻唑烷二酮类HDAC抑制剂(16-27)的制备方法包括以多取代苯甲醛(6a-6I)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(7a-7I);中间体(7a-7I)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(8a-8I);中间体(8a-8I)在酸性条件下发生水解反应得到中间体(9a-9I);中间体(9a-9I)与盐酸羟胺缩合反应得到目标化合物(16-27),制备路线如下:
。
9.根据权利要求6所述噻唑烷二酮类HDAC抑制剂的制备方法,其特征在于:所述噻唑烷二酮类HDAC抑制剂(28-38)的制备方法包括以芳香醛(11a-11k)和噻唑烷二酮为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(12a-12k);中间体(12a-12k)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(13a-13k);中间体(13a-13k)在酸性条件下发生水解反应得到中间体(14a-14k);中间体(14a-14k)与盐酸羟胺缩合反应得到目标化合物(28-38),制备路线如下:
。
10.根据权利要求6所述噻唑烷二酮类HDAC抑制剂的制备方法,其特征在于:所述噻唑烷二酮类HDAC抑制剂(39-42)的制备方法包括对位取代苯甲醛(16a-16d)和罗丹宁为原料,在β-丙氨酸的作用下发生Knoevenagel缩合反应得到中间体(17a-17d);中间体(17a-17d)与7-溴代庚酸乙酯发生亲核取代反应,得到关键中间体(18a-18d);中间体(18a-18d)在酸性条件下发生水解反应得到中间体(19a-19d);中间体(19a-19k)与盐酸羟胺缩合反应得到目标化合物(39-42),制备路线如下:
。
11. 一种药物组合物,其包含权利要求 1 ~ 6 中任一项所述化合物或其药学上可接受的盐和药学上可接受的载体,其中,权利要求 1 ~ 6 中任一项所述化合物或其药学上可接受的盐为活性成分。
12.权利要求1-6任一项所述化合物在制备用于预防或治疗与HDACs有关的临床病症的药物中的用途。
13.根据权利要求12所述化合物的用途,其特征在于:与HDACs有关的疾病是肺癌、黑色素瘤、肝癌、肾癌、白血病、前列腺癌、甲状腺癌、皮肤病、胰腺癌、卵巢癌、睾丸癌、乳腺癌、膀胱癌、胆囊癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、星型细胞瘤、神经母细胞瘤、神经胶质瘤、神经鞘瘤、间皮瘤、非胰岛素依赖型糖尿病、自身免疫性疾病。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410218999.0A CN117777049B (zh) | 2024-02-28 | 一种噻唑烷二酮类hdac抑制剂、制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410218999.0A CN117777049B (zh) | 2024-02-28 | 一种噻唑烷二酮类hdac抑制剂、制备方法及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117777049A true CN117777049A (zh) | 2024-03-29 |
CN117777049B CN117777049B (zh) | 2024-05-31 |
Family
ID=
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1997649A (zh) * | 2004-03-26 | 2007-07-11 | 梅特希尔基因公司 | 组蛋白脱乙酰基酶的抑制剂 |
US20130035304A1 (en) * | 2010-01-29 | 2013-02-07 | Walensky Loren D | Small molecules for the modulation of mcl-1 and methods of modulating cell death, cell division, cell differentiation and methods of treating disorders |
CN105884712A (zh) * | 2016-05-09 | 2016-08-24 | 中国药科大学 | 一种具有nedd8激活酶抑制活性的化合物、其制备方法及医药用途 |
CN108685916A (zh) * | 2017-04-05 | 2018-10-23 | 复旦大学附属华山医院 | 噻唑烷二酮类化合物双靶点治疗垂体生长激素腺瘤的用途 |
CN116554079A (zh) * | 2023-07-11 | 2023-08-08 | 南京市鸿舜医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂及用途 |
CN116693521A (zh) * | 2023-05-10 | 2023-09-05 | 五邑大学 | 一种含色酮结构的噻唑烷二酮乙酯类化合物及其制备方法、药物组合物和应用 |
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1997649A (zh) * | 2004-03-26 | 2007-07-11 | 梅特希尔基因公司 | 组蛋白脱乙酰基酶的抑制剂 |
US20130035304A1 (en) * | 2010-01-29 | 2013-02-07 | Walensky Loren D | Small molecules for the modulation of mcl-1 and methods of modulating cell death, cell division, cell differentiation and methods of treating disorders |
CN105884712A (zh) * | 2016-05-09 | 2016-08-24 | 中国药科大学 | 一种具有nedd8激活酶抑制活性的化合物、其制备方法及医药用途 |
CN108685916A (zh) * | 2017-04-05 | 2018-10-23 | 复旦大学附属华山医院 | 噻唑烷二酮类化合物双靶点治疗垂体生长激素腺瘤的用途 |
CN116693521A (zh) * | 2023-05-10 | 2023-09-05 | 五邑大学 | 一种含色酮结构的噻唑烷二酮乙酯类化合物及其制备方法、药物组合物和应用 |
CN116554079A (zh) * | 2023-07-11 | 2023-08-08 | 南京市鸿舜医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂及用途 |
Non-Patent Citations (6)
Title |
---|
CATHERINE ZINGLÉ ET AL.: "Catechol–rhodanine derivatives: Specific and promiscuous inhibitors of Escherichia coli deoxyxylulose phosphate reductoisomerase (DXR)", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 22, 14 May 2014 (2014-05-14), pages 3713 * |
LALITA DAHIYA ET AL.: "Validation of TZD Scaffold as Potential ARIs: Pharmacophore Modeling, Atom-Based 3D QSAR and Docking Studies", COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING, vol. 20, 31 December 2017 (2017-12-31), pages 310 - 320 * |
MARKUS SCHWEIPERT ET AL.: "Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4", PHARMACEUTICALS, vol. 14, 11 October 2021 (2021-10-11), pages 1 - 30 * |
NEHA UPADHYAY ET AL.: "Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation", BIOORGANIC CHEMISTRY, vol. 100, 15 May 2020 (2020-05-15), pages 1 - 15, XP086186304, DOI: 10.1016/j.bioorg.2020.103934 * |
ROSANNA MACCARI ET AL.: "Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2, 4-thiazolidinedione derivatives", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 16, 3 May 2008 (2008-05-03), pages 5840 - 5852, XP022700314, DOI: 10.1016/j.bmc.2008.04.072 * |
SWASTIKA GANGULY ET AL.: "Molecular docking studies of novel thiazolidinedione analogs as HIV-1-RT inhibitors", MED CHEM RES, vol. 22, 21 November 2012 (2012-11-21), pages 3350 - 3363 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102604876B1 (ko) | Mcl-1 억제제의 합성 | |
EP2468717B1 (en) | Heterocyclic Amide Compounds Useful as Kinase Inhibitors | |
CA2874110C (en) | Processes to produce certain 2-(pyridine-3-yl)thiazoles | |
US10611770B2 (en) | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof | |
JP5479105B2 (ja) | 新規ユビキリン結合性小分子 | |
JP7046968B2 (ja) | 2-(置換フェニルヘテロ)芳香族カルボン酸系fto阻害剤、その製造方法およびその使用 | |
CN101636397A (zh) | 脲类化合物、其制备方法及其医药用途 | |
PL205321B1 (pl) | Zastosowanie podstawionych heterocyklicznych moczników do wytwarzania leku do hamowania kinazy raf, podstawione heterocykliczne moczniki oraz kompozycja farmaceutyczna je zawierająca | |
CA2785204C (en) | Hedgehog inhibitors | |
JP2012507535A (ja) | 二置換フタラジンヘッジホッグ経路アンタゴニスト | |
DK2599774T3 (en) | DEHYDRATED pyridine AS CB2 cannabinoid receptor ligands | |
TW201625633A (zh) | 科帕利普(copanlisib)及其二鹽酸鹽之合成 | |
KR101827660B1 (ko) | 플루오로페닐 피라졸 화합물 | |
CN117777049B (zh) | 一种噻唑烷二酮类hdac抑制剂、制备方法及应用 | |
WO2011085261A1 (en) | Hedgehog inhibitors | |
JP2008519015A (ja) | 4,7−ジオキソベンゾチアゾール−2−カルボキサミド誘導体、それらの製造方法及びそれらの治療上の使用 | |
CN100420678C (zh) | 取代的苯并噻唑衍生物的环化方法 | |
WO2004106317A1 (ja) | ベンゾフラン化合物、およびそれを含有してなる医薬組成物 | |
CN117777049A (zh) | 一种噻唑烷二酮类hdac抑制剂、制备方法及应用 | |
KR102542698B1 (ko) | 신규한 벤조사이오펜 유도체 및 bet 억제제로서의 용도 | |
CN115703758B (zh) | 一类用作激酶抑制剂的化合物及其制备方法和用途 | |
CN110172058B (zh) | 7-氮杂螺[5.6]十二烷-10-酮类化合物及其制备方法与用途 | |
CN118026949A (zh) | 一种噻唑类组蛋白去乙酰化酶抑制剂及其制备方法与用途 | |
JP4328873B2 (ja) | 放射線増感剤 | |
Daha et al. | Syntheses of 1‐(4‐methylsulfonylphenyl)‐5‐aryl‐1, 2, 3‐triazoles and‐(4‐aminosulfonylphenyl)‐5‐aryl‐1, 2, 3‐triazoles |
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 |