CN111499611B - 吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 - Google Patents
吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 Download PDFInfo
- Publication number
- CN111499611B CN111499611B CN202010336234.9A CN202010336234A CN111499611B CN 111499611 B CN111499611 B CN 111499611B CN 202010336234 A CN202010336234 A CN 202010336234A CN 111499611 B CN111499611 B CN 111499611B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyridine
- pharmaceutically acceptable
- preparation
- hif
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 amino acid compound Chemical class 0.000 title abstract description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 208000007502 anemia Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 13
- 230000002103 transcriptional effect Effects 0.000 claims abstract description 13
- 102000008109 Mixed Function Oxygenases Human genes 0.000 claims abstract description 12
- 108010074633 Mixed Function Oxygenases Proteins 0.000 claims abstract description 12
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 208000023589 ischemic disease Diseases 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 230000005855 radiation Effects 0.000 claims description 10
- 230000006378 damage Effects 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000014509 gene expression Effects 0.000 abstract description 17
- 108090000623 proteins and genes Proteins 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 9
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 6
- 102000003951 Erythropoietin Human genes 0.000 abstract description 5
- 108090000394 Erythropoietin Proteins 0.000 abstract description 5
- 229940105423 erythropoietin Drugs 0.000 abstract description 5
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 abstract description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 abstract description 4
- 230000001105 regulatory effect Effects 0.000 abstract description 4
- 230000001950 radioprotection Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 239000012043 crude product Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 9
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- ULQWGBCNOHBNDB-MRVPVSSYSA-N n-(carboxycarbonyl)-d-phenylalanine Chemical compound OC(=O)C(=O)N[C@@H](C(=O)O)CC1=CC=CC=C1 ULQWGBCNOHBNDB-MRVPVSSYSA-N 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 6
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical group C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 5
- 229960004365 benzoic acid Drugs 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 208000019155 Radiation injury Diseases 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- BNJOZDZCRHCODO-UHFFFAOYSA-N dimethyloxalylglycine Chemical compound COC(=O)CNC(=O)C(=O)OC BNJOZDZCRHCODO-UHFFFAOYSA-N 0.000 description 3
- 230000003394 haemopoietic effect Effects 0.000 description 3
- 230000001146 hypoxic effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- SWVMLNPDTIFDDY-SBSPUUFOSA-N methyl (2r)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-SBSPUUFOSA-N 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- MNNQIBXLAHVDDL-UHFFFAOYSA-N 5-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)C=N1 MNNQIBXLAHVDDL-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000005758 transcription activity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GODZNYBQGNSJJN-UHFFFAOYSA-N 1-aminoethane-1,2-diol Chemical compound NC(O)CO GODZNYBQGNSJJN-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- XURXQNUIGWHWHU-UHFFFAOYSA-N 6-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(Br)=N1 XURXQNUIGWHWHU-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108010040163 CREB-Binding Protein Proteins 0.000 description 1
- 102100021975 CREB-binding protein Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 101150002621 EPO gene Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 1
- 229940122439 Hydroxylase inhibitor Drugs 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical group C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005264 aryl amine group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical compound O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
- 238000012900 molecular simulation Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940124553 radioprotectant Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Toxicology (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及一类吡啶甲酰芳基(杂芳基)α位取代的氨基酸类化合物I，该类化合物具有选择性抑制天冬酰胺酰羟化酶活性，可以促进细胞内乏氧诱导因子(hypoxia‑inducible factor，HIF)的转录活性，促进乏氧诱导因子调控的下游基因包括促红细胞生成素(erythropotin，EPO)、血管内皮生长因子(vascular endothelial growth factor，VEGF)等基因的表达。本发明还涉及该类化合物的制备方法、含有所述化合物或其药学上可接受的盐的药物组合，以及所述化合物或其药学上可接受的盐在制备用于抑制天冬酰胺酰羟化酶的药物或制备治疗贫血、缺血性疾病以及辐射防护作用的药物中的用途。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类吡啶甲酰芳基(杂芳基)α位取代的氨基酸类化合物，该类化合物具有选择性抑制天冬酰胺酰羟化酶活性，可以增加细胞内乏氧诱导因子的转录活性(hypoxia-inducible factor，HIF)，促进乏氧诱导因子调控的下游基因包括促红细胞生成素(erythropotin,EPO)、血管内皮生长因子(vascular endothelialgrowth factor,VEGF)等基因的表达，可应用于治疗贫血、预防贫血等相关疾病以及通过增强乏氧诱导因子转录活性而起到的辐射防护作用。
背景技术
随着核能利用不断发展和放射治疗及同位素技术广泛应用，核与辐射事故发生的几率增加。辐射造成的急性损伤成为人员死亡的主要原因，临床上迫切需要使用辐射防护剂，特别是辐射损伤后的治疗药物。由于急性辐射损伤往往导致多组织、多器官损害，辐射损伤防治药物研制难度大。发现新的治疗靶点，研制作用机制明确、治疗效果确切的创新药物迫在眉睫。
乏氧诱导因子(hypoxia-inducible factor，HIF)是一种低氧条件下被激活的转录因子，由α亚基和β亚基组成。HIF-α是目前研究最清楚和氧浓度有关的蛋白。目前证实主要有两条途径调节HIF-α蛋白稳定性和转录活性。一是利用乏氧诱导因子抑制因子(factorinhibiting hypoxia-inducible factor,FIH)，将HIF-αC末端反式激活结构域内第803位的天冬氨酸残基羟基化，阻止HIF-α与转录辅助激活因子(CREB-binding protein,CBP/P300)结合，从而抑制HIF-α转录激活。二是通过脯氨酸羟化酶(proly hydroxylase,PHD)使HIF-α的第564位和402位的脯氨酸残基羟基化，并经泛素连接蛋白酶复合体途径降解。低氧情况下，FIH不能激活天冬氨酸残基羟基化，促进了HIF-α转录活性，启动低氧应激调控网络。HIF-α在红细胞产生、血管形成、糖能量代谢、细胞存活与凋亡以及肿瘤的发展、转移过程中发挥重要作用。文献报道表明稳定的表达HIF蛋白可预防并减轻辐射诱导的胃肠道毒性和造血功能障碍，FIH抑制剂能够减轻辐射引起的DNA损伤和凋亡，在辐射损伤的修复中发挥重要作用。
目前，减轻HIF-α降解的脯氨酸羟化酶(PHD)抑制剂研究较多，因其明显改善贫血并发症以及化疗药物导致的贫血，先后十余个化合物进入临床研究，其中FG-4592(FibroGen)已于2108年在中国上市。
针对FIH的抑制剂研究不多，并且主要集中于α-酮戊二酸竞争性抑制剂，这些化合物在活性和选择性方面存在不足。
因此，本发明基于氢原子转移抑制HIF-1α803N羟基化催化过程，实现活性抑制。根据PHD、FIH酶底物结合空腔深度与宽度存在差异，设计高选择性的FIH抑制剂，从化合物空间位阻上体现FIH与PHD选择性差异。本发明的FIH抑制剂具有更好的活性、选择性。
发明内容
本发明合成了一类吡啶甲酰芳基(杂芳基)α位取代的氨基酸类化合物，作为选择性天冬酰胺酰羟化酶抑制剂，其通过抑制FIH酶激活HIF-α的转录活性，从而促进其下游EPO、VEGF等基因的表达，可用于治疗与预防贫血以及预防并减轻辐射诱导的胃肠道毒性和造血功能损伤，本发明结构如下：
其中，R1选自：C1-C3侧链的芳基、C1-C3侧链的氨基取代芳基、C1-C3侧链的羟基取代芳基、C1-C3侧链的卤代芳基、C1-C3侧链的杂芳基、C1-C3侧链的氨基取代杂芳基、C1-C3侧链的羟基取代杂芳基、C1-C3侧链的卤代杂芳基。
进一步地，其中R1中的杂芳基是：环成员中含有1-3个任意选自N、O、S杂原子的芳基，杂原子可以相同，也可以不同。
L选自：C1-C3烯基、1,3取代三氮唑基；并且还有0-4个原子长度的连接链，链主链原子选自碳、氧原子。
进一步地，L位于R2与吡啶5位或6位原子之间。
R2选自：氢、卤素取代基、羟基、氨基、烷氧基、C5-C7含杂环烷烃取代基、芳基羧酸取代基、芳基酰胺基取代基、芳基胺取代基、芳基酚取代基、金刚烷取代基、金刚烷胺取代基。
更进一步地，R1可选自：
独立地，L可选自：
独立地，R2可选自：
具体地，本发明化合物I及其药学上可用的盐，选自：
本发明同时包括化合物(I)的药学上可接受的盐，也是本发明所主张的权利要求保护范围
本发明还提供通式I化合物和/或其可用盐或，在制备用于抑制天冬酰胺酰羟化酶来治疗该酶介导的疾病的药物中的用途，其可通过抑制天冬酰胺酰羟化酶达到治疗效果。
本发明还提供通式I化合物和/或其可用盐在制备促进HIF-α转录活性的药物中的应用。
本发明还提供通式I化合物和/或其可用盐在制备用于辐射损伤防护药物中的应用。
本发明还提供通式Ⅰ化合物和/或其可用盐在制备治疗贫血症、缺血性疾病药物中的应用。
在某些实验方案中，根据通式(I)的化合物可含足以形成盐的酸性官能团。选自的盐包括可药用金属盐如：钠、钾、锂、钙、镁、铝和锌盐；可药用金属阳离子如：钠、钾、锂、钙、镁、铝和锌的碳酸盐和碳酸氢盐；可药用有机伯胺、仲胺和叔胺，包括脂肪胺、芳香胺、脂肪二胺和羟基烷基胺，如甲胺、乙二胺、2-羟基乙基胺、二乙胺、三乙胺、乙醇胺、乙二醇胺。
本发明还提供了通式(I)的相关化合物可用下列方法制备：
其中R1、L以及R2的定义如前所述。
由2-吡啶甲酸衍生物与氨基酸衍生物在缩合剂条件下得到中间体1，其中催化剂可选HOBT，EDCI或DCC体系；中间体1在不同条件下链接R2生成中间体2，其中反应条件可为：Heck reaction，Husigen环加成反应(Copper-Catalyzed Azide–Alkyne Cycloaddition)等；最后中间体2经酯水解得通式I化合物。
本发明所述化合物具有天冬酰胺酰羟化酶抑制活性，能够有效激活HIF-α转录活性，从而促进了EPO和VEGF等基因的表达，可用于治疗和预防贫血以及预防和减轻辐射诱导的胃肠道毒性和造血功能损伤。
附图说明
图1为本发明部分化合物细胞水平的RT-PCR实验结果图；
图2为本发明部分化合物细胞水平的WT实验结果图；
图3为NOFD与FIH相互作用模式图；
图4为组织病理学染色结果图。
具体实施例
实施例1
Methyl(6-bromopicolinoyl)phenylalaninate(化合物I-1)：在室温搅拌下，将6-溴-2-吡啶羧酸(2.0g,9.9mmol,1.0eq)中加入20ml无水N,N-二甲基甲酰胺，随后依次加入EDCI(2.81g,14.7mmol,1.5eq)、HOBT(2.0g,14.8mmol,1.5eq)，然后再加入苯丙氨酸甲酯盐酸盐(3.2g,14.8mmol,1.5eq)最后加入TEA(7.0g,69mmol,7.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取3次，稀盐酸洗3次，饱和碳酸氢钠溶液洗3次，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1～石油醚：乙酸乙酯＝1:1)，得2.9g淡黄色固体，收率81％；；1H NMR(300MHz,DMSO)δ8.89(d,J＝8.2Hz,1H,-NH-),8.75(dd,J＝2.2,0.8Hz,1H,-pyridine-H),8.09(dd,J＝8.2,2.1Hz,1H,-pyridine-H),7.98(dd,J＝8.1,0.8Hz,1H,-pyridine-H),7.29–7.15(m,5H,-PhH),4.80(dd,J＝15.2,7.1Hz,1H,-CH-CH2-),4.68(s,1H,-CH),3.66(s,3H,-COOCH3),3.22(d,J＝7.1Hz,2H,-CH-CH2-)。
实施例2
Methyl(5-bromopicolinoyl)phenylalaninate(化合物I-2)：，在室温搅拌下，将5-溴-2-吡啶羧酸(2.81g,13.9mmol,1.5eq)中加入50ml无水二氯甲烷，随后依次加入EDCI(2.67g,13.9mmol,1.5eq)、HOBT(1.88g,13.9mmol,1.5eq)，然后再加入苯丙氨酸甲酯盐酸盐(2.0g,9.28mmol,1.0eq)最后加入TEA(6.7g,65mmol,7.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取，稀盐酸洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1～石油醚：乙酸乙酯＝1:1)，得2.28g淡黄色固体，收率68％；1H NMR(300MHz,DMSO)δ8.99(d,J＝8.2Hz,1H,-NH-),7.85(dd,J＝8.3,7.3Hz,1H,-pyridine-H),7.61(dd,J＝7.2,0.7Hz,1H,-pyridine-H),7.33–7.18(m,5H,-PhH),7.14(dd,J＝8.3,0.7Hz,1H,pyridine-H),,4.80(dd,J＝15.2,7.1Hz,1H,-CH-CH2-),4.68(s,1H,-CH),3.66(s,3H,-COOCH3),3.22(d,J＝7.1Hz,2H,-CH-CH2-)。
实施例3
Methyl(5-bromopicolinoyl)tyrosinate(化合物I-3)：，在室温搅拌下，将5-溴-2-吡啶羧酸(500mg,2.48mmol,1.0eq)中加入50ml无水二氯甲烷，随后依次加入EDCI(721mg,3.71mmol,1.5eq)、HOBT(502mg,3.71mmol,1.5eq)，然后再加入酪氨酸甲酯盐酸盐(860mg,3.71mmol,1.5eq)最后加入DIPEA(1.92g,14.9mmol,6.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取，稀盐酸洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1～石油醚：乙酸乙酯＝1:1)，得293mg淡黄色固体，收率32％；1H NMR(300MHz,DMSO)δ9.23(s,1H,-PhOH),8.83(d,J＝8.1Hz,1H,-NH-),8.80(d,J＝1.9Hz,1H,-pyridine-H),8.25(dd,J＝8.4,2.3Hz,1H,-pyridine-H),7.93(d,J＝8.3Hz,1H,-pyridine-H),7.00(d,J＝8.4Hz,2H,-PhHOH),6.63(d,J＝8.4Hz,2H,-PhHOH),4.71(q,J＝6.9Hz,1H,-CH-CH2-),3.65(s,3H),3.09(d,J＝6.9Hz,2H,-CH-CH2-)。
实施例4
Picolinoylphenylalanine(化合物I-4)：在室温搅拌下，将吡啶-2-甲酸(0.34g,2.76mmol,3.0eq)中加入5ml无水N,N-二甲基甲酰胺，随后依次加入EDCI(0.53g,2.76mmol,3.0eq)、HOBT(0.38g,2.76mmol,3.0eq)，然后再加入D-苯丙氨酸甲酯盐酸盐(0.2g,0.93mmol,1.0eq)最后加入DIPEA(0.6g,4.6mmol,5.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取，稀盐酸洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化，得0.3g黄色油状液体，直接投入下一步；
在室温搅拌下，将上一步(0.3g,1.06mmol,1.0eq)中加入5ml四氢呋喃，滴加1N氢氧化钠溶液(0.2g,5mmol,5.0eq)后强烈搅拌，反应3h(TLC检测反应终点)；减压旋除四氢呋喃，1N盐酸调节溶液PH值至1～2，乙酸乙酯萃取合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂得粗产物。粗产物通过快速硅胶柱纯化，得0.23g无色油状液体，收率80％。1H NMR(300MHz,DMSO)δ12.94(s,1H,-COOH),8.45(d,J＝8.0Hz,1H,-NH-),δ7.35(d,J＝7.3Hz,1H,-pyridine-H),7.31–7.17(m,2H,-pyridine-H),7.10(d,J＝8.3Hz,1H,-pyridine-H),4.70(m,1H,-CH-CH2-),2.92–2.69(m,2H,-CH-CH2-)。
实施例5：
(6-methoxypicolinoyl)phenylalanine(化合物I-5)：在室温搅拌下，将6-甲氧基吡啶-2-甲酸(0.2g,1.3mmol,1.0eq)中加入5ml无水N,N-二甲基甲酰胺，随后依次加入EDCI(0.38g,2.0mmol,1.5eq)、HOBT(0.27g,2.0mmol,1.5eq)，然后再加入D-苯丙氨酸甲酯盐酸盐(0.42g,2.0mmol,1.5eq)最后加入TEA(0.93g,9.1mmol,7.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取，稀盐酸洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化，得0.33g无色油状液体，收率80％；
在室温搅拌下，将上一步(0.33g,1.05mmol,1.0eq)加入5ml四氢呋喃中，生成澄清透明溶液，滴加1N氢氧化钠溶液(0.21g,5.25mmol,5.0eq)后强烈搅拌，反应3h(TLC检测反应终点)；减压旋除四氢呋喃，1N盐酸调节溶液PH值至1～2，乙酸乙酯萃取合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂得粗产物。粗产物通过快速硅胶柱纯化，得0.187g白色固体，收率58％；1H NMR(300MHz,DMSO)δ13.06(s,1H,-COOH),8.42(d,J＝8.0Hz,1H,-NH-),7.87(dd,J＝8.3,7.3Hz,1H,-pyridine-H),7.58(dd,J＝7.2,0.7Hz,1H,-pyridine-H),7.33–7.18(m,5H,-PhH),7.04(dd,J＝8.3,0.7Hz,1H,pyridine-H),4.67(dd,J＝14.4,6.5Hz,1H,-CH-CH2-),3.91(s,4H,-OCH3),3.21(d,J＝6.4Hz,2H,-CH-CH2-)。
实施例6：
(6-morpholinopicolinoyl)phenylalanine(化合物I-6)：在室温搅拌下，将6-(4-吗啉基)-2-吡啶甲酸(0.2g,0.96mmol,1.0eq)中加入5ml无水N,N-二甲基甲酰胺，随后依次加入EDCI(0.28g,1.44mmol,1.5eq)、HOBT(0.2g,1.44mmol,1.5eq)，然后再加入D-苯丙氨酸甲酯盐酸盐(0.31g,1.44mmol,1.5eq)最后加入TEA(0.68g,6.0mmol,7.0eq)，反应过夜(TLC检测终点)。反应结束后加水搅拌，分别乙酸乙酯萃取，稀盐酸洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥有机相，减压旋除乙酸乙酯，得粗产物。粗产物通过快速硅胶柱纯化，得0.28g无色油状液体，收率80％；
在室温搅拌下，将上一步(0.28g,0.75mmol,1.0eq)中加入5ml四氢呋喃，生成澄清透明溶液，滴加1N氢氧化钠溶液(0.15g,3.75mmol,5.0eq)后强烈搅拌，反应3h(TLC检测反应终点)；减压旋除四氢呋喃，1N盐酸调节溶液PH值至1～2，乙酸乙酯萃取3次合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂得粗产物。粗产物通过快速硅胶柱纯化，得0.20g淡黄色色固体，收率75％；1H NMR(300MHz,DMSO)δ12.95(s,1H,-COOH),8.31(d,J＝8.2Hz,1H,-NH-),7.71(dd,J＝8.5,7.3Hz,1H,-pyridine-H),7.34–7.18(m,6H,-PhH)(5H,-PhH,1H,-pyridine-H),7.04(d,J＝8.5Hz,1H,-pyridine-H),4.66(dd,J＝14.5,6.5Hz,1H,-CH-CH2-),3.73(t,J＝4.8Hz,4H,-CH2-CH2-O-),3.49–3.44(m,4H,-N-CH2-CH2-O-),3.25–3.16(m,2H,-CH-CH2-)。
实施例7：
4-(4-(6-((1-carboxy-2-phenylethyl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ben zoic acid(化合物I-7)：在室温搅拌下，将(6-乙炔基吡啶啉基)-D-苯丙氨酸(300mg,1.02mmol,1.0eq)加入12ml水/叔丁醇(1:1)，随后加入对叠氮苯甲酸(166mg,1.02mmol,1.0eq)，抗坏血酸钠溶液(60mg,0.10mmol,0.3eq)，随后滴加五水硫酸铜溶液(7.6mg,0.01mmol,0.03eq)。反应过夜(TLC检测终点)，反应结束后加入冰水，减压旋除溶剂，1N盐酸调节溶液pH值至5，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂，得粗产物。粗产物通过快速硅胶柱纯化，得296mg淡黄色色固体，收率63％。1HNMR(300MHz,DMSO)δ13.16(s,2H,-COOH),9.60(s,1H,-N3H),8.87(d,J＝8.3Hz,1H,-NH-),
8.30(dd,J＝7.8,0.7Hz,1H,-pyridine-H),8.24(d,J＝8.4Hz,2H,-PhHCOOH),
8.17–8.11(m,3H)(8.15(d,J＝8.4Hz,2H,-PhHCOOH),8.13(t,J＝7.7Hz,1H,-pyridine-H)),7.98(dd,J＝7.7,0.7Hz,1H,-pyridine-H),7.24(m,5H,-PhH)(7.34(d,J＝7.1Hz,1H),7.25(t,J＝7.3Hz,1H),7.16(t,J＝7.2Hz,1H)),4.75(dd,J＝13.6,8.2Hz,1H,-CH-CH2-),3.55–3.09(m,2H,-CH-CH2-)。
实施例8：
4-(4-(6-((1-carboxy-2-phenylethyl)carbamoyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoic acid(化合物I-8)：在室温搅拌下，将对应中间体2(R)-4-(4-(6-(((1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基甲酰基)吡啶-3-基)-1H-1,2,3-三唑-1-基)苯甲酸(0.33g,0.70mmol,1.0eq)加入5ml四氢呋喃中，生成澄清透明溶液。滴加1N氢氧化钠溶液(0.17g,4.25mmol,6.0eq)后强烈搅拌。反应3h(TLC检测反应终点)，减压旋除四氢呋喃，1N盐酸调节溶液PH值至5～6，乙酸乙酯萃取3次合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂，得粗产物。粗产物通过快速硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1～石油醚：乙酸乙酯＝1:1～二氯甲烷：甲醇＝10:1，+1％乙酸)，得287mg黄褐色色固体，收率90％。1H NMR(400MHz,DMSO)δ13.27(s,2H,-COOH),9.68(s,1H,-CH),9.21(s,1H,-pyridine-H),8.80(d,J＝8.1Hz,1H,-NH-),8.51(dd,J＝8.1,2.1Hz,1H,-pyridine-H),8.21(d,J＝8.6Hz,2H,-PhHCOOH),8.15(d,J＝8.2Hz,1H,-pyridine-H),8.12(d,J＝8.6Hz,2H,-PhHCOOH),7.34–7.16(m,5H,-PhH),4.76(dd,J＝13.7,7.4Hz,1H,-CH-CH2-),3.25(d,J＝5.8Hz,2H,-CH-CH2-)。
实施例9：
4-(4-(6-((1-carboxylato-2-phenylethyl)carbamoyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoate(化合物I-9)：在室温搅拌下，将具体化合物I-8中加入1,4-dioxane中，加入4N NaOH(2.0eq)与NH3(25％aq)(2.0eq)反应30min(TLC检测)，旋除溶剂。得白色固体钠盐。1H NMR(400MHz,D2O)δ9.03(s,1H,-pyridine-H),8.98(s,1H,-CH),8.35(dd,J＝8.1,1.9Hz,1H-pyridine-H),8.16(d,J＝8.6Hz,2H,-PhHCOOH),8.04(d,J＝8.1Hz,1H,-pyridine-H),7.90(d,J＝8.6Hz,2H,-PhHCOOH),7.58–7.34(m,5H,-PhH),4.74(dd,J＝7.0,5.5Hz,1H,-CH-CH2-),3.41(dd,J＝13.8,5.1Hz,1H,-CH-CH2-),3.27(dd,J＝13.8,7.3Hz,1H,-CH-CH2-)。
实施例10：
(4-(4-(6-((1-carboxy-2-(4-fluorophenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoic acid(化合物I-10)：在室温搅拌下，将对应中间体2(R)-4-(4-(6-((3-(4-氟苯基)-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)吡啶-3-基)-1H-1,2,3-三唑-1-基)苯甲酸(135mg,0.28mmol,1.0eq)加入5ml四氢呋喃中。滴加1N氢氧化钠溶液(66mg,1.65mmol,6.0eq)后强烈搅拌。反应3h(TLC检测反应终点)，减压旋除四氢呋喃，1N盐酸调节溶液PH值至5～6，乙酸乙酯萃取3次合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂，得粗产物。粗产物通过快速硅胶柱纯化，得104mg黄褐色色固体，收率80％。1H NMR(400MHz,DMSO)δ13.16(s,2H,-COOH),9.67(s,1H,-CH),9.21(d,J＝1.6Hz,1H,-pyridine-H),8.84(d,J＝8.3Hz,1H,-NH-),8.50(dd,J＝8.1,2.1Hz,1H,-pyridine-H),8.21(d,J＝8.7Hz,2H,-PhHCOOH),8.14(d,J＝8.6Hz,2H,-PhHCOOH),8.12(d,J＝8.8Hz,1H,-pyridine-H),7.29(dd,J＝8.6,5.6Hz,2H,-PhHF),7.09(t,J＝8.9Hz,2H,-PhHF),4.89–4.58(m,1H,-CH-CH2-),3.27–3.20(m,1H,-CH-CH2-)。
实施例11：
(5-(1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,3-triazol-4-yl)picolinoyl)phenylalanine(化合物I-11)：在室温搅拌下，将对应中间体2(5-(1-(((3S，5S，7S)-金刚烷-1-基)-1H-1,2,3-三唑-4-基)吡啶啉甲基)-D-苯丙氨酸甲酯(150mg,0.30mmol,1.0eq)加入5ml四氢呋喃中。滴加1N氢氧化钠溶液(74mg,1.85mmol,6.0eq)后强烈搅拌。反应3h(TLC检测反应终点)，减压旋除四氢呋喃，1N盐酸调节溶液PH值至5～6，乙酸乙酯萃取3次合并有机相，无水硫酸钠干燥有机相，减压旋除溶剂，得粗产物。粗产物通过快速硅胶柱纯化，得107.6mg黄褐色色固体，收率74％。1H NMR(300MHz,DMSO)δ13.03(s,1H,-COOH),9.12(d,J＝1.6Hz,1H,-pyridine-H),8.98(s,1H,-CH),8.76(d,J＝8.2Hz,1H,-NH-),8.42(dd,J＝8.1,1.9Hz,1H,-pyridine-H),8.08(d,J＝8.2Hz,1H,-pyridine-H),7.33–7.14(m,5H,-PhH),4.76(dd,J＝14.6,6.7Hz,1H,-CH-CH2-),3.24(d,J＝6.6Hz,2H,-CH-CH2-),2.24(m,8H),1.77(m,5H),1.38–1.14(m,2H)。13C NMR(75MHz,DMSO)δ173.30(-COOH),163.40(-CONH),150.40(pyridine-C),141.47(pyridine-C),139.69(pyridine-C),138.10(pyridine-C),131.02(pyridine-C),129.59(2C,-PhC),128.71(2C,-PhC),127.21(-PhC),122.71(-PhC),83.22(-N-C＝C-N-),82.10(-N-C＝C-N-),54.21–53.09(adamantane),37.11(adamantane)。
实施例12：RT-PCR方法测定化合物对HIF-1α调控的基因EPO的表达影响EPO为细胞内激活HIF-α转录活性后的标志物，当天冬酰胺酰羟化酶抑制后，HIF-α活性将增加，会激活下游HRE(Hypoxia Response Element)基因的表达，包括EPO，VEGF等。因此通过检测EPO的表达来验证化合物在细胞水平是否具有天冬酰胺酰羟化酶抑制活性，同时是否促进了HIF-α转录活性。
测试化合物(化合物I-4、I-5、I-6、I-7、I-8、I-11)在不同浓度(25、50μM)，不同时间(18h、24h)与HCT116细胞共孵育，实验设置空白对照(DMSO)和阳性对照(NOFD),PCR体系采用：SYBR Green 10μl，上游和下游引物各1μl，待测样品cDNA4μl，H2O 4μl，总体积20μl。将配置好的PCR反应液置于Real-time PCR仪上进行扩增。利用2-△△CT对得到的CT值，进行分析，检测不同组别HCT16细胞中mRNA的表达水平。
图1是本发明部分化合物细胞水平的QRT-PCR实验结果(HCT166细胞：人结直肠癌细胞。A)化合物浓度：25μM，给药时间：18h；B)化合物浓度：50μM，给药时间：24h)。
实验结果表明，本发明合成的化合物可以促进EPO的表达，说明其具有天冬酰胺酰羟化酶抑制活性，促进了HIF-α转录活性。
实施例13：免疫印迹实验(Western-Blot)法考察HCT116细胞内HIF蛋白的表达
通式I化合物为FIH选择性抑制剂，为证明其促进EPO表达是通过抑制天冬酰胺酰羟化酶提高HIF-α转录活性，而不是抑制脯氨酰羟化酶抑制HIF-α蛋白的降解。通过免疫印迹实验(Western-blot)法考察HCT116细胞内HIF蛋白的表达。测试化合物I-8以50μM给药浓度与HCT116细胞孵育24h。按照蛋白稀释浓度等体积上样。电泳时，浓缩胶时电压80V，电流40A，分离胶时电压可以提高到120V，等跑至分离胶下1/3时，停止电泳。依据HIF和内参分子量切下的胶并浸于转移缓冲液中。后转膜，1x TBS洗膜5min。室温下于脱脂奶粉封闭液中摇动1h。随后用TBST洗一抗，4℃下过夜。TBST洗3次。室温下，加入二抗孵育1h。最后TBST洗3次。滴加显色剂拍照曝光观察。
结果表明，化合物I-8和NOFD不能促进HIF-1α蛋白的表达，DMOG可以明显促进HIF-1α蛋白的表达。
图2本发明部分化合物细胞水平的WT实验结果(HCT166细胞：人结直肠癌细胞；化合物浓度：50μM，给药时间：24h)。
测试种所用的阳性对照药分别为：NOFD，是一个作用机理明确、选择性强的FIH抑制剂；DMOG为PHD，FIH双重抑制剂。
结果可以说明，本发明化合物和NOFD一样是FIH选择性抑制剂，对稳定HIF-1α蛋白表达没有影响，其促进EPO的表达是通过激活了HIF-1α转录活性。
实施例14：分子模拟验证FIH抑制剂空间选择性
比较NOFD，DMOG，通式I化合物，R1处的优化，对于FIH抑制剂的选择性与活性具有重要作用。由图1可见，NOFD的苄基位置与FIH活性空腔会形成额外作用力，同时由于FIH与PHD活性空腔大小不一，R1的存在能使通式I化合物具有较大的空间位阻，从而较难进入PHD活性空腔。因此，其选择性更好。
图3为NOFD与FIH相互作用模式图(PDB ID：1YCI)。
实施例15FIH抑制剂对小鼠肠道辐射损伤的防护作用
C57小鼠被平均分成三组，分别是对照组、单纯照射组，5mg/Kg具体实施例5抑制剂组，每组5只小鼠。分组后按照上述给药方式进行给药:照射前16h和2h各给药一次，以及照射后三天每天各给药一次。FIH抑制剂用无菌生理盐水溶解并稀释，给药剂量0.2ml。对照组和单纯照射组小鼠在相同的时间，用相同的给药方式，注射0.2ml的无菌生理盐水。除对照组外，其余两组小鼠在照射前10分钟，用3.5％的水合氯醛，腹腔注射方式进行麻醉。麻醉后的小鼠接受13Gy单剂量腹部局部照射。照射3.5天后，取小鼠十二指肠和回肠部位小肠，各1cm，放到包埋盒中，在4％多聚甲醛中固定48小时。固定后用石蜡进行包埋，并切成5μm厚的切片。切好后的组织切片用苏木素和伊红(HE)染色，晾干后在光学显微镜下观察观察绒毛、隐窝完整程度，根据结果评估小肠损伤状况，结果见图4。
结果表明，对照组小鼠小肠绒毛和隐窝完整，数量充足。相比于对照组小鼠，13Gy腹腔照射后小鼠小肠的绒毛损伤严重，长度明显下降，隐窝受到明显损伤，隐窝数量显著降低。同样接受13Gy局部照射，FIH抑制剂组小鼠小肠的绒毛完整性明显好于单纯照射组，隐窝数量也明显增加。
图4是组织病理学染色结果图，从左到右依次为对照组、照射组、照射给药组。
促红细胞生成素(EPO)又称红细胞刺激因子、促红素，是一种人体内源性糖蛋白激素，可刺激红细胞生成。缺氧可刺激促红细胞生成素产生，早已有重组人促红细胞生成素用于临床，用于治疗肾功能不全合并的贫血、获得性免疫缺陷综合征/艾滋病本身或治疗引起的贫血、恶性肿瘤伴发的贫血及风湿病贫血等多种贫血。
本发明的化合物，通过促进了HIF-1α转录活性，增加了细胞中EPO基因的表达，因此该类化合物可以作为治疗贫血症或缺血性疾病的药物使用。
Claims (6)
1.下述化合物或其药学上接受的盐，选自：
2.一种药物组合物，其含有权利要求1所述的化合物或其药学上接受的盐、以及药学上接受的载体。
3.权利要求1所述的化合物或其药学上接受的盐在制备治疗天冬酰胺酰羟化酶介导的疾病药物中的应用。
4.权利要求1所述的化合物或其药学上接受的盐在制备治促进乏氧诱导因子转录活性药物中的应用。
5.权利要求1所述的化合物或其药学上接受的盐在制备用于辐射损伤防护、治疗药物中的应用。
6.权利要求1所述的化合物或其药学上接受的盐在制备治疗贫血症、缺血性疾病药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010336234.9A CN111499611B (zh) | 2020-04-24 | 2020-04-24 | 吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010336234.9A CN111499611B (zh) | 2020-04-24 | 2020-04-24 | 吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111499611A CN111499611A (zh) | 2020-08-07 |
| CN111499611B true CN111499611B (zh) | 2023-06-06 |
Family
ID=71871356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010336234.9A Active CN111499611B (zh) | 2020-04-24 | 2020-04-24 | 吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111499611B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2021391453A1 (en) * | 2020-12-04 | 2023-07-13 | Eubulus Biotherapeutics Inc. | Heteroaryl-acetylenes, pharmaceutical compositions thereof, and their therapeutic applications |
-
2020
- 2020-04-24 CN CN202010336234.9A patent/CN111499611B/zh active Active
Non-Patent Citations (3)
| Title |
|---|
| "Asymmetric allylic substitution catalyzed by C1-symmetrical complexes of molybdenum: structural requirements of the ligand and the stereochemical course of the reaction";Malkov, Andrei V.et al.;《Chemistry - A European Journal》;20060829;第6910-6929页 * |
| registry.registry.《STN》.2014, * |
| registry;registry;《STN》;20140516;第1页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111499611A (zh) | 2020-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110128415B (zh) | 用作免疫调节剂的吲哚啉类化合物及其制备方法 | |
| CN109776377B (zh) | 吲哚啉类化合物及其制备方法和应用 | |
| CN105175394B (zh) | 具有抗癌活性的化合物 | |
| CN113444069B (zh) | 一类2-芳基-4-(1h-吡唑-3-基)吡啶类lsd1/hdac双靶点抑制剂 | |
| WO2021238007A1 (zh) | 可诱导prc2蛋白复合物核心亚基降解的双功能化合物和药物组合物及应用 | |
| WO2011020288A1 (zh) | 取代酰肼类化合物及其应用 | |
| CN115768761A (zh) | 新颖苯并咪唑衍生物 | |
| CN111499611B (zh) | 吡啶甲酰芳基杂芳基α位取代的氨基酸类化合物、其制备方法及用途 | |
| WO2015021894A1 (zh) | 新型羟肟酸衍生物及其医疗应用 | |
| CN114605407B (zh) | 一种吲哚喹啉酮类化合物及其合成方法和应用 | |
| US20040097539A1 (en) | Hsp inductor | |
| JP4828142B2 (ja) | 新規な融合ピラゾリル化合物 | |
| CN105541859B (zh) | 二氢呋喃并色满酮衍生物及其制备方法与医药用途 | |
| CN111454229B (zh) | 二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用 | |
| CN109897036B (zh) | 三唑并吡啶类化合物及其制备方法和用途 | |
| CN104211661A (zh) | 查尔酮类化合物及其制法和药物用途 | |
| CN109867661B (zh) | 调节wnt信号通路的酰胺类化合物及其用途 | |
| CN117618422A (zh) | 3-羟基-2-氨基苯并咪唑衍生物在制备防治心肌缺血再灌注损伤的药物中的应用 | |
| EP3560914A1 (en) | Sulfonyl amidine as indoleamine-2,3-dioxygenase inhibitor, and preparation method therefor and use thereof | |
| CN108530439B (zh) | 呋喃甲酰胺衍生物及其制备方法与应用 | |
| WO2006102363A1 (en) | Methods for treating or preventing acute myelogenous leukemia | |
| CN114835624B (zh) | 一类2,3-二取代吲哚衍生物、制备方法及应用和抗新型冠状病毒药物组合物 | |
| CN114933589B (zh) | 基于crbn配体诱导fgfr降解的化合物及其制备方法和应用 | |
| KR102576102B1 (ko) | Uch37 탐지용 프로브 및 이의 용도 | |
| WO2014183670A1 (zh) | 苯并咪唑酰胺类化合物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |