CN107848976A - 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 - Google Patents
炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 Download PDFInfo
- Publication number
- CN107848976A CN107848976A CN201580079971.2A CN201580079971A CN107848976A CN 107848976 A CN107848976 A CN 107848976A CN 201580079971 A CN201580079971 A CN 201580079971A CN 107848976 A CN107848976 A CN 107848976A
- Authority
- CN
- China
- Prior art keywords
- propine
- compound
- hydroxyl
- methyl
- preparation
- 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
- -1 Alkynyl pyridines Chemical class 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title abstract description 67
- 102000004079 Prolyl Hydroxylases Human genes 0.000 title abstract description 31
- 108010043005 Prolyl Hydroxylases Proteins 0.000 title abstract description 31
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 208000007502 anemia Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 208000023589 ischemic disease Diseases 0.000 claims abstract description 6
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 4
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002390 heteroarenes Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 2
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
- 229950002366 nafoxidine Drugs 0.000 claims description 2
- 150000002926 oxygen Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 12
- 210000004027 cell Anatomy 0.000 abstract description 8
- 210000003743 erythrocyte Anatomy 0.000 abstract description 7
- 208000020832 chronic kidney disease Diseases 0.000 abstract description 5
- 230000028327 secretion Effects 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000010171 animal model Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 164
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 128
- VKFAUCPBMAGVRG-UHFFFAOYSA-N dipivefrin hydrochloride Chemical compound [Cl-].C[NH2+]CC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 VKFAUCPBMAGVRG-UHFFFAOYSA-N 0.000 description 128
- 238000005160 1H NMR spectroscopy Methods 0.000 description 73
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 72
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 53
- 239000012265 solid product Substances 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 31
- 239000007787 solid Substances 0.000 description 22
- 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 description 20
- 102100031939 Erythropoietin Human genes 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 14
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 11
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 230000001413 cellular effect Effects 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 7
- VNYBIBSZZDAEOK-UHFFFAOYSA-N 5-bromopyridin-3-ol Chemical compound OC1=CN=CC(Br)=C1 VNYBIBSZZDAEOK-UHFFFAOYSA-N 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- OOMSXHKVSHVWAV-UHFFFAOYSA-N NCC(=O)OC.N1=C(C=CC=C1)C(=O)O Chemical compound NCC(=O)OC.N1=C(C=CC=C1)C(=O)O OOMSXHKVSHVWAV-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- ZFNYKZIQYSIJMK-UHFFFAOYSA-N C(#N)C1=CC=CC=C1.[O] Chemical compound C(#N)C1=CC=CC=C1.[O] ZFNYKZIQYSIJMK-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- GHUURDQYRGVEHX-UHFFFAOYSA-N prop-1-ynylbenzene Chemical group CC#CC1=CC=CC=C1 GHUURDQYRGVEHX-UHFFFAOYSA-N 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- OYYJABSCRGBEAO-UHFFFAOYSA-N 2-bromo-6-methylpyridine formic acid Chemical compound C(=O)O.BrC1=NC(=CC=C1)C OYYJABSCRGBEAO-UHFFFAOYSA-N 0.000 description 2
- AXQNJCVTWOBBNH-UHFFFAOYSA-N 2-methoxyethynylbenzene Chemical group COC#CC1=CC=CC=C1 AXQNJCVTWOBBNH-UHFFFAOYSA-N 0.000 description 2
- IYXVSRXFGYDNEV-UHFFFAOYSA-N 3-phenylprop-2-ynenitrile Chemical group N#CC#CC1=CC=CC=C1 IYXVSRXFGYDNEV-UHFFFAOYSA-N 0.000 description 2
- KNYSNNRQXSFAGE-UHFFFAOYSA-N 5-bromo-3-hydroxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(Br)C=C1O KNYSNNRQXSFAGE-UHFFFAOYSA-N 0.000 description 2
- 208000030760 Anaemia of chronic disease Diseases 0.000 description 2
- OPDWZFGUIDTPRY-UHFFFAOYSA-N C(C)(=O)NN.N1=C(C=CC=C1)C(=O)O Chemical compound C(C)(=O)NN.N1=C(C=CC=C1)C(=O)O OPDWZFGUIDTPRY-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 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
- LJYCGVJETDZTRP-UHFFFAOYSA-N O=CCCC(=O)O.N1=CC=CC=C1 Chemical compound O=CCCC(=O)O.N1=CC=CC=C1 LJYCGVJETDZTRP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 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
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002875 fluorescence polarization Methods 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical group NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YLGOWOYJZYKTDO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate Chemical compound CC(C)OC(=O)CN YLGOWOYJZYKTDO-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ZNTJVJSUNSUMPP-UHFFFAOYSA-N 1-ethyl-4-ethynylbenzene Chemical group CCC1=CC=C(C#C)C=C1 ZNTJVJSUNSUMPP-UHFFFAOYSA-N 0.000 description 1
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 description 1
- JWTZSVLLPKTZJP-UHFFFAOYSA-N 2-bromo-6-chloropyridine Chemical compound ClC1=CC=CC(Br)=N1 JWTZSVLLPKTZJP-UHFFFAOYSA-N 0.000 description 1
- RADQQJATVQIEFW-UHFFFAOYSA-N 2-cyclopropylethynylbenzene Chemical group C1CC1C#CC1=CC=CC=C1 RADQQJATVQIEFW-UHFFFAOYSA-N 0.000 description 1
- IOPDYTCCKSYLJG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-ynylbenzene Chemical group FC(F)(F)C#CC1=CC=CC=C1 IOPDYTCCKSYLJG-UHFFFAOYSA-N 0.000 description 1
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical group CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- USCSRAJGJYMJFZ-UHFFFAOYSA-N 3-methyl-1-butyne Chemical group CC(C)C#C USCSRAJGJYMJFZ-UHFFFAOYSA-N 0.000 description 1
- HTNFRWNPQNKTAU-UHFFFAOYSA-N 4-bromo-3-hydroxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(Br)=C1O HTNFRWNPQNKTAU-UHFFFAOYSA-N 0.000 description 1
- YEXKTBDBLNHYDT-UHFFFAOYSA-N 5-bromo-2-hydroxy-1h-pyridine-2-carboxylic acid Chemical compound OC(=O)C1(O)NC=C(Br)C=C1 YEXKTBDBLNHYDT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- BWWDIEZUBYDPCS-UHFFFAOYSA-N C(=O)O.BrC1=NC(=CC=C1)Cl Chemical compound C(=O)O.BrC1=NC(=CC=C1)Cl BWWDIEZUBYDPCS-UHFFFAOYSA-N 0.000 description 1
- YZCSROAILMMVAL-UHFFFAOYSA-N C1(CC1)CCC#CC1=CC=CC=C1 Chemical group C1(CC1)CCC#CC1=CC=CC=C1 YZCSROAILMMVAL-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- ZUELFMRETVRCSH-MERQFXBCSA-N Cl.COC([C@@H](N(CCC)CC(C)C)CCO)=O Chemical group Cl.COC([C@@H](N(CCC)CC(C)C)CCO)=O ZUELFMRETVRCSH-MERQFXBCSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 1
- 108010065338 N-ethylglycine Proteins 0.000 description 1
- AGCFULNNLKCLJS-UHFFFAOYSA-N NC#CC1=CC=CC=C1.C(CCC)(=O)N Chemical group NC#CC1=CC=CC=C1.C(CCC)(=O)N AGCFULNNLKCLJS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XQFARSXVMYNQRL-UHFFFAOYSA-N acetylene chlorobenzene Chemical group C#C.ClC1=CC=CC=C1 XQFARSXVMYNQRL-UHFFFAOYSA-N 0.000 description 1
- CRFJRGSTIQFTQW-UHFFFAOYSA-N acetylene fluorobenzene Chemical group C#C.FC1=CC=CC=C1 CRFJRGSTIQFTQW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000022400 anemia due to chronic disease Diseases 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical compound C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-N butanedioic acid monomethyl ester Natural products COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- YXDHQHDIBFDYDD-UHFFFAOYSA-N cyclopropyl 2-aminoacetate Chemical compound NCC(=O)OC1CC1 YXDHQHDIBFDYDD-UHFFFAOYSA-N 0.000 description 1
- OZYHLCOUAISLLG-UHFFFAOYSA-N cyclopropyl acetate Chemical compound CC(=O)OC1CC1 OZYHLCOUAISLLG-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- KDKYADYSIPSCCQ-UHFFFAOYSA-N ethyl acetylene Natural products CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- HQZMRJBVCVYVQA-UHFFFAOYSA-N hydron;methyl 2-(methylamino)acetate;chloride Chemical compound Cl.CNCC(=O)OC HQZMRJBVCVYVQA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical group COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108700027361 sarcosine methyl ester Proteins 0.000 description 1
- VXGABWCSZZWXPC-UHFFFAOYSA-N sarcosine methyl ester hydrochloride Natural products CNCC(=O)OC VXGABWCSZZWXPC-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及药物化学领域。具体涉及一类炔基吡啶类脯氨酰羟化酶抑制剂(I)。实验表明该类化合物具有良好的脯氨酰羟化酶抑制活性,可以在细胞或动物模型上增强促红细胞生成素的生成与分泌,从而可以促进红细胞的生成,可应用于治疗或预防贫血症如慢性肾病贫血以及缺血性疾病如缺血性脑卒中、心肌缺血等相关疾病。本发明还公开了该类化合物的制备方法。
Description
本发明涉及药物化学领域。具体涉及一类炔基吡啶类脯氨酰羟化酶抑制剂。该类化合物可增强促红细胞生成素及的生成与分泌,从而可以促进红细胞的生成,可应用于治疗或预防贫血症如慢性肾病贫血以及缺血性疾病如缺血性脑卒中、心肌缺血等相关疾病。
贫血一般是指导致血液中氧水平降低的血红蛋白或红细胞的任何异常。贫血也可以与慢性感染、肿瘤疾病、慢性炎症包括接下来发生骨髓的炎症性抑制的病变等慢性疾病相关而发生。慢性疾病性贫血是医学领域中最常见的综合征之一,例如慢性肾病贫血。慢性肾病贫血形成的主要原因是促红细胞生成素(erythropoietin,EPO)分泌不足(Nephrol Dial Transplant 17(2002)2-7)。EPO分泌不足会阻碍红细胞的生成,从而导致贫血的发生。EPO的表达与分泌受转录因子低氧诱导因子(hypoxia inducible factor,HIF)的调控。具有完整转录功能的HIF蛋白由HIF-α及HIF-β两个亚基组成,其中HIF-α亚基受脯氨酰羟化酶(prolyl hydroxylase,PHD)的调控,PHD酶可以羟基化HIF-α从而促使其降解。在人体中,脯氨酰羟化酶2(PHD2)(Journal of Medicinal Chemistry 56(2013)9369-9402)是调控HIF水平的最主要亚型。当抑制体内脯氨酸羟化酶(PHD)的活性时,可以稳定体内HIF-α亚基,从而使其进入细胞核同细胞核内HIF-β亚基相结合,形成稳定的HIF二聚体,进一步引起下游基因的表达,从而促进EPO的表达与分泌。因此抑制脯氨酸羟化酶的活性可以提高HIF-α的水平,增加EPO的生成,从而促进红细胞成熟及提升血液输送氧气的能力,改善贫血或缺血症状。
发明内容
本发明提供了一种可以抑制脯氨酸羟化酶(PHD)活性的小分子化合物,其通过抑制PHD酶提高HIF-α的含量,从而增加EPO的生成与分泌,促进红细胞成熟及提升血液输送氧气的能力,用于治疗和预防贫血症以及缺血性疾病,如慢性肾病贫血、心肌缺血、脑缺血、中风等。本发明化合物结构如下:
其中X代表NH、NCH3或CH2;Y代表氢、羟基、甲氧基或乙氧基;L代表–CH2–、–CH2O–或R6代表氢、C1-C4烷基或苯基;n代表0或1;
R1代表C1-C4烷基、苯基、取代苯基、含氧或氮的5~6员芳杂环、取代的含氧或氮的5~6员芳杂环,所述取代基是C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基、 苯基或含氧或氮的5~6员芳杂环,其中R7代表C1-C4烷基;R8、R9各自独立地代表氢或C1-C4烷基,或者R8、R9连接形成3~7员含氮杂环;
R2代表氢、卤素或甲基;R3、R4各自独立地代表氢、甲基或乙基;
R5代表羟基、C1-C4烷氧基或–NR10R11;R10、R11各自独立地代表氢、甲基或乙基。
X优选代表NH。L优选代表–CH2–、–CH2O–或R6优选代表氢、甲基、叔丁基或苯基。R1优选代表取代苯环,取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、叔丁氧基、环丙氧基、苯基、氰基、卤素、氟甲基、三氟甲基、咪唑基、乙酰氨基、环丙基甲酰氨基或其中R8、R9各自独立地代表氢、甲基、丁基或叔丁基,或两者连接形成环丙氨基、四氢吡咯基或N-甲基高哌嗪基。
R1还优选代表环丙基、叔丁基、苯基、萘基、喹啉基或苯并呋喃基。
R3或R4优选代表氢。R5优选代表-NH2、-NHCH3、羟基、甲氧基、异丙氧基、环丙氧基或环丙基甲氧基。
本发明同时包括化合物(I)的药学上可接受的盐,及其溶剂化物,都与化合物(I)有同样的药理功效。
本发明公开了一种药物组合物,其包含化合物(I)或其可药用盐,或溶剂合物,以及一种或多种可药用载体、稀释剂和赋形剂。
本发明还提供式(I)化合物和/或其可药用盐或溶剂合物在制备用于通过抑制脯氨酰羟化酶来治疗该酶介导的疾病的药物中的用途,所述疾病如贫血症,其可通过抑制脯氨酰羟化酶来治疗。
本发明的化合物临床所用剂量为0.01mg~1000mg/天,也可以根据病情的轻重或剂型的不同偏离此范围。
在某些实施方案中,根据式I的化合物可含有足以形成盐的酸性官能团。代表性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、乙胺、2-羟基乙基胺、二乙胺、三乙胺、乙二胺、乙醇胺、二乙醇。
同时本发明还提供了式(I)相关化合物的制备方法,包括以下步骤:
其中R1、R2、R3、R4、X、Y、n、L定义同前。
其中中间体VI可通过下式进行合成得到,
下面是本发明化合物的部分药效学实验数据:
血管内皮生长因子(vascular endothelial growth factor,VEGF)和EPO为体内HIF升高后的两个标志物(Journal of Medicinal Chemistry 55(2012)2945-2959),当PHD活性受到抑制后,体内HIF含量升高,其会进入细胞核诱导下游相关基因表达,使体内EPO、VEGF等蛋白表达含量升高,通过检测VEGF和EPO的表达来验证化合物在细胞水平是否具有抑制PHD活性,提高HIF的能力。同时FG-4592(专利WO 2013013609A1)是一个目前已经进入临床III期的用于治疗贫血的PHD2抑制剂,本发明中FG-4592作为阳性对照化合物。
表1本发明中部分化合物的脯氨酰羟化酶抑制活性及其相关生物学活性
aND为未进行测试;b化合物的结构见具体实施例;cFG-4592的结构:
由表1可见,本发明的化合物具有较强的脯氨酰羟化酶2的抑制活性。
此外,专利US2007/0299086 A1公开了一系列脯氨酰羟化酶抑制剂,其中活性较好的化合物结构:本发明化合物的特征在于吡啶母核5位含有炔基直接与吡啶环相连,并且该位点炔基的引入,可以大幅度提升化合物对脯氨酰羟化酶的抑制活性。为了对比本发明化合物与US2007/0299086 A1化合物的活性,我们合成了US2007/0299086 A1专利中的部分化合物(合成方法见Tetrahedron Lett.,2015,56(35),5017–5019.),并采用本发明中相同的活性测试方法、同一批次进行脯氨酰羟化酶抑制活性测定。本发明中部分化合物与US2007/0299086专利中化合物的对比结果如下:
表2本发明中部分化合物与专利US2007/0299086中化合物的对比情况
由表2化合物的数据对比可以看出,在其他基团基本相同的情况下,本发明中炔基的引入,可以显著提升化合物对脯氨酰羟化酶2的抑制活性。
荧光偏振法(Biochemical and Biophysical Research Communications 337(2005)275–280),加药过后1h,使用荧光偏振仪器进行数据读取,以溶剂为对照,使用下面公式计算化合物对脯氨酰羟化酶的抑制剂率,同时使进行IC50的计算,结果见表1、3。
除了脯氨酰羟化酶2(PHD2)亚型之外,脯氨酰羟化酶3(PHD3)亚型可以调控HIF的含量,因此我们也测定了代表性化合物的PHD3抑制活性,其测试结果如下:
表3本发明部分化合物对脯氨酰羟化酶3的抑制活性
其中计算公式如下:%抑制率=100*(1-(实测数值-空白)/(阴性数值-空白))
由表1、3可见,本发明的化合物具有较强的脯氨酰羟化酶2、3的抑制活性,其中分部分化合物活性明显优于阳性药FG-4592。
以下是本发明部分化合物的细胞水平VEGF和细胞水平EPO活性的实验,方法参照(Bioorganic&Medicinal Chemistry Letters 23(2013)5953-5957),给药24h后分别采用VEGF、EPO试剂盒进行检测结果如表1所示。
Hep3B细胞:人肝癌细胞
由表1可见,本发明的化合物具有明显的提高细胞内VEGF,EPO水平的能力,表现出较好的细胞水平活性。
同时本发明的部分化合物也进行了细胞水平的免疫印迹试验(Western-blot),表4为本发明部分化合物是否对细胞HIF-α水平具有提高作用的实验结果
表4本发明部分化合物是否能够提高细胞HIF-α水平
同时部分化合物的细胞水平的免疫印迹试验(Western-blot)结果见图1.
以下是本发明部分化合物的动物水平VEGF和细胞水平EPO活性的实验,方法参照(Journal of Medicinal Chemistry 55(2012)2945-2959),给药4h时之后分别采用VEGF、EPO试剂盒进行检测结果如下图2所示。
由图2可见,本发明的化合物在动物水平可以明显提高VEGF、EPO的表达,说明本发明化合物在动物水平的有效性。
本发明的炔基吡啶类化合物无论在分子水平、细胞水平以及动物水平都具有良好的生物学活性。本发明的化合物可以在动物水平提升血液中红细胞生成素(EPO)的水平,进而促进红细胞的生成,可用于治疗或预防慢性疾病性相关的贫血、缺血性疾病及造血系统相关疾病。
图1是部分化合物细胞水平的免疫印迹试验结果(Hep3B细胞:人肝癌细胞;化合物浓度50μM、250μM,给药24小时)
图2是化合物14、15、47、FG-4592在50μM浓度给药24h后细胞VEGF、EPO的提高水平
实验(模型:小鼠C57Bl/6雄性8-9周)
实施例1
2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸
1)2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯的制备
将化合物III 3-羟基-5-溴吡啶甲酸(3.47g,16mmol)溶于150mL二氯甲烷中,加入三乙胺7.3mL及HOBt(3.26g,24mmol),搅拌10min后加入EDCI(4.59g,24mmol),搅拌10min,加入甘氨酸甲酯盐酸盐(2.4g,19.2mmol)。室温反应,搅拌6h。分别用饱和碳酸氢钠(100mL),水洗(2×100mL),饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1),得白色固体化合物1.88g,率65.3%。m.p.143.6-145.7℃.1H-NMR(300MHz,CDCl3)δ11.90(s,1H),8.16(s,1H),7.54(d,J=1.83Hz,1H),7.28(d,J=1.86Hz,1H),4.25(d,J=3.3Hz,2H,),3.83(s,3H);EI-MS m/z:288/290[M]+.
2)2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯的制备
将化合物2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯(288mg,1mmol)、丙炔(44mg,1.1mmol)溶于6mL DMF中,加入6mL N,N-二异丙基乙胺,40mg碘化亚铜,40mg二氯(二三苯基膦)钯,常规加热至80℃6h,或者微波加热至80℃反应15min,反应基本完全。反应结束后,加入二氯甲烷100mL,3mmol盐酸60mL,分液后用水(2×100mL),饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=6:1),得白色固体化合物124.5mg,收率50.2%。m.p.119.2-121.5℃。1H-NMR(300MHz,CDCl3)δ8.91(s,1H),8.76(d,J=1.2Hz,1H),8.20(s,1H),7.69(d,J=1.2Hz,1H),3.92(s,2H),3.64(s,3H),1.85(s,3H);EI-MS m/z:248[M]+.
3)标题化合物2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸的制备
将2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯(100.0mg,0.4mmol)溶于10mL四氢呋喃中,加入1M氢氧化锂3mL,加热至30℃反应3h,反应完全。反应结束后,加压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸,有白色固体吸出,抽滤干燥后得白色产物61.0mg,收率65.2%。m.p.179.1-181.3℃。1H-NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.76
(d,J=1.2Hz,1H),8.20(s,1H),7.70(d,J=1.3Hz,1H),3.60(s,2H),1.85(s,3H);EI-MS m/z:234[M]+.
实施例2
2-(3-羟基-5-异丙基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法,用异丙基乙炔(74.8mg,1.1mmol)替换丙炔,得白色固体产物112.0mg,两部收率42.7%。m.p.155.5-157.8℃。1H-NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.79(d,J=1.2Hz,1H),8.20(s,1H),7.70(d,J=1.2Hz,1H),3.60(s,2H),2.89-2.85(m,1H),1.26(d,J=6.8Hz,6H);EI-MS m/z:262[M]+.
实施例3
2-(3-羟基-5-叔丁基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法,用叔丁基乙炔(90.2mg,1.1mmol)替换丙炔,得白色固体化合物98.0mg,两步收率35.5%。m.p.165.2-167.8℃。1H NMR(300MHz,DMSO-d6)δ8.78(d,J=1.2Hz,1H),8.20(s,1H),7.69(d,J=1.2Hz,1H),3.60(s,2H),1.27(s,9H);EI-MS m/z:276[M]+.
实施例4
2-(3-羟基-5-环丙乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法,用环丙基乙炔(72.6mg,1.1mmol)替换丙炔,得白色固体化合物得白色固体化合物79.1mg,两部收率30.42%。m.p.154.2-155.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J=1.3Hz,1H),8.20(s,1H),7.63(d,J=1.3Hz,1H),3.60(s,2H),1.41-1.32(m,1H),0.63–0.44(m,2H),0.45–0.25(m,2H);EI-MS m/z:261[M]+.
实施例5
2-(3-羟基-5-苯基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法,用苯乙炔(112.2mg,1.1mmol))替换丙炔,得白色固体化合物得白色固体化合物102.2mg,两步收率34.4%。m.p.172.1-173.9℃。1HNMR(300MHz,DMSO-d6)δ8.75(d,J=1.2Hz,1H),8.20(s,1H),7.68(d,J=1.3Hz,1H),7.60–7.49(m,2H),7.48–7.27(m,3H),3.89(s,2H);EI-MS m/z:296[M]+.
实施例6
2-(3-羟基-5-苯基乙炔基)吡啶甲酰氨基乙酸甲酯
将化合物2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯(288mg,1mmol)、苯基乙炔(110.2mg,1.1mmol)溶于6mL DMF中,加入6mL N,N-二异丙基乙胺,40mg碘化亚铜,40mg二氯(二三苯基膦)钯,常规加热至80℃6h,或者微波加热至80℃反应15min,反应基本完全。反应结束后,加入二氯甲烷100mL,3mmol盐酸60mL,分液后用水(2×100mL),饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=6:1),得白色固体化合物140.0mg,收率45.2%。m.p.109.7-111.9℃。1HNMR(300MHz,DMSO-d6)δ8.77(d,J=1.2Hz,1H),8.20(s,1H),7.69(d,J=1.2Hz,1H),7.60–7.49(m,2H),7.48–7.27(m,3H),3.92(s,2H),3.64(s,3H);EI-MS m/z:310[M]+.
实施例7
2-(3-羟基-5-对甲苯基乙炔基-6-甲基)吡啶甲酰氨基乙酸
按实施例1的方法,用3-羟基-5-溴-6-甲基吡啶甲酸(372mg,2mmol)替换3-羟基-5-溴吡啶甲酸,对甲基苯乙炔(127.6mg,1.1mmol)替换丙炔,得到白色固体产物120.3mg,三步收率18.5%。m.p.223.3-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.67(s,1H),7.51–7.40(m,2H),7.01-7.17(m,1.1Hz,2H),3.88(s,2H),2.73(s,3H),2.34(t,J=1.1Hz,3H);EI-MS m/z:324[M]+.
实施例8
2-(3-羟基-5-对甲氧基苯基乙炔基-6-氯)吡啶甲酰氨基乙酸
按实施例1的方法,用3-羟基-5-溴-6-氯吡啶甲酸(412mg,2mmol)替换3-羟基-5-溴吡啶甲酸,对甲氧基苯乙炔(145.2mg,1.1mmol)替换丙炔,得到淡黄色固体产物127.0mg,三步收率17.6%。m.p.232.2-2.34.3℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.85(s,1H),7.51–7.40(m,2H),7.00–6.89(m,2H),3.80(s,3H),3.60(s,2H);EI-MS m/z:360[M]+.
实施例9
2-(3-羟基-5-对环丙基苯基乙炔基吡啶)甲酰氨基丙酸
按实施例1的方法,用丙氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐,用对环丙基苯乙炔(156.2mg,1.1mmol)替换丙炔得到白色固体产物77mg,两步收率22.0%;m.p.202.5-204.7℃。1H NMR(300MHz,DMSO-d6)δ8.85(d,J=1.2Hz,1H),7.74(d,J=1.2Hz,1H),7.57–7.46(m,2H),7.20–7.04(m,3H),4.31-4.40(m,=1H),1.94–1.77(m,1H),1.42(d,J=6.8Hz,3H),1.21–1.06(m,2H),0.82-0.90(m,2H);EI-MS m/z:350[M]+.
实施例10
2-(3-羟基-5-对氟苯基乙炔基吡啶)甲酰氨基丁酸
按实施例1的方法,用丁氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐,用对氯苯乙炔(149.6mg,1.1mmol)替换丙炔得到淡黄色固体产物145mg,两步收率40.5%。m.p.177.6-179.9℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=1.2Hz,1H),7.69(d,J=1.3Hz,1H),7.58–7.48(m,2H),7.46–7.35(m,2H),7.08(s,1H),4.60(d,J=1.4Hz,1H),2.11–1.82(m,2H),1.02(t,J=6.0Hz,3H).EI-MS m/z:342[M]+.
实施例11
2-(3-羟基-5-对氟苯基乙炔基吡啶)甲酰氨基丁酸
按实施例1的方法,用异丁氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐,用对氟苯乙炔(149.6mg,1.1mmol)替换丙炔得到淡黄色固体产物115mg,两步收率32.12%。m.p.175.4-177.5℃。1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),8.75(d,J=1.2Hz,1H),7.67(d,J=1.3Hz,1H),7.58–7.47(m,2H),7.45–7.35(m,2H),1.55(s,6H).EI-MS m/z:342[M]+.
实施例12
4-(3-羟基5-(4-乙基苯基炔基))吡啶-4-氧代丁酸
(1)4-(3-羟基-5-溴吡啶-2基)-4-氧代丁酸甲酯的制备
将化合物3-羟基-5-溴吡啶(348mg,2mmol)溶于40mL二氯甲烷,冰浴条件下加入丁二酸单甲酯酰氯(400mg,4mmol),三氯化铝100mg,常温反应2小时。反应结束后,加入水,3M盐酸,分液后,以此用(2×100mL),饱和食盐水(1×100mL)依次洗涤。无水硫酸钠干燥,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1),得白色固体化合物196.5mg,收率34..1%。156.6-158.2m.p.℃。1H NMR(300MHz,CDCl3)δ8.64(d,J=1.3Hz,1H),7.77(d,J=1.3Hz,1H),3.63(s,3H),3.05(t,J=7.1Hz,2H),2.78(t,J=7.0Hz,2H).EI-MS m/z:287[M]+.
(2)4-(3-羟基-5-对乙基苯基炔基吡啶-2基)-4-氧代丁酸甲酯的制备
将化合物4-(3-羟基-5-溴吡啶-2基)-4-氧代丁酸甲酯(190mg,0.66mmol)、对乙基苯乙炔(94mg,0.72mmol)溶于6mL DMF中,加入6mL N,N-二异丙基乙胺,40mg碘化亚铜,40mg二氯(二三苯基膦)钯,常规加热至80℃6h,或者微波加热至80℃反应15min,反应基本完全。反应结束后,加入二氯甲烷100mL,3mmol盐酸60mL,分液后用水(2×100mL),饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=6:1),得白色固体化合物84.5mg,收率38.1%。m.p.109.5-112.1℃。1H NMR(300MHz,CDCl3)δ8.76(d,J=1.2Hz,1H),7.63(d,J=1.3Hz,1H),7.57–7.46(m,2H),7.20-7.06(m,2H),3.63(s,3H),2.84–2.64(m,4H),2.58(t,J=5.7Hz,2H),1.19(t,J=6.6Hz,3H).EI-MS m/z:337[M]+.
(3)标题化合物4-(3-羟基5-(4-乙基苯基炔基))吡啶-4-氧代丁酸的制备
将2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯(70.0mg,0.2mmol)溶于10mL四氢呋喃中,加入1M氢氧化锂3mL,加热至30℃反应3h,反应完全。反应结束后,加压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸,有白色固体吸出,抽滤干燥后得白色产
物41.0mg,收率56.9%。m.p.185.7-187.8℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=1.2Hz,1H),7.64(d,J=1.2Hz,1H),7.57–7.46(m,2H),7.20-7.17(m,2H),2.87(t,J=5.4Hz,2H),2.78–2.62(m,4H),1.19(t,J=6.6Hz,3H).EI-MS m/z:358[M]+.
实施例13
N-(6-溴-5-对甲基苯基乙炔-3-羟基-2-吡啶)甲酰基-N-甲基甘氨酸
制备方法同实施例1,用N-甲基甘氨酸甲酯盐酸盐(333.2mg,2.4mmol),对甲基苯乙炔(255.2mg,2.2mmol),5,6-二溴-3-羟基吡啶甲酸(592mg,2mmol)分别替代甘氨酸甲酯盐酸盐,丙炔,5-溴-3-羟基吡啶甲酸,水解后得淡黄色固体,121.0mg,三步收率15.1%.m.p.227.1-229.4℃。1H NMR(300MHz,DMSO-d6)δ7.79(s,1H),7.55–7.44(m,2H),7.12-7.09(m,2H),3.90(s,2H),3.05(s,3H),2.34(s,2H),2.34(d,J=2.3Hz,1H).EI-MS m/z:402/404[M]+.
实施例14
2-(3-羟基-5-间甲基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用间甲基苯乙炔(127.6mg,1.1mmol)替换丙炔,得白色固体产物106.0mg,三步反应收率34.2%。m.p.229.2-231.3℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J=1.3Hz,1H),8.20(s,1H),7.67(d,J=1.2Hz,1H),7.54–7.43(m,2H),7.15–7.05(m,2H),3.60(s,2H),2.34(d,J=1.1Hz,3H).EI-MS m/z:310[M]+.
实施例15
2-(3-羟基-5-对氟苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用对氟苯基乙炔(132.0mg,1.1mmol)替换丙炔,得白色固体产物112.4mg,三步反应收率36.1%。m.p.187.8-200.7℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J=1.3Hz,1H),8.20(s,1H),7.69–7.52(m,3H),7.13–6.99(m,2H),3.60(s,2H).EI-MS m/z:314[M]+.
实施例16
2-(3-羟基-5-对甲氧基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用对甲氧基苯乙炔(145.2mg,1.1mmol)替换丙炔,得白色固体产物142.4mg,三步反应收率43.5%。m.p.219.2-221.3℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.2Hz,1H),8.20(s,1H),7.67(d,J=1.2Hz,1H),7.50–7.39(m,2H),7.00–6.89(m,2H),3.80(s,3H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例17
2-(3-羟基-5-间甲氧基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用间甲氧基苯乙炔(145.2mg,1.1mmol)替换丙炔,得淡黄色固体产物92.4mg,三步反应收率28.3%。m.p.220.2-222.5℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=1.3Hz,1H),8.20(s,1H),7.67(d,J=1.2Hz,1H),7.29(t,J=7.4Hz,1H),7.24–7.08(m,2H),6.95-6.91(m,1H),3.81(s,3H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例18
2-(3-羟基-5-(联苯-4-基乙炔基))吡啶甲酰氨基乙酸
制备方法同实施例1,用联苯基乙炔(195.8mg,1.1mmol)替换丙炔,得棕色固体产物82.2mg,三步反应收率22.1%。m.p.242.5-244.3℃。1H NMR(300MHz,DMSO-d6)δ8.87(d,J=1.2Hz,1H),8.20(s,1H),7.81–7.69(m,3H),7.67–7.53(m,4H),7.51–7.37(m,2H),7.39–7.26(m,1H),3.60(s,2H).EI-MS m/z:372[M]+.
实施例19
2-(3-羟基-5-对氰基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用对氰基苯乙炔(139.7mg,1.1mmol)替换丙炔,得白色固体产物65.7mg,三步反应收率20.4%。m.p.195.2-197.7℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J=1.3Hz,1H),8.20(s,1H),7.81–7.64(m,3H),7.63–7.52(m,2H),3.60(s,2H).EI-MS m/z:321[M]+.
实施例20
2-(3-羟基-5-邻氰基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用邻氰基苯乙炔(139.7mg,1.1mmol)替换丙炔,得白色固体产物55.2mg,三步反应收率17.2%。m.p.182.2-184.8℃。1H NMR(300MHz,DMSO-d6)δ8.87(d,J=1.3Hz,1H),8.20(s,1H),7.76(dd,J=7.4,2.1Hz,1H),7.67-7.65(m,2H),7.60-7.55(m,1H),7.51-7.47(m,1H),3.60(s,2H).EI-MS m/z:321[M]+.
实施例21
2-(3-羟基-5-对三氟甲基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用对三氟甲基苯乙炔(187.0mg,1.1mmol)替换丙炔,得乳白色固体产物105.2mg,三步反应收率28.8%。m.p.201.5-2.3.8℃。1H NMR(300MHz,DMSO-d6)δ8.78(d,J=1.2Hz,1H),8.20(s,1H),7.70(d,J=1.2Hz,1H),7.63–7.47(m,4H),3.60(s,2H).EI-MS m/z:364[M]+.
实施例22
2-(3-羟基-5-对乙酰氨基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用对乙酰氨基苯乙炔(174.0mg,1.1mmol)替换丙炔,得白色固体产物75.9mg,三步反应收率21.5%。m.p.251.2-253.7℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=1.3Hz,1H),8.20(s,1H),7.85–7.63(m,5H),3.60(s,2H),2.10(s,3H).EI-MS m/z:353[M]+.
实施例23
2-(3-羟基-5-对二甲氨基甲酰基苯基乙炔基)吡啶甲酰氨基乙酰胺
制备方法同实施例1,用对二甲氨基甲酰基苯乙炔(190.3mg,1.1mmol)替换丙炔,用甘氨酰胺(110mg,1.5mmol)替换甘氨酸甲酯盐酸盐,得白色固体产物95.9mg,三步反应收率26.2%。m.p.229.1-231.5℃。1H NMR(300MHz,CDCl3)δ8.78(d,J=1.3Hz,1H),8.20(s,1H),7.77–7.59(m,5H),6.49(s,2H),3.84(s,2H),3.03(s,6H).EI-MS m/z:366[M]+.
实施例24
2-(3-羟基-5-对丁酰胺氨基苯基乙炔基)吡啶甲酰氨基乙酸环丙甲酯
制备方法同实施例6,用对丁酰胺基苯乙炔(205.7mg,1.1mmol)替换丙炔,用甘氨酸环丙甲酯替换甘氨酸甲酯盐酸盐得棕色固体产物75.4mg,三步反应收率12.3%。m.p.178.5-180.2℃。1H NMR(300MHz,CDCl3)δ8.87(d,J=1.2Hz,1H),7.85–7.65(m,6H),4.00(d,J=7.0Hz,2H),3.92(s,2H),2.42(t,J=8.0Hz,2H),1.76-1.66(m,2H),1.50–1.17(m,3H),0.95(t,J=7.9Hz,3H),0.61–0.48(m,2H),0.29-0.23(m,2H).EI-MS m/z:449[M]+.
实施例25
2-(3-羟基-5-对丁氨甲酰基苯基乙炔基)吡啶甲酰氨基乙酸异丙酯
制备方法同实施例6,用对丁氨甲酰基苯乙炔(205.7mg,1.1mmol)替换丙炔,用甘氨酸异丙酯替换甘氨酸甲酯盐酸盐,得棕色固体产物81.4mg,三步反应收率18.6%。m.p.187.2-189.5℃。1H NMR(300MHz,CDCl3)δ8.81(s,1H),8.20(s,1H),7.85–7.73(m,3H),7.71–7.61(m,2H),5.88(s,1H),5.02-4.93(m,1H),3.92(s,2H),3.31(t,J=7.5Hz,2H),1.59-1.56(m,J=7.8Hz,2H),1.39–1.25(m,2H),1.16(d,J=6.8Hz,6H),0.88(t,J=7.9Hz,3H).EI-MS m/z:437[M]+.
实施例26
N-乙基-(2-(3-羟基-5-对环丙甲酰氨基苯基乙炔基)吡啶甲酰氨基)乙酰胺
制备方法同实施例6,用对环丙甲酰氨基苯乙炔(203.5mg,1.1mmol)替换丙炔,用N-乙基甘氨酰胺替换甘氨酸甲酯盐酸盐,得棕色固体产物71.4mg,三步反应收率18.3%。m.p.195.2-197.7℃。1H NMR(300MHz,CDCl3)δ9.50(s,1H),9.23(s,1H),8.83(d,J=1.3Hz,1H),8.20(s,1H),7.83–7.64(m,5H),3.85(s,2H),3.21(q,J=6.3Hz,2H),1.73-1.64(m,1H),1.22(t,J=6.3Hz,3H),1.11–0.90(m,4H).EI-MS m/z:406[M]+.
实施例27
N-甲基-(2-(3-羟基-5-(3-苯氧基丙炔-1-基)吡啶甲酰氨基)乙酰胺
制备方法同实施例6,用3-苯氧基丙炔(145.2mg,1.1mmol)替换丙炔,用N-甲基甘氨酰胺替换甘氨酸甲酯盐酸盐,得棕色固体产物91.2mg,三步反应收率26.9%。m.p.192.2-194.4℃。1H NMR(300MHz,CDCl3)δ8.67(d,J=1.2Hz,1H),8.20(s,1H),7.66(d,J=1.2Hz,1H),7.37–7.23(m,2H),6.94-6.85(m,3H),6.09(s,1H),4.68(s,2H),3.85(s,2H),2.82(s,3H).EI-MS m/z:339[M]+.
实施例28
2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酰胺
制备方法同实施例1,用3-(对氯苯氧基)丙炔(182.6mg,1.1mmol)替换丙炔,干氨酰胺替换甘氨酸甲酯盐酸盐,得到棕色产物54.0mg,三步收率15.1%。m.p.152.2-154.6℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.64(d,J=1.3Hz,1H),7.68(d,J=1.3Hz,1H),7.36–7.26(m,2H),7.12(s,2H),6.99–6.89(m,2H),4.73(s,2H),3.85(s,2H).EI-MS m/z:359[M]+.
实施例29
2-(3-羟基-5-(3-对乙基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸甲酯
制备方法同实施例6,用3-(对乙基苯氧基)丙炔(160.6mg,1.1mmol)替换丙炔,得白色固体产物105.0mg,收率28.5%。m.p.112.2-114.3℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.67(d,J=1.3Hz,1H),7.69(d,J=1.3Hz,1H),7.19-7.13(m,2H),6.92–6.82(m,2H),4.68(s,2H),3.86(s,2H),3.63(s,3H),2.73-2.70(m,J=6.6,1.1Hz,2H),1.19(t,J=6.6Hz,3H).EI-MS m/z:368[M]+.
实施例30
2-(3-羟基-5-(3-对氰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸异丙酯
制备方法同实施例6,用3-(对氰基苯氧基)丙炔(172.7mg,1.1mmol)替换丙炔,甘氨酸异丙酯替换甘氨酸甲酯盐酸盐,得白色固体产物126.0mg,收率32.1%。m.p.120.2-123.1℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.62(d,J=1.2Hz,1H),7.79–7.66(m,3H),7.20–7.09(m,2H),4.91-4.87(m,J=6.8Hz,1H),4.68(s,2H),3.86(s,2H),1.14(d,J=6.8Hz,6H).EI-MS m/z:393[M]+.
实施例31
2-(3-羟基-5-(3-对氟苯氧基丙炔-1-基))吡啶甲酰氨基乙酸环丙酯
制备方法同实施例6,用3-(对氟基苯氧基)丙炔(165.0mg,1.1mmol)替换丙炔,甘氨酸环丙酯替换甘氨酸甲酯盐酸盐,得白色固体产物117.0mg,收率30.4%。m.p.107.2-109.9℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.76(d,J=1.3Hz,1H),7.78(d,J=1.3Hz,1H),7.26–7.12(m,2H),7.09–6.96(m,2H),4.68(s,2H),3.86(s,2H),3.33(p,J=7.0Hz,1H),0.47-0.45(m,2H),0.43–0.18(m,2H).EI-MS m/z:384[M]+.
实施例32
N,N’-二甲基-(2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基)乙酰胺
制备方法同实施例1,用3-(对氯基苯氧基)丙炔(182.6mg,1.1mmol)替换丙炔,N,N’-二甲基氨酰胺替换甘氨酸甲酯盐酸盐,得白色固体产物97.0mg,收率24.2%。m.p.177.2-179.9℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.67(d,J=1.3Hz,1H),7.68(d,J=1.2Hz,1H),7.36–7.26(m,2H),7.00–6.89(m,2H),4.68(s,2H),3.85(s,2H),2.87(s,6H).EI-MS m/z:387[M]+.
实施例33
2-(3-羟基-5-(3-苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-苯氧基丙炔(145.2mg,1.1mmol)替换丙炔,得到白色固体产物77.1mg,两步收率23.6%。m.p.112.2-114.6℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.65(d,J=1.3Hz,1H),7.37–7.23(m,2H),6.94-6.85(m,3H),4.68(s,2H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例34
2-(3-羟基-5-(3-对甲苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(对甲基苯氧基)丙炔(160.6mg,1.1mmol)替换丙炔,得到白色固体产物89.2mg,两步收率24.7%。m.p.162.2-164.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.2Hz,1H),7.08-7.04(m,2H),6.83–6.72(m,2H),4.68(s,2H),3.60(s,2H),2.31(s,2H),2.31(d,J=2.2Hz,1H).EI-MS m/z:340[M]+.
实施例35
2-(3-羟基-5-(3-邻甲基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(邻甲基苯氧基)丙炔(160.6mg,1.1mmol)替换丙炔,得到白色固体产物99.4mg,两步收率29.1%。m.p.154.3-156.7℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.3Hz,1H),7.19–7.03(m,2H),6.94-6.85(m,1H),6.69-6.65(m,1H),4.68(s,2H),3.60(s,2H),2.22(d,J=1.0Hz,3H).EI-MS m/z:340[M]+.
实施例36
2-(3-羟基-5-(3-对乙基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(对乙基苯氧基)丙炔(176.0mg,1.1mmol)替换丙炔,得到白色固体产物110.3mg,两步收率31.1%。m.p.172.4-174.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.65(d,J=1.2Hz,1H),7.14-7.10(m,2H),6.85–6.75(m,2H),4.68(s,2H),3.60(s,2H),2.73-2.69(m,J=6.6,1.1Hz,2H),1.19(t,J=6.6Hz,3H).EI-MS m/z:354[M]+.
实施例37
2-(3-羟基-5-(3-对叔丁基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(对叔丁基苯氧基)丙炔(206.8mg,1.1mmol)替换丙炔,得到白色固体产物110.3mg,两步收率31.1%。m.p.180.1-182.5℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.2Hz,1H),7.37–7.26(m,2H),6.82–6.72(m,2H),4.68(s,2H),3.60(s,2H),1.28(s,9H).EI-MS m/z:382[M]+.
实施例38
2-(3-羟基-5-(3-(2,3-二甲基苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用对3-(2,3-二甲基苯基)氧基丙炔(176.0mg,1.1mmol)替换丙炔,得到白色固体产物60.3mg,两步收率16.9%。m.p.182.2-184.3℃。1H NMR(300MHz,DMSO-d6)
δ8.69(d,J=1.3Hz,1H),8.20(s,1H),7.65(d,J=1.2Hz,1H),7.06(t,J=7.5Hz,1H),6.76–6.63(m,2H),4.68(s,2H),3.60(s,2H),2.25–2.13(m,6H).EI-MS m/z:354[M]+.
实施例39
2-(3-羟基-5-(3-对甲氧基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对甲氧基苯氧基丙炔(180.0mg,1.1mmol)替换丙炔,得到白色固体产物80.1mg,两步收率22.4%。m.p.223.3-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.3Hz,1H),8.20(s,1H),7.65(d,J=1.2Hz,1H),6.79(s,4H),4.68(s,2H),3.80(s,3H),3.60(s,2H).EI-MS m/z:356[M]+.
实施例40
2-(3-羟基-5-(3-间叔丁基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-间叔丁氧苯氧基丙炔(224.4mg,1.1mmol)替换丙炔,得到白色固体产物85.5mg,两步收率21.5%。m.p.237.2-239.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J=1.2Hz,1H),8.20(s,1H),7.62(d,J=1.2Hz,1H),7.24(t,J=7.5Hz,1H),6.69-6.67(m,J=5.7,1.9Hz,2H),6.48(t,J=2.0Hz,1H),4.68(s,2H),3.60(s,2H),1.41(s,9H).EI-MS m/z:398[M]+.
实施例41
2-(3-羟基-5-(3-间环丙氧基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-间环丙氧基苯氧基丙炔(206.8mg,1.1mmol)替换丙炔,得到白色固体产物95.0mg,两步收率24.9%。m.p.212.3-214.7℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J=1.3Hz,1H),8.20(s,1H),7.78(d,J=1.2Hz,1H),7.25(t,J=7.5Hz,1H),6.69-6.67(m,
2H),6.48(t,J=2.1Hz,1H),4.68(s,2H),3.60(s,2H),3.17-3.14(m,1H),0.74–0.57(m,2H),0.52–0.32(m,2H).EI-MS m/z:382[M]+.
实施例42
2-(3-羟基-5-(3-对三氟甲基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对三氟甲基苯氧基丙炔(220.0mg,1.1mmol)替换丙炔,得到白色固体产物79.0mg,两步收率20.3%。m.p.197.2-199.5℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.20(s,1H),7.66(d,J=1.2Hz,1H),7.56–7.47(m,2H),6.92–6.82(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例43
2-(3-羟基-5-3-(5-氟甲基呋喃-2-基氧基)-1-丙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(5-氟甲基呋喃2-基氧基)丙炔(180.0mg,1.1mmol)替换丙炔,得到白色固体产物95.0mg,两步收率26.5%。m.p.187.2-189.3℃。1H NMR(300MHz,DMSO-d6)δ8.71(d,J=1.2Hz,1H),8.20(s,1H),7.63(d,J=1.2Hz,1H),7.35-7.31(m,1H),6.90–6.79(m,1H),5.43(t,J=1.1Hz,1H),5.27(t,J=1.1Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:348[M]+.
实施例44
2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对氯苯氧基丙炔(182.6mg,1.1mmol)替换丙炔,得到白色固体产物95.0mg,两步收率26.5%。m.p.132.7-134.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.65(d,J=1.3Hz,1H),7.33–7.22(m,2H),6.84–6.73(m,2H),4.80(s,2H),3.88(s,2H).EI-MS m/z:360[M]+.
实施例45
2-(3-羟基-5-(3-邻氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-邻氯苯氧基丙炔(182.6mg,1.1mmol)替换丙炔,得到白色固体产物84.0mg,两步收率23.6%。m.p.127.1-129.4℃。1H NMR(300MHz,DMSO-d6)δ8.74(d,J=1.2Hz,1H),8.20(s,1H),7.64(d,J=1.3Hz,1H),7.31(dd,J=7.5,2.0Hz,1H),7.16-7.10(m,1H),6.98-6.92(m,1H),6.83(dd,J=7.5,2.1Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:360[M]+.
实施例46
2-(3-羟基-5-(3-间氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-间氯苯氧基丙炔(182.6mg,1.1mmol)替换丙炔,得到白色固体产物74.0mg,两步收率20.5%。m.p.110.2-112.6℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.64(d,J=1.2Hz,1H),7.24(t,J=7.5Hz,1H),7.09-7.05(m,1H),6.94–6.76(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:360[M]+.
实施例47
2-(3-羟基-5-(3-对氟苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对氟苯氧基丙炔(165.0mg,1.1mmol)替换丙炔,得到白色固体产物88.0mg,两步收率25.5%。m.p.171.2-173.7℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.20(s,1H),7.64(d,J=1.3Hz,1H),7.09–6.96(m,2H),6.88–6.75(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:344[M]+.
实施例48
2-(3-羟基-5-(3-间溴苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-间溴苯氧基丙炔(165.0mg,1.1mmol)替换丙炔,得到白色固体产物88.0mg,两步收率25.5%。m.p.132.1-134.5℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.64(d,J=1.3Hz,1H),7.37-7.33(m,1H),7.15(t,J=7.5Hz,1H),7.01–6.84(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:404[M]+.
实施例49
2-(3-羟基-5-(3-间氰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-间氰基苯氧基丙炔(127.7mg,1.1mmol)替换丙炔,得到白色固体产物68.0mg,两步收率19.4%。m.p.181.2-183.4℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.3Hz,1H),8.20(s,1H),7.75–7.61(m,3H),7.19–7.09(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:351[M]+.
实施例50
2-(3-羟基-5-(3-对乙酰氨基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对乙酰胺基苯氧基丙炔(207.9mg,1.1mmol)替换丙炔,得到黄色固体产物77.0mg,两步收率20.1%。m.p.117.1-119.3℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.3Hz,1H),8.20(s,1H),7.65(d,J=1.2Hz,1H),7.57(s,1H),7.48–7.37(m,2H),6.88–6.78(m,2H),4.68(s,2H),3.60(s,2H),2.10(s,3H).EI-MS m/z:383[M]+.
实施例51
2-(3-羟基-5-(3-对叔丁氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(对叔丁基氨甲酰基苯氧基)丙炔(254.1mg,1.1mmol)替换丙炔,得到棕色固体产物77.0mg,两步收率20.1%。m.p.141.2-143.5℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.3Hz,1H),8.20(s,1H),7.73–7.62(m,3H),6.97–6.86(m,2H),5.99(s,1H),4.68(s,2H),3.60(s,2H),1.47(s,9H).EI-MS m/z:425[M]+.
实施例52
2-(3-羟基-5-(3-对氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对氨基甲酰基苯氧基丙炔(190.3mg,1.1mmol)替换丙炔,得到棕色固体产物76.0mg,两步收率20.6%。m.p.122.1-124.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.2Hz,1H),8.20(s,1H),7.69–7.56(m,3H),6.97–6.86(m,2H),6.15(s,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:369[M]+.
实施例53
2-(3-羟基-5-(3-(N-甲基-N-叔丁基氨甲酰基)吡啶-3-基氧基)丙炔-1-基)吡啶甲酰氨基乙酸
制备方法同实施例1,用3-((N-甲基-N-叔丁基氨甲酰基)吡啶-3-基氧基)丙炔(269.5mg,1.1mmol)替换丙炔,得到白色固体产物106.0mg,两步收率24.1%。m.p.137.1-139.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.20(s,1H),7.63–7.52(m,2H),7.06–6.95(m,2H),4.68(s,2H),3.60(s,2H),2.99(s,3H),1.21(s,9H).EI-MS m/z:440[M]+.
实施例54
2-(3-羟基-5-(3-对环戊氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(对环戊氨基甲酰基苯氧基)丙炔(251.9mg,1.1mmol)替换丙炔,得到白色固体产物56.0mg,两步收率13.2%。m.p.154.1-156.8℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.2Hz,1H),7.55–7.44(m,2H),6.95–6.84(m,2H),4.68(s,2H),3.60(s,2H),3.56–3.42(m,4H),2.03–1.87(m,4H).EI-MSm/z:423[M]+.
实施例55
2-(3-羟基-5-(3-对环丙氨基甲酰基苯氧基丙炔-1-基)-6-氯)吡啶甲酰氨基乙酸
制备方法同实施例1,用3-羟基-5-溴-6-氯吡啶2-甲酸替换2-羟基-5-溴吡啶-2-甲酸,用3-(对环丙氨基甲酰基苯氧基)丙炔(251.9mg,1.1mmol)替换丙炔,得到白色固体产物76.0mg,三步收率17.7%。m.p.147.2-149.2℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.92–7.77(m,3H),7.23–7.12(m,2H),4.68(s,2H),3.60(s,2H),1.61(s,4H).EI-MS m/z:429[M]+.
实施例56
2-(3-羟基-5-(3-对(甲基高哌嗪基甲酰基)苯氧基丙炔-1-基)-苯氧基-1-丙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1,用3-((甲基高哌嗪基)甲酰基苯氧基)丙炔(299.2mg,1.1mmol)替换丙炔,得到白色固体产物86.0mg,两步收率18.4%。m.p.168.9-172.1℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.2Hz,1H),8.20(s,1H),7.66(d,J=1.3Hz,1H),7.55–7.45(m,2H),6.95–6.85(m,2H),4.68(s,2H),3.60(s,2H),3.60-3.27(m,4H),2.90(t,J=5.9Hz,2H),2.66(t,J=6.4Hz,2H),2.27(s,3H),1.73-1.65(m,2H).EI-MS m/z:466[M]+.
实施例57
2-(3-羟基-5-(3-对苯基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对苯基苯氧基丙炔(228.8mg,1.1mmol)替换丙炔,得到白色固体产物95.0mg,两步收率23.6%。m.p.201.5-203.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J=1.3Hz,1H),8.20(s,1H),7.73(d,J=1.3Hz,1H),7.64–7.53(m,2H),7.55–7.38(m,4H),7.36-7.30(m,1H),7.12–7.01(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:402[M]+.
实施例58
2-(3-羟基-5-(3-(萘-2-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(萘-2-氧基)丙炔(200.2mg,1.1mmol)替换丙炔,得到白色固体产物45.0mg,两步收率11.9%。m.p.211.5-213.7℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J=1.2Hz,1H),8.20(s,1H),7.76(d,J=1.3Hz,1H),7.72–7.62(m,2H),7.56(dt,J=7.3,1.6Hz,1H),7.41-7.36(m,2H),7.14(dd,J=7.9,1.5Hz,1H),6.97(t,J=1.7Hz,1H),4.91(s,2H),3.89(s,2H).EI-MS m/z:376[M]+.
实施例59
2-(3-羟基-5-(3-(喹啉-5-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(喹啉-5-氧基)丙炔(201.3mg,1.1mmol)替换丙炔,得到棕色固体产物65.0mg,两步收率17.2%。m.p.223.1-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.83–8.71(m,2H),8.44(dd,J=7.4,1.5Hz,1H),8.20(s,1H),7.80–7.67(m,2H),7.53-7.49(m,2H),6.70-6.68(m,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:377[M]+.
实施例60
2-(3-羟基-5-(3-(苯并呋喃-7-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(苯并呋喃-7-氧基)丙炔(201.3mg,1.1mmol)替换丙炔,得到棕色固体产物75.0mg,两步收率20.4%。m.p.196.1-198.7℃。1H NMR(300MHz,DMSO-d6)δ8.70
(d,J=1.2Hz,1H),8.20(s,1H),7.66(d,J=1.3Hz,1H),7.52(d,J=7.5Hz,1H),7.23–7.06(m,2H),6.99(dd,J=7.3,1.8Hz,1H),6.72(dd,J=7.5,1.5Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:366[M]+.
实施例61
2-(3-羟基-5-(3-(2,3-二氯苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(2,3-二氯苯基)氧基丙炔(218.9mg,1.1mmol)替换丙炔,得到白色固体产物62.0mg,两步收率15.7%。m.p.152.2-154.6℃。1H NMR(300MHz,DMSO-d6)δ8.74(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.3Hz,1H),7.28(dd,J=7.5,2.1Hz,1H),7.17(t,J=7.5Hz,1H),6.71(dd,J=7.4,2.0Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例62
2-(3-羟基-5-(3-(3,4-二氯苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-(3,5-二氯苯基)氧基丙炔(218.9mg,1.1mmol)替换丙炔,得到白色固体产物74.0mg,两步收率18.7%。m.p.157.5-159.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J=1.2Hz,1H),8.20(s,1H),7.66(d,J=1.2Hz,1H),7.42(d,J=2.0Hz,1H),7.26(dd,J=7.5,2.0Hz,1H),6.97(d,J=7.5Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例63
2-(3-羟基-5-(3-对环丙基苯氧基丙炔-1-基)-6-甲基)吡啶甲酰氨基乙酸
按实施例1的方法,用3-羟基-5-溴-6-甲基吡啶甲酸(372mg,2mmol)替换3-羟基-5-溴吡啶甲酸,3-对环丙基苯氧基丙炔替换丙炔(189.2,1.1mmol),得到谈黄色固体产物82mg,收率21.5%。m.p.177.5-179.4℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),7.77(s,1H),7.17–
7.06(m,2H),6.93–6.82(m,2H),4.68(s,2H),3.60(s,2H),2.76(s,3H),1.18–1.03(m,2H),0.90–0.72(m,2H).EI-MS m/z:380[M]+.
实施例64
2-(3-羟基-5-(3-苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-苯氨基丙炔(144.1mg,1.1mmol)替换丙炔,得到白色固体产物64.0mg,两步收率20.0%。m.p.131.1-133.5℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J=1.3Hz,1H),8.20(s,1H),7.63(d,J=1.2Hz,1H),7.11–6.97(m,2H),6.74-6.69(m,1H),6.64–6.52(m,2H),4.29(s,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:325[M]+.
实施例65
2-(3-羟基-5-((3-对氯苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对氯苯氨基丙炔(181.1mg,1.1mmol)替换丙炔,得到白色固体产物78.0mg,两步收率21.7%。m.p.137.2-139.3℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=1.3Hz,1H),8.20(s,1H),7.71(d,J=1.2Hz,1H),7.07–6.96(m,2H),6.56–6.45(m,2H),4.13(s,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:359[M]+.
实施例66
2-(3-羟基-5-(3-对乙基苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-对乙基苯氨基丙炔(174.9mg,1.1mmol)替换丙炔,得到白色固体产物68.0mg,两步收率19.2%。m.p.145.1-147.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J=1.3Hz,1H),8.20(s,1H),7.64(d,J=1.2Hz,1H),6.99-6.90(m,2H),6.63–6.53(m,2H),4.11(s,1H),3.80(s,2H),3.60(s,2H),2.64-2.5(m,2H),1.19(t,J=6.6Hz,3H).EI-MS m/z:353[M]+.
实施例67
2-(3-羟基-5-(3-((N-甲基-N-对咪唑-2基苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-((N-甲基-N-对咪唑-2基苯基)氨基)丙炔(131.2mg,1.1mmol)替换丙炔,得到白色固体产物68.0mg,两步收率16.7%。m.p.199.1-201.7℃。1H NMR(300MHz,DMSO-d6)δ8.49(d,J=1.3Hz,1H),8.20(s,1H),7.91(s,1H),7.65–7.53(m,3H),7.41(s,1H),6.97–6.86(m,2H),4.09(s,2H),3.60(s,2H),2.97(s,3H).EI-MS m/z:405[M]+.
实施例68
2-(3-羟基-5-(3-((N-苯基-N-3,4-二氟苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-((N-苯基-N-3,4-二氟苯基)氨基)丙炔(267.3mg,1.1mmol)替换丙炔,得到白色固体产物72.0mg,两步收率16.4%。m.p.205.2-207.3℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J=1.2Hz,1H),8.20(s,1H),7.63(d,J=1.3Hz,1H),7.30–7.17(m,4H),7.11–6.96(m,1H),6.93-6.90(m,1H),6.79-6.76(m,1H),6.66-6.56(m,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:437[M]+.
实施例69
2-(3-羟基-5-(3-((N-叔丁基-N-3-甲基-4-乙氧基苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1,用3-((N-叔丁基-N-3-甲基-4-乙氧基苯基)氨基)丙炔(269.5mg,1.1mmol)替换丙炔,得到白色固体产物82.0mg,两步收率18.6%。m.p.210.2-212.6℃。1H NMR(300MHz,DMSO-d6)δ8.62(d,J=1.3Hz,1H),8.20(s,1H),7.37(d,J=1.2Hz,1H),6.99-6.96(m,1H),6.54(s,1H),6.58–6.48(m,1H),4.09(s,3H),4.07(s,1H),3.60(s,2H),2.23(d,J=1.0Hz,3H),1.43(t,J=5.9Hz,3H),1.22(s,10H).EI-MS m/z:439[M]+.
Claims (10)
- 通式(I)的化合物或其药学上可接受的盐:其中X代表NH、NCH3或CH2;Y代表氢、羟基、甲氧基或乙氧基;L代表–CH2–、–CH2O–或R6代表氢、C1-C4烷基或苯基;n代表0或1;R1代表C1-C4烷基、苯基、取代苯基、含氧或氮的5~6员芳杂环、取代的含氧或氮的5~6员芳杂环,所述取代基是C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基、 苯基或含氧或氮的5~6员芳杂环,其中R7代表C1-C4烷基;R8、R9各自独立地代表氢或C1-C4烷基,或者R8、R9连接形成3~7员含氮杂环;R2代表氢、卤素或甲基;R3、R4各自独立地代表氢、甲基或乙基;R5代表羟基、C1-C4烷氧基或–NR10R11;R10、R11各自独立地代表氢、甲基或乙基。
- 权利要求1的化合物或其药学上可接受的盐,其中X代表NH。
- 权利要求1的化合物或其药学上可接受的盐,其中L代表–CH2–、–CH2O–或R6代表氢、甲基、叔丁基或苯基。
- 权利要求1的化合物或其药学上可接受的盐,其中R1代表取代苯环,取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、叔丁氧基、环丙氧基、苯基、氰基、卤素、氟甲基、三氟甲基、咪唑基、乙酰氨基、环丙基甲酰氨基或其中R8、R9各自独立地代表氢、甲基、丁基或叔丁基,或两者连接形成环丙氨基、四氢吡咯基或N-甲基高哌嗪基。
- 权利要求1的化合物或其药学上可接受的盐,其中R1代表环丙基、叔丁基、苯基、萘基、喹啉基或苯并呋喃基。
- 权利要求1的化合物或其药学上可接受的盐,其中R3或R4代表氢。
- 权利要求1的化合物或其药学上可接受的盐,其中R5代表-NH2、-NHCH3、羟基、甲氧基、 异丙氧基、环丙氧基或环丙基甲氧基。
- 一种药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
- 权利要求1的化合物或其药学上可接受的盐用于制备治疗贫血症或缺血性疾病的药物的用途。
- 权利要求9的用途,其中缺血性疾病是缺血性脑卒中或心肌缺血相关疾病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2015106483429 | 2015-10-09 | ||
CN201510648342.9A CN105130888A (zh) | 2015-10-09 | 2015-10-09 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
PCT/CN2015/095728 WO2017059623A1 (zh) | 2015-10-09 | 2015-11-27 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107848976A true CN107848976A (zh) | 2018-03-27 |
CN107848976B CN107848976B (zh) | 2020-11-17 |
Family
ID=54716523
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510648342.9A Pending CN105130888A (zh) | 2015-10-09 | 2015-10-09 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
CN201580079971.2A Active CN107848976B (zh) | 2015-10-09 | 2015-11-27 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510648342.9A Pending CN105130888A (zh) | 2015-10-09 | 2015-10-09 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
Country Status (21)
Country | Link |
---|---|
US (2) | US10889546B2 (zh) |
EP (1) | EP3360862B1 (zh) |
JP (1) | JP6635562B2 (zh) |
KR (1) | KR20180063229A (zh) |
CN (2) | CN105130888A (zh) |
AU (1) | AU2015411258B2 (zh) |
BR (1) | BR112018005969A2 (zh) |
CA (1) | CA3000040A1 (zh) |
DK (1) | DK3360862T3 (zh) |
ES (1) | ES2794002T3 (zh) |
HK (1) | HK1247613A1 (zh) |
HR (1) | HRP20200907T1 (zh) |
HU (1) | HUE049409T2 (zh) |
LT (1) | LT3360862T (zh) |
MX (1) | MX2018003832A (zh) |
PL (1) | PL3360862T3 (zh) |
PT (1) | PT3360862T (zh) |
RU (1) | RU2692494C1 (zh) |
SI (1) | SI3360862T1 (zh) |
UA (1) | UA120407C2 (zh) |
WO (1) | WO2017059623A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116120340A (zh) * | 2021-11-15 | 2023-05-16 | 艾立康药业股份有限公司 | 一种吡啶并噁嗪类化合物及其制备方法、组合物和用途 |
CN116514710A (zh) * | 2022-01-21 | 2023-08-01 | 中国药科大学 | 环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105130888A (zh) | 2015-10-09 | 2015-12-09 | 中国药科大学 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
CN107417605A (zh) * | 2017-08-02 | 2017-12-01 | 江苏艾立康药业股份有限公司 | 作用于脯氨酰羟化酶的吡啶衍生化合物 |
JP2021500315A (ja) * | 2017-10-25 | 2021-01-07 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co.,Ltd. | アルキニルピリジンプロリル水酸化酵素阻害剤の結晶型及びその製造方法 |
CN110240562B (zh) * | 2018-03-08 | 2022-04-12 | 江苏恒瑞医药股份有限公司 | 一种脯氨酰羟化酶抑制剂的可药用盐、晶型及其制备方法 |
EP3805204A4 (en) * | 2018-05-24 | 2021-12-15 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | METHOD OF MANUFACTURING AN ALKINYLPYRIDINEPROLYLHYDROXYLASE INHIBITOR |
CN109593084B (zh) * | 2019-01-23 | 2021-09-28 | 中国药科大学 | 脯氨酰羟化酶小分子光敏前药及其制备方法与应用 |
EP3936119A1 (en) * | 2019-03-04 | 2022-01-12 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition of prolyl hydroxylase inhibitor and preparation method therefor |
CN112741834A (zh) * | 2021-02-07 | 2021-05-04 | 复旦大学附属中山医院 | HIF-1α降解抑制剂在制备酮体水平升高的冠心病药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101506149A (zh) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | 脯氨酰羟化酶抑制剂及使用方法 |
CN101626685A (zh) * | 2007-01-12 | 2010-01-13 | 史密丝克莱恩比彻姆公司 | N-取代的甘氨酸衍生物:羟化酶抑制剂 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4410480A1 (de) * | 1994-03-25 | 1995-09-28 | Hoechst Ag | Sulfonamidocarbonylpyridin-2-carbonsäureesteramide sowie ihre Pyridin-N-oxide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
AU2007334321B2 (en) * | 2006-12-18 | 2012-03-08 | Amgen Inc. | Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
WO2011132633A1 (ja) * | 2010-04-19 | 2011-10-27 | 第一三共株式会社 | 置換5-ヒドロキシピリミジン-4-カルボキサミド化合物 |
US9738604B2 (en) * | 2010-09-03 | 2017-08-22 | Duke University | Ethynylbenzene derivatives |
US9206134B2 (en) | 2011-07-22 | 2015-12-08 | Beijing Betta Pharmaceuticals Co. Ltd. | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
CN105130888A (zh) | 2015-10-09 | 2015-12-09 | 中国药科大学 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
-
2015
- 2015-10-09 CN CN201510648342.9A patent/CN105130888A/zh active Pending
- 2015-11-27 UA UAA201804628A patent/UA120407C2/uk unknown
- 2015-11-27 RU RU2018113258A patent/RU2692494C1/ru active
- 2015-11-27 KR KR1020187012413A patent/KR20180063229A/ko not_active Application Discontinuation
- 2015-11-27 CN CN201580079971.2A patent/CN107848976B/zh active Active
- 2015-11-27 ES ES15905721T patent/ES2794002T3/es active Active
- 2015-11-27 SI SI201531228T patent/SI3360862T1/sl unknown
- 2015-11-27 HU HUE15905721A patent/HUE049409T2/hu unknown
- 2015-11-27 BR BR112018005969-2A patent/BR112018005969A2/zh not_active Application Discontinuation
- 2015-11-27 AU AU2015411258A patent/AU2015411258B2/en not_active Ceased
- 2015-11-27 CA CA3000040A patent/CA3000040A1/en not_active Abandoned
- 2015-11-27 PL PL15905721T patent/PL3360862T3/pl unknown
- 2015-11-27 US US15/765,387 patent/US10889546B2/en active Active
- 2015-11-27 LT LTEP15905721.5T patent/LT3360862T/lt unknown
- 2015-11-27 PT PT159057215T patent/PT3360862T/pt unknown
- 2015-11-27 WO PCT/CN2015/095728 patent/WO2017059623A1/zh active Application Filing
- 2015-11-27 DK DK15905721.5T patent/DK3360862T3/da active
- 2015-11-27 JP JP2018515119A patent/JP6635562B2/ja not_active Expired - Fee Related
- 2015-11-27 EP EP15905721.5A patent/EP3360862B1/en active Active
- 2015-11-27 MX MX2018003832A patent/MX2018003832A/es unknown
-
2018
- 2018-05-29 HK HK18107005.8A patent/HK1247613A1/zh unknown
-
2020
- 2020-06-07 HR HRP20200907TT patent/HRP20200907T1/hr unknown
- 2020-09-11 US US17/018,221 patent/US20200407319A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101506149A (zh) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | 脯氨酰羟化酶抑制剂及使用方法 |
CN101626685A (zh) * | 2007-01-12 | 2010-01-13 | 史密丝克莱恩比彻姆公司 | N-取代的甘氨酸衍生物:羟化酶抑制剂 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116120340A (zh) * | 2021-11-15 | 2023-05-16 | 艾立康药业股份有限公司 | 一种吡啶并噁嗪类化合物及其制备方法、组合物和用途 |
CN116514710A (zh) * | 2022-01-21 | 2023-08-01 | 中国药科大学 | 环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用 |
CN116514710B (zh) * | 2022-01-21 | 2024-07-05 | 中国药科大学 | 环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN105130888A (zh) | 2015-12-09 |
DK3360862T3 (da) | 2020-06-02 |
JP6635562B2 (ja) | 2020-01-29 |
SI3360862T1 (sl) | 2020-08-31 |
PL3360862T3 (pl) | 2020-09-21 |
CN107848976B (zh) | 2020-11-17 |
CA3000040A1 (en) | 2017-04-13 |
HUE049409T2 (hu) | 2020-10-28 |
HRP20200907T1 (hr) | 2020-09-04 |
EP3360862A1 (en) | 2018-08-15 |
JP2018529690A (ja) | 2018-10-11 |
EP3360862B1 (en) | 2020-04-22 |
AU2015411258B2 (en) | 2020-09-17 |
PT3360862T (pt) | 2020-05-27 |
US10889546B2 (en) | 2021-01-12 |
UA120407C2 (uk) | 2019-11-25 |
EP3360862A4 (en) | 2018-08-15 |
AU2015411258A1 (en) | 2018-05-10 |
MX2018003832A (es) | 2018-06-18 |
US20180305317A1 (en) | 2018-10-25 |
WO2017059623A1 (zh) | 2017-04-13 |
HK1247613A1 (zh) | 2018-09-28 |
LT3360862T (lt) | 2020-07-10 |
BR112018005969A2 (zh) | 2018-10-16 |
KR20180063229A (ko) | 2018-06-11 |
US20200407319A1 (en) | 2020-12-31 |
ES2794002T3 (es) | 2020-11-17 |
RU2692494C1 (ru) | 2019-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107848976A (zh) | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 | |
EP2238110B1 (fr) | Dérivés de 5.6-bisaryl-2-pyr1dine-carboxamide, leur préparatio leur application en thérapeutique comme antagonistes des recepteurs a l'urotensine ii | |
EP3162801B1 (en) | Salt of halogen-substituted heterocyclic compound | |
KR20040030668A (ko) | 헤테로아릴설포닐 측쇄를 갖는 안트라닐산 아미드, 이의제조방법, 약제 또는 진단제로서의 이의 용도 및 당해화합물을 함유하는 약제학적 제제 | |
US8299066B2 (en) | Compounds having NPY Y5 receptor antagonistic activity | |
JP2011503042A (ja) | p38MAPキナーゼ阻害剤 | |
KR102132744B1 (ko) | 당뇨병 치료에 유용한 이미다조피리딘 유도체들 | |
JP7177577B2 (ja) | 新規な化合物およびこれを含む薬学的組成物 | |
JP2022516195A (ja) | ヒドロキサム酸誘導体並びその調製方法及び使用 | |
JPH02229168A (ja) | ピラゾロン誘導体 | |
TWI762634B (zh) | 胺基-芳基-苯甲醯胺化合物及其使用方法 | |
JP2002502840A (ja) | ビフェニルスルホニルシアナミド、それらの製法および医薬としてのそれらの使用 | |
CN111072586B (zh) | 一种n-羟基-3-取代-5-甲酰胺化合物及其制备方法和用途 | |
US20180064665A1 (en) | N-phenyl-n'-phenoxycarbonyl-phenylsulfonhydrazide derivative and pharmaceutical composition comprising the same | |
CN109232426A (zh) | 一种n-羟基-5-取代-1h-吡唑-3-甲酰胺化合物及其制备方法和用途 | |
CN113209066B (zh) | 氨基-芳基-苯甲酰胺化合物及其使用方法 | |
CN117229259B (zh) | 一种8-喹啉磺酰胺苯基咪唑类化合物及其应用 | |
KR102343936B1 (ko) | 신규한 카르복스아마이드계 화합물 및 이를 포함하는 대사성 질환의 예방 또는 치료용 조성물 | |
CN118164983A (zh) | 一种β-咔啉并[1',2':1,2]咪唑衍生物及其制备方法和应用、药物组合物 | |
TW202404577A (zh) | 預防或治療特發性肺纖維化(ipf)之組合物 | |
WO2011022928A1 (zh) | 喹啉类化合物、其制备方法、包含该化合物的药物组合物及该化合物的用途 |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1247613 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |