CN111712491B - 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 - Google Patents
四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 Download PDFInfo
- Publication number
- CN111712491B CN111712491B CN201980012210.3A CN201980012210A CN111712491B CN 111712491 B CN111712491 B CN 111712491B CN 201980012210 A CN201980012210 A CN 201980012210A CN 111712491 B CN111712491 B CN 111712491B
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesis
- maj
- esi
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 title claims description 830
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title 1
- -1 tetrahydroisoquinoline compound Chemical class 0.000 claims abstract description 45
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims abstract description 24
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 18
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 6
- 208000026278 immune system disease Diseases 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 14
- 229910052805 deuterium Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 229910052757 nitrogen Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 201000008937 atopic dermatitis Diseases 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 8
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 208000010668 atopic eczema Diseases 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 206010012434 Dermatitis allergic Diseases 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 5
- 201000010105 allergic rhinitis Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 238000006407 Bischler-Napieralski reaction Methods 0.000 claims description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 2
- 238000007126 N-alkylation reaction Methods 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 238000011278 co-treatment Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 208000013403 hyperactivity Diseases 0.000 claims description 2
- 125000005647 linker group Chemical group 0.000 claims description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims 1
- 150000001556 benzimidazoles Chemical class 0.000 claims 1
- 150000005528 benzodioxoles Chemical class 0.000 claims 1
- 150000001907 coumarones Chemical class 0.000 claims 1
- 150000005232 imidazopyridines Chemical class 0.000 claims 1
- 150000002473 indoazoles Chemical class 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 claims 1
- 150000002545 isoxazoles Chemical class 0.000 claims 1
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 150000003248 quinolines Chemical class 0.000 claims 1
- 150000003252 quinoxalines Chemical class 0.000 claims 1
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 abstract description 12
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 abstract description 9
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 8
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 8
- 206010003246 arthritis Diseases 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 417
- 238000003786 synthesis reaction Methods 0.000 description 416
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 187
- 238000001308 synthesis method Methods 0.000 description 112
- 238000005481 NMR spectroscopy Methods 0.000 description 103
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical group C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000003814 drug Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 19
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 17
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 17
- 230000002401 inhibitory effect Effects 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000004896 high resolution mass spectrometry Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 13
- 230000028327 secretion Effects 0.000 description 12
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000002158 endotoxin Substances 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 229920006008 lipopolysaccharide Polymers 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 7
- 229960001164 apremilast Drugs 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- TXQAZWIBPGKHOX-UHFFFAOYSA-N 1H-indol-3-amine Chemical compound C1=CC=C2C(N)=CNC2=C1 TXQAZWIBPGKHOX-UHFFFAOYSA-N 0.000 description 6
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 6
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 6
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 6
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 6
- RDHPKYGYEGBMSE-VQEHIDDOSA-N bromoethane Chemical group C[13CH2]Br RDHPKYGYEGBMSE-VQEHIDDOSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 4
- 208000038016 acute inflammation Diseases 0.000 description 4
- 230000006022 acute inflammation Effects 0.000 description 4
- 210000004712 air sac Anatomy 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000002085 irritant Substances 0.000 description 4
- 231100000021 irritant Toxicity 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical class 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- ZGJAXOTYURVTAI-UHFFFAOYSA-N 3-(5-acetamido-1H-indol-3-yl)propanoic acid Chemical compound CC(=O)Nc1ccc2[nH]cc(CCC(O)=O)c2c1 ZGJAXOTYURVTAI-UHFFFAOYSA-N 0.000 description 3
- YZIYXJVRBIAHGN-UHFFFAOYSA-N 3-(5-hydroxy-1H-indol-3-yl)propanoic acid Chemical compound C1=C(O)C=C2C(CCC(=O)O)=CNC2=C1 YZIYXJVRBIAHGN-UHFFFAOYSA-N 0.000 description 3
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000006278 bromobenzyl group Chemical group 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- GOLXRNDWAUTYKT-UHFFFAOYSA-N 3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(CCC(=O)O)=CNC2=C1 GOLXRNDWAUTYKT-UHFFFAOYSA-N 0.000 description 2
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical group FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010036281 Cyclic Nucleotide-Gated Cation Channels Proteins 0.000 description 2
- 102000012003 Cyclic Nucleotide-Gated Cation Channels Human genes 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 102000012074 GAF domains Human genes 0.000 description 2
- 108050002598 GAF domains Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 2
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- YSLFMGDEEXOKHF-UHFFFAOYSA-N difluoro(iodo)methane Chemical group FC(F)I YSLFMGDEEXOKHF-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- DKWNYTKOLIZNAX-UHFFFAOYSA-N 1-chloro-2-methylsulfonylethane Chemical group CS(=O)(=O)CCCl DKWNYTKOLIZNAX-UHFFFAOYSA-N 0.000 description 1
- KURKJXZWCPWPFX-UHFFFAOYSA-N 2,2-difluoroacetyl chloride Chemical group FC(F)C(Cl)=O KURKJXZWCPWPFX-UHFFFAOYSA-N 0.000 description 1
- IDKLNGUDPJCFML-UHFFFAOYSA-N 2,3-dihydro-1h-imidazo[4,5-b]pyridine Chemical compound C1=CN=C2NCNC2=C1 IDKLNGUDPJCFML-UHFFFAOYSA-N 0.000 description 1
- FJSAJUXIHJIAMD-UHFFFAOYSA-N 2,4-difluorobenzenesulfonyl chloride Chemical group FC1=CC=C(S(Cl)(=O)=O)C(F)=C1 FJSAJUXIHJIAMD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 1
- FSGLUBQENACWCC-UHFFFAOYSA-N 3,4-difluorobenzenesulfonyl chloride Chemical group FC1=CC=C(S(Cl)(=O)=O)C=C1F FSGLUBQENACWCC-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OKYSUJVCDXZGKE-UHFFFAOYSA-N 3-fluorobenzenesulfonyl chloride Chemical group FC1=CC=CC(S(Cl)(=O)=O)=C1 OKYSUJVCDXZGKE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- OKAMMYAHLWEFBP-UHFFFAOYSA-N 5-(difluoromethyl)-1h-indole Chemical group FC(F)C1=CC=C2NC=CC2=C1 OKAMMYAHLWEFBP-UHFFFAOYSA-N 0.000 description 1
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 1
- ANGRSSWNBDJESO-UHFFFAOYSA-N 6-chloro-5-fluoro-1h-indole Chemical group C1=C(Cl)C(F)=CC2=C1NC=C2 ANGRSSWNBDJESO-UHFFFAOYSA-N 0.000 description 1
- SSBPRGFEADRKDA-UHFFFAOYSA-N 6-chloro-5-methoxy-1h-indole Chemical group C1=C(Cl)C(OC)=CC2=C1NC=C2 SSBPRGFEADRKDA-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 101710096438 DNA-binding protein Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108091065684 PDE4 family Proteins 0.000 description 1
- 102000039036 PDE4 family Human genes 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- MJWVCJUSRGLHFO-UHFFFAOYSA-N cyclohexanesulfonyl chloride Chemical group ClS(=O)(=O)C1CCCCC1 MJWVCJUSRGLHFO-UHFFFAOYSA-N 0.000 description 1
- PFWWSGFPICCWGU-UHFFFAOYSA-N cyclopropanesulfonyl chloride Chemical group ClS(=O)(=O)C1CC1 PFWWSGFPICCWGU-UHFFFAOYSA-N 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical group CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical group CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 102000048135 human PDE4D Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 description 1
- 230000013016 learning Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- JHHMSRLTZAUMOJ-UHFFFAOYSA-N methanamine;oxolane Chemical compound NC.C1CCOC1 JHHMSRLTZAUMOJ-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- DRYBMFJLYYEOBZ-UHFFFAOYSA-N methyl 1h-indole-5-carboxylate Chemical group COC(=O)C1=CC=C2NC=CC2=C1 DRYBMFJLYYEOBZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940127284 new molecular entity Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003234 polygenic effect Effects 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical group ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000565 sulfonamide group Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical group FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
-
- 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
- C07D401/08—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 carbon chain containing alicyclic rings
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种新型四氢异喹啉类化合物及其中间体的制备方法、药物组合物和用途。本发明的四氢异喹啉类化合物对磷酸二酯酶(PDE4)具有良好的抑制效果,可以用于预防、治疗或辅助治疗与磷酸二酯酶活性或表达相关的多种疾病,尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。
Description
技术领域
本发明涉及新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途,属于医药技术领域。涉及通式(I)所示的新型四氢异喹啉类化合物,其药物上可接受盐、异构体、溶剂化物、代谢产物、代谢前体,含有他们的药物组合以及这类化合物在预防和、或治疗或辅助治疗与磷酸二酯酶活性相关的银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、***性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症和精神***症等疾病,尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。
背景技术
环核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases,PDEs)选择性催化水解细胞内第二信使环磷酸腺苷(cAMP)或环磷酸鸟苷(cGMP)中的3-磷酸酯键,生成产物5-AMP或5-GMP,从而灭活cAMP或cGMP信号。PDEs活性功能发挥正常与否直接影响细胞内cAMP和/或cGMP浓度,进而影响此类第二信使参与的信号通路下游信号传递(Omori K,etal.Circ.Res.2007,100:309-327;Maurice DH,et al.Nat.Rev.Drug Discov.2014,13:290-314)。目前已知cAMP下游存在多种与其直接相互作用的蛋白质,包括PDEs、经典的cAMP浓度依赖蛋白激酶、cAMP直接激活交换蛋白、环核苷酸门控离子通道、cAMP直接结合DNA结合蛋白CRP/CAP和部分包含GAF结构域的蛋白质等。相应地,与cGMP直接相互作用蛋白质除了PDEs以外还有cGMP浓度依赖蛋白激酶、环核苷酸门控离子通道和部分包含GAF结构域的蛋白质等。这些信号通路与细胞周期控制、细胞分化、炎症、心脏功能、平滑肌舒张与收缩、视觉信号传导、学习与记忆等生理及相关病理过程密切相关。抑制PDEs水解活性,改变细胞内cAMP或cGMP浓度,从而直接调控cAMP或cGMP相关的信号通路,改变相关功能症状。因此,PDEs是重要的药物作用靶标家族,PDEs抑制剂已经广泛应用于多种疾病病理机制研究及治疗(Maurice DH,et al.Nat.Rev.Drug Discov.2014,13:290-314;Menniti FS,etal.Nat.Rev.Drug Discov.2006,5(8),660-670)。
PDEs是一个多基因的超家族。迄今为止已在哺乳动物中发现21个PDE基因,分为11个亚家族,共包含100余种具有不同底物专一性、酶动力学特征、异构调控特点以及在组织和亚细胞中分布、参与信号通路和对抑制剂敏感性等不同的PDE同功酶(或称为亚型)(Lugnier C,Pharmacol.Ther.2006,109:366-398;Francis SH,etal.Handb.Exp.Pharmacol.2011,204:47-84)。例如PDE4、7和8主要水解cAMP;PDE5、6和9则选择性作用于cGMP;而PDE1、2、3、10和11既可以水解cAMP又可以水解cGMP,虽然不同同工酶对两底物的亲合力和水解活性有所差别。与对底物具有不同选择性不同,PDEs家族成员的结构特征非常相似,通常由靠近N端调控结构域和邻近C端催化结构域组成,催化结构域(约270个氨基酸)负责对底物进行水解反应。目前已知的PDEs抑制剂主要通过作用于PDEs的催化结构域而实现抑制其活性的功能。
PDE4特异性水解细胞内第二信使分子cAMP,抑制PDE4的活性将导致cAMP的积累,高浓度的cAMP将激活蛋白激酶A,活化的蛋白激酶A可以将下游转录因子磷酸化,从而调控大量细胞因子的转录和表达(Houslay MD,et al.Biochem.J.,2003,370:1-18)。PDE4家族包括四个基因(PDE4A/B/C/D),在表达过程中选择性剪接形成超过25种同工酶。PDE4在体内分布广泛,主要表达于免疫相关细胞如中性粒细胞、嗜酸性粒细胞和单核细胞等(MauriceDH,et al.Mol.Pharmacol.,2003,64:533-546)。PDE4涉及的疾病种类繁多,其中与PDE4在炎症进程中的作用相关的有慢性阻塞性肺疾病、哮喘、银屑病、过敏性鼻炎、特发性肺纤维化和风湿性关节炎等疾病,而涉及神经***的疾病包括阿尔兹海默症、帕金森氏症、抑郁症和精神***症等(Menniti FS,et al.Nat.Rev.Drug Discov.,2006,5:660-670;BurginAB,et al.Nat.Biotechnol.,2010,28:63-70;Garcia-Osta A,et al.ACSChem.Neurosci.,2012,3:832-844.)。
银屑病是一种免疫介导的、以角质形成细胞增殖和大量白细胞浸润为特征的慢性复发性皮肤炎症,该疾病顽固难治且严重影响患者的生活质量及身心健康,是当今世界皮肤科领域拟解决的重要疾病之一。该疾病是全球最为常见的自身免疫疾病之一,发病率占世界人口的0.1%-3%。此外银屑病还与其它炎症性疾病如银屑病性关节炎、炎症性肠病和冠状动脉疾病等密切相关。目前虽已有一系列药物(包括外用、口服和生物药物等)用于银屑病的对症治疗,但仍在巨大缺口,迫切需要发现新靶点和研发新药物。TNF-α在银屑病中高度表达,针对TNF-α的阻断治疗在临床上效果显著。通过抑制PDE4水解活性而增加cAMP的浓度能下调TNF-α等促炎因子的表达,因此,PDE4的抑制剂Apremilast于2014年被FDA批准为斑块型银屑病和银屑病关节炎治疗的口服药物(Man H-W,et al.J.Med.Chem.,2009,52:1522-1524)。此外,2016年12月,FDA批准Anacor制药公司的湿疹(即过敏性皮炎)局部治疗药Crisaborole上市。与银屑病类似,过敏性皮炎是一种常见的复发性慢性炎性皮肤疾病,而Crisaborole是非甾体PDE4抑制剂,该药物是FDA在过去15年中批准治疗过敏性皮炎的首个新分子实体。
因此,由于PDE4涉及多种重要疾病且已有部分PDE4抑制剂用于临床治疗,设计和发现靶向PDE4的新型抑制剂是新药研发领域的一大热点。
发明内容
本发明的目的是提供一类新型的四型磷酸二酯酶(PDE4)抑制剂即一类新型四氢异喹啉类化合物、其中间体、制备方法、药物组合物和应用。
本发明的第一方面,提供了一种通式(I)所示的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
手性碳原子C*独立地为S型、R型,或其组合;
n=1或2;
X为-CH2-或-NH-;
Y选自连接基团:C1~C6直链或支链亚烷基、C2~C6直链或支链亚烯基、-CH2O-、-CH2NH2-、-CH2S-、-CONH-、-NHCO-、-COO-、-OOC-、
R1、R2各自独立地选自下组:氢、氘、羟基、卤素、取代或未取代的C1~C6直链或支链烷氧基、取代或未取代的C2~C6直链或支链烯氧基、取代或未取代的C2~C6直链或支链炔氧基、取代或未取代的C3~C7环烷氧基、取代或未取代的C3~C7环烷基甲氧基、苄氧基、C1-C6酰氧基、羧基取代的C2~C8直链烷氧基、N,N-二甲基氨基取代的C2~C8直链烷氧基,COOR5或CONR5R6;所述取代基选自氘或者卤素;或者R1、R2连同与其连接的碳原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环);
R3选自未被取代或者被1-3个取代基取代的以下基团:-C(O)-5~7元杂芳基、-C(O)-4~7元杂环基、-C1~C4酰基(优选为甲酰基-CHO)、-C1~C4烷基、R7SO2-、NH2(CH2)mSO2-、R7SO2(CH2)m-、R7O(CH2)mCO-、R7OCO(CH2)m-、二氟甲基,三氟甲基,C1~C4亚磺酰基,苯磺酰基,5-7元杂芳基磺酰基,苯基,苄基,5~7元杂芳基,4~7元杂环基;其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、C1~C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1~C4酰胺基、C0~C4磺酰基、氨基C0~C4磺酰基、C1-C4烷基取代的磺酰基苯基,苄基,5~7元杂芳基,4~7元杂环基,其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;
R5、R6、R7各自独立地选自氢、取代或未取代的C1~C4直链或支链烷基、取代或未取代的C3~C8环烷基、取代或未取代的C6-C10芳基;所述取代基选自氘或者卤素;
m选自0、1、2、3或者4;
R4选自未被取代或者被1-3个取代基取代的以下基团:C3~C7环烷基、5~12元杂环基、C7~C12芳基、5~12元杂芳基(优选为苯并5~7元杂芳基);其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷基、C2~C6直链或支链烯基、C2~C6直链或支链炔基、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR5、CONR5R6、C1-C6羧基、巯基、C1~C4酰基、C1~C4酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,C1~C4烷基取代的磺酰胺基,N,N-二甲基取代的C1-C6烷氧基,羧基取代的C1-C6烷氧基,或者两个相邻的取代基连同与其连接的碳原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环);
在另一优选例中,通式(I)中:
n=1;
R1、R2各自独立地选自下组:取代或未取代的C1~C6直链或支链烷氧基、取代或未取代的C3~C7环烷氧基、取代或未取代的C3~C7环烷基甲氧基、C1-C6酰氧基、羧基取代的C2~C8直链烷氧基、N,N-二甲基氨基取代的C2~C8直链烷氧基、羧基取代的C2~C8直链烷氧基、N,N-二甲基氨基取代的C2~C8直链烷氧基,COOR5或CONR5R6;所述取代基选自氘或者卤素(包括氟、氯、溴和碘)。
在另一优选例中,R5、R6各自独立地选自氢、C1~C4直链或支链烷基。
在另一优选例中,通式(I)中:
X为-CH2-;
Y选自下组:-CH2-、-CH2-CH2-、-CH=CH-、
R4选自未被取代或者被1-3个取代基取代的以下基团:5~12元杂环基、C6~C12芳基、5~12元杂芳基(优选为苯并5~7元杂芳基);优选地,所述基团中的杂环和杂芳环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
在另一优选例中,通式(I)中:
R3选自未被取代或者被1-3个取代基取代的以下基团:C1~C4酰基(优选为甲酰基),C1~C4烷基,、R7SO2-、NH2(CH2)m SO2-、R7SO2(CH2)m-、R7O(CH2)mCO-、二氟甲基、三氟甲基、C1~C3亚磺酰基、苯磺酰基、5-7元杂芳基磺酰基、苯基、苄基、5~7元杂芳基、4~7元杂环基;其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、C1~C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1~C4酰胺基、C1~C4磺酰基、氨基C1~C4磺酰基、C1-C4烷基取代的磺酰基苯基,苄基,5~7元杂芳基,4~7元杂环基,其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;
R7选自氢、C1~C4直链或支链烷基;
m选自0、1或者2。
在另一优选例中,所述的R1、R2各自独立地为C1~C6直链或支链烷氧基、三氟甲氧基、二氟甲氧基、COOR5、CONR5R6。
在另一优选例中,所述的R4为未被取代或者被1-3个取代基取代的吲哚基;优选地,所述的吲哚基被选自下组的取代基取代:卤素、C1~C4烷基、C1~C4烷氧基、氰基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR5、CONR5R6。
在另一优选例中,通式(I)中:
手性碳原子C*为S型。
本发明的第二方面,提供了一种如本发明第一方面所述通式(I)所示的化合物的制备方法,包括步骤:
(1)在惰性溶剂中,在缩合剂存在下,用式II化合物和式Ic化合物反应,得到式Id化合物;优选地,所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐);
(2)在惰性溶剂中,用式Id化合物进行Bischler–Napieralski关环反应,得到式Ie化合物;优选地,所述的关环反应用三氯氧磷作为路易斯酸;
(3)在惰性溶剂中,用式Ie化合物进行还原反应,得到式If化合物;优选地,所述的还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂;
(4)在惰性溶剂中,用式If化合物进行成缩合反应或N-烷基化反应或Buchwald–Hartwig反应,得到式(I)化合物;
上述各式中,各基团的定义如本发明第一方面所述。
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括:治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物,或其药学上可接受的盐。
本发明的第四方面,提供了一种如本发明第一方面所述的通式(I)的用途,用于制备预防、治疗或辅助治疗与PDE4活性或表达量相关的疾病的药物组合物;优选地,所述的疾病为与PDE4活性或表达量相关的免疫和炎症性疾病。
在另一优选例中,所述的与PDE4活性或表达量相关的疾病选自下组:银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、***性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症、和精神***症。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了受试化合物ZN17、ZN42对小鼠背部气囊急性炎症模型的治疗作用。
具体实施方式
本发明人经过长期而深入的研究,制备得到了一类能够抑制磷酸二酯酶(PDE4)的式I化合物。且与现有技术中的磷酸二酯酶4(PDE4)抑制化合物相比,所述的化合物具有更高的抑制活性。基于上述发现,发明人完成了本发明。
本发明的一个目的在于提供一种通式(I)所示的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
本发明的另一个目的在于提供一种上述通式(I)所示化合物的制备方法。
本发明的再一个目的在于提供一种包含治疗有效量的一种或多种上述通式(I)所示化合物或其药学上可接受的盐的药物组合物。
本发明的又一个目的在于提供上述通式(I)所示化合物在制备用于治疗自身免疫性疾病,例如银屑病、银屑病关节炎、特应性皮炎等的药物中的用途。
本发明的化合物可用于抑制磷酸二酯酶4(PDE4)。
术语
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:C1~C10烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基;所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基,所述取代基选自:卤素、C1-C10烷基、氰基、羟基、硝基、C3~C10环烷基、C1~C10烷氧基、氨基。
除特别说明之处,本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
术语“C1~C6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3~8元饱和环失去一个氢原子形成的基团:N、S、O;例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6~10元芳基失去一个氢原子形成的基团;例如苯基、萘基,或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5~8元芳基失去一个氢原子形成的基团:N、S、O,其中每个杂芳基的环状体系可以是单环或多环的;例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1~C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(=O)-基团,如-COOCH3、-COOC2H5、-COOC3H7、-COOC4H9,或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团,所述的烯烃可以是单烯烃、二烯烃或三烯烃,例如-CH=CH2、-C2H4=CH2、-CH=C2H4,或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑,化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中,形如“C1~C6”,表示该基团可以具有1个至6个碳原子,例如1个、2个、3个、4个或5个。
如无特别说明,本申请的化合物可以包括本领域已知的同位素形成的化合物,例如氢的同位素(氘、氚等)、碳的同位素(C14)。通常,上述同位素的丰度不大于其在天然环境中的丰度,但也可以通过采用含有该同位素的反应原料进行制备,从而得到丰度高于自然丰度的同位素取代化合物,例如氘代化合物等。在优选的实施方式中,氘代化合物中氘原子的丰度>99%。
式(I)所示的四氢异喹啉类化合物
本发明提供一种通式(Ⅰ)表示的四氢异喹啉类化合物,其对映异构体、非对映异构体、外消旋体及其混合物或其药学上可接受的盐,
其中,各基团的定义如上所述。
在另一优选例中,n、X、Y、R1、R2、R3、R4各自独立地为实施例中各个具体化合物所对应的相应基团。
特别地,本发明所述的四氢异喹啉类化合物优选自下表1中所示的化合物:
表1
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
式(I)化合物的制备
本发明还提供了一种具有通式I的化合物的合成方法,具体地,所述的式I化合物通过下列所示流程进行制备:
步骤a:将Ic溶解在溶剂中,在缩合剂辅助下与II进行缩合反应得到化合物Id;所述溶剂为二氯甲烷;
步骤b:将Id溶解在溶剂中,加入过量三氯氧磷,回流搅拌,得化合物Ie;所述溶剂为无水乙腈;
步骤c:将Ie溶解在溶剂中,加入过量硼氢化钠,搅拌至反应完全,旋干溶剂得化合物If,所述溶剂为甲醇;或加入Noyori催化剂,搅拌至反应完全,所述溶剂为水和二氯甲烷混合溶剂。
步骤d:将If溶于溶剂中,与相应原料反应得到化合物Ig;所述溶剂为甲酸乙酯或DMF或四氢呋喃;
X、Y、R1、R2、R3、R4与前述要求中的定义相同。
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物,所述药物组合物包含治疗有效量的选自式(Ⅰ)表示的四氢异喹啉类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地,药学上可接受的载体,其可用于治疗银屑病等自身免疫性相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明所述的式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种,或者上述包含治疗有效量的选自式(Ⅰ)表示的四氢异喹啉类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物可以作为磷酸二酯酶4(PDE4)抑制剂,用于治疗银屑病等自身免疫性相关疾病。
本发明化合物的药用盐的制备,可以采用化合物的游离碱与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
由于本发明化合物具有优异的对磷酸二酯酶4(PDE4)的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗以及缓解与磷酸二酯酶4(PDE4)相关的疾病,例如治疗与磷酸二酯酶4(PDE4)表达异常相关的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:银屑病、银屑病关节炎、特应性皮炎、慢性阻塞性肺病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
如上所述的根据本发明的化合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径,更优选为口服。日剂量优选为0.01~200mg/kg体重,一次性服用,或0.01~100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明的主要优点包括:
本发明的四氢异喹啉类化合物对四型磷酸二酯酶(PDE4)具有良好的抑制效果,可以用于预防、治疗或辅助治疗与磷酸二酯酶活性相关的银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、***性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症和精神***症等疾病,尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明,但不以任何方式限制本发明。实施例中的所有参数以及其余的说明,除另有说明外,都是以质量为说明依据的。
样品的分析数据由以下仪器测定:核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定,TMS(四甲基硅烷)为内标,化学位移单位为ppm,耦合常数单位为Hz;质谱由Finnigan MAT-711型,MAT-95和LCQ-DECA型质谱仪以及IonSpec4.7Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产);TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板;石油醚沸程为60-90℃;采用紫外灯,碘缸显色。除另有说明外,以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例A1:化合物A1的合成
合成路线:
化合物1-3的合成:
1-2溶于二氯甲烷中,加入EDCI,HOBT,TEA搅拌30min,缓慢加入1-1的二氯甲烷溶液,搅拌过夜,加二氯甲烷稀释,依次用饱和碳酸氢钠、1N稀盐酸、饱和氯化钠洗涤,无水硫酸钠干燥,蒸干,石油醚/乙酸乙酯=1:1柱层析纯化得黄白色固体1.2g,收率为92%。1HNMR(400MHz,CDCl3)δ7.75(s,1H),7.57(dd,J=7.5,1.4Hz,1H),7.33(dd,J=7.5,1.4Hz,1H),7.23–7.15(m,2H),6.98(td,J=7.4,1.5Hz,1H),6.79(d,J=7.5Hz,1H),6.74(d,J=1.4Hz,1H),6.60(dd,J=7.5,1.4Hz,1H),5.62(s,1H),3.83(s,3H),3.75(s,3H),3.37(t,J=7.7Hz,2H),2.68(t,J=8.1Hz,2H),2.60(t,J=7.7Hz,2H),2.28(t,J=8.1Hz,2H).ESI-MS m/z 353.2[M+H]+.
化合物1-4的合成:
将化合物1-3 1g溶于100mL无水乙腈中,加入三氯氧磷,在氩气保护下,回流搅拌。TLC监测反应完全后减压蒸干,加入冰的饱和碳酸氢钠调至弱碱性,二氯甲烷萃取,无水硫酸钠干燥,蒸干得橙色油状物,未经纯化直接投下一步反应。
化合物1-5的合成:
将化合物1-4溶于甲醇中,冰浴下分批加入硼氢化钠,室温搅拌4小时,饱和氯化铵溶液淬灭反应,加入二氯甲烷萃取,饱和碳酸氢钠,饱和氯化钠洗涤,无水硫酸钠干燥有机层,浓缩,二氯甲烷/甲醇=20:1柱层析纯化得黄色固体,两步收率70%。1HNMR(400MHz,CDCl3)δ8.19(brs,1H),7.53(d,J=7.8Hz,1H),7.32(d,J=8.1Hz,1H),7.20–7.03(m,3H),6.51(s,1H),6.23(s,1H),4.41(t,J=5.8Hz,1H),3.81(s,3H),3.58(s,3H),3.54–3.43(m,1H),3.31–3.18(m,1H),3.08–2.78(m,4H),2.39(dd,J=13.7,7.1Hz,2H).ESI-MS m/z337.2[M+H]+.
化合物A1的合成:
将1-5 100mg溶于甲酸乙酯中、滴入催化量的三乙胺,搅拌回流过夜。TLC监测反应完全后蒸干溶剂,石油醚/乙酸乙酯=1:1柱层析纯化得白色固体A1,收率为90%。1H NMR(400MHz,CDCl3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J=8.0Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s,1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.47(dd,J=7.6,6.3Hz,1H(min)),4.55(dd,J=13.4,5.2Hz,1H(maj)),4.44(dd,J=9.5,4.1Hz,1H(maj)),3.84(s,3H(maj)),3.83(s,3H(min)),3.78–3.70(m,1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J=13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J=13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H).ESI-MS m/z 365.2[M+H]+.
实施例(S)-A1:化合物(S)-A1的合成
将1-4溶于少量二氯甲烷,加入去离子水,加入(R,R)-Noyori催化剂、六氟锑酸银、三氟甲烷磺酸镧、TBAB、甲酸钠,氩气保护下40度搅拌过夜,二氯甲烷萃取,水洗,有机层硅藻土助滤,浓缩,二氯甲烷/甲醇=40:1柱层析得2-5,参考化合物A1的合成方法,得到化合物(S)-A1。或由A1经手性色谱柱分离得到(S)-A1。1H NMR(400MHz,CDCl3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J=8.0Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s,1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.47(dd,J=7.6,6.3Hz,1H(min)),4.55(dd,J=13.4,5.2Hz,1H(maj)),4.44(dd,J=9.5,4.1Hz,1H(maj)),3.84(s,3H(maj)),3.83(s,3H(min)),3.78–3.70(m,1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J=13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J=13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H).ESI-MS m/z 365.2[M+H]+.
实施例(R)-A1:化合物(R)-A1的合成
用(S,S)-Noyori催化剂替换实施例(S)-A1中的(R,R)-Noyori催化剂,合成方法参考化合物(S)-A1的合成,得到化合物(R)-A1。或由A1经手性色谱柱分离得到(R)-A1。1HNMR(400MHz,CDCl3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J=8.0Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s,1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.47(dd,J=7.6,6.3Hz,1H(min)),4.55(dd,J=13.4,5.2Hz,1H(maj)),4.44(dd,J = 9.5,4.1 Hz, 1H (maj)), 3.84 (s, 3H (maj)), 3.83 (s, 3H (min)), 3.78 – 3.70 (m, 1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J=13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J=13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H).1H NMR ESI-MS m/z365.2[M+H]+.
实施例A2:化合物A2的合成
化合物4-3的合成:
4-1溶于丙酮,加入碳酸钾、滴加4-2,回流搅拌过夜。反应液过滤,蒸干,二氯甲烷稀释,加水搅拌10min,静置分层,有机层蒸干得黄色固体4-3,未经纯化直接投下步。
化合物4-4的合成:
4-3溶于硝基甲烷,加醋酸铵回流2h,蒸干溶剂,加入冰水中搅拌2h,静置,过滤得黄色固体,产率90%。1H NMR(400MHz,CDCl3)δ7.96(s,2H),7.42(dd,J=7.5,1.4Hz,1H),7.23(d,J=1.4Hz,1H),6.93(d,J=7.5Hz,1H),4.58(dd,J=7.8Hz,1H),3.85(s,3H),2.12–2.00(m,2H),1.84–1.66(m,2H),1.67–1.54(m,1H).ESI-MS m/z264.1[M+H]+
化合物4-5的合成:
冰浴下分批将四氢铝锂加入氩气保护的四氢呋喃中,搅拌下滴加4-4的四氢呋喃溶液,加毕回流2h,冰浴下缓慢加水淬灭反应,过滤,乙酸乙酯洗涤滤饼,蒸干得微黄透明油状物。未经纯化直接投下步。
用化合物4-5替换实施例A1中的1-1,合成方法参考化合物A1的合成,得到化合物A2。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J=7.9Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J=8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J=9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J=13.4,5.3Hz,1H(min)),3.62(ddd,J=13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J=13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H]+.
实施例(S)-A2:化合物(S)-A2的合成
用化合物4-5替换实施例A1中的1-1,合成方法参考化合物(S)-A1,得化合物(S)-A2。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J=7.9Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J=8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J=9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J=13.4,5.3Hz,1H(min)),3.62(ddd,J=13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J=13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H]+.
实施例(R)-A2:化合物(R)-A2的合成
用化合物4-5替换实施例A1中的1-1,合成方法参考化合物(R)-A1,得化合物(R)-A2。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J=7.9Hz,1H(maj)),7.58(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J=8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J=9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J=13.4,5.3Hz,1H(min)),3.62(ddd,J=13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J=13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H]+.
实施例A3:化合物A3的合成
用化合物6-1替换实施例A2中的4-2,合成方法参考化合物A2的合成,得到化合物A3。H1 NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J=7.9Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.38(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J=8.6,5.0Hz,1H(min)),4.54(dd,J=13.2,5.0Hz,1H(maj)),4.40(dd,J=9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J=12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H]+.
实施例(S)-A3:化合物(S)-A3的合成
用化合物6-1替换实施例A2中的4-2,合成方法参考化合物(S)-A2的合成,得到化合物(S)-A3。H1 NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J=7.9Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.38(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J=8.6,5.0Hz,1H(min)),4.54(dd,J=13.2,5.0Hz,1H(maj)),4.40(dd,J=9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J=12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H]+.
实施例(R)-A3:化合物(R)-A3的合成
用化合物6-1替换实施例A2中的4-2,合成方法参考化合物(R)-A2的合成,得到化合物(R)-A3。H1 NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J=7.9Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.38(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J=8.6,5.0Hz,1H(min)),4.54(dd,J=13.2,5.0Hz,1H(maj)),4.40(dd,J=9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J=12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H]+.
实施例A4:化合物A4的合成
用溴乙烷替换实施例A2中的4-2,合成方法参考化合物A2的合成,得到化合物A4。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J=7.8Hz,1H(maj)),7.57(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J=8.2,5.1Hz,1H(min)),4.54(dd,J=13.0,4.4Hz,1H(maj)),4.42(dd,J=9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J=13.3,5.3Hz,1H(min)),3.62(ddd,J=13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J=13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J=7.0Hz,3H(maj)),1.36(t,J=7.0Hz,3H(min)).ESI-MSm/z 379.2[M+H]+.
实施例(S)-A4:化合物(S)-A4的合成
用溴乙烷替换实施例A2中的4-2,合成方法参考化合物(S)-A2的合成,得到化合物(S)-A4。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J=7.8Hz,1H(maj)),7.57(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J=8.2,5.1Hz,1H(min)),4.54(dd,J=13.0,4.4Hz,1H(maj)),4.42(dd,J=9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J=13.3,5.3Hz,1H(min)),3.62(ddd,J=13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J=13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J=7.0Hz,3H(maj)),1.36(t,J=7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H]+.
实施例(R)-A4:化合物(R)-A4的合成
用溴乙烷替换实施例A2中的4-2,合成方法参考化合物(R)-A2的合成,得到化合物(R)-A4。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J=7.8Hz,1H(maj)),7.57(d,J=7.9Hz,1H(min)),7.39(d,J=8.1Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J=8.2,5.1Hz,1H(min)),4.54(dd,J=13.0,4.4Hz,1H(maj)),4.42(dd,J=9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J=13.3,5.3Hz,1H(min)),3.62(ddd,J=13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J=13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J=7.0Hz,3H(maj)),1.36(t,J=7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H]+.
实施例A5:化合物A5的合成
用溴苄替换实施例A2中的4-2,合成方法参考化合物A2的合成,得到化合物A5。1HNMR(400MHz,CDCl3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J=8.0Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J=9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J=13.1,4.9Hz,1H(maj)),4.34(dd,J=8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J=13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H]+.
实施例(S)-A5:化合物(S)-A5的合成
用溴苄替换实施例A2中的4-2,合成方法参考化合物(S)-A2的合成,得到化合物(S)-A5。1H NMR(400MHz,CDCl3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J=8.0Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J=9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J=13.1,4.9Hz,1H(maj)),4.34(dd,J=8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J=13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H]+.
实施例(R)-A5:化合物(R)-A5的合成
用溴苄替换实施例A2中的4-2,合成方法参考化合物(R)-A2的合成,得到化合物(R)-A5。1H NMR(400MHz,CDCl3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J=8.0Hz,1H(maj)),7.56(d,J=7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J=9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J=13.1,4.9Hz,1H(maj)),4.34(dd,J=8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J=13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H]+.
实施例A6:化合物A6的合成
化合物A5经钯碳催化加氢,脱去苄基,与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得A6
实施例(S)-A6:化合物A6的合成
化合物(S)-A5经钯碳催化加氢,脱去苄基,与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得(S)-A6
实施例(R)-A6:化合物A6的合成
化合物(R)-A5经钯碳催化加氢,脱去苄基,与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得(S)-A6
实施例A7:化合物A7的合成
化合物A5经钯碳催化加氢,脱去苄基,与3-溴丙酸在碳酸钾、乙腈体系中反应得A7
实施例(S)-A7:化合物A7的合成
/>
化合物(S)-A5经钯碳催化加氢,脱去苄基,与3-溴丙酸在碳酸钾、乙腈体系中反应得(S)-A7
实施例(R)-A7:化合物A7的合成
化合物(R)-A5经钯碳催化加氢,脱去苄基,与3-溴丙酸在碳酸钾、乙腈体系中反应得(S)-A7
实施例B1:化合物B1的合成
11-1溶于二氯甲烷中,加入EDCI,HOBT,TEA搅拌30min,缓慢加入1-5的二氯甲烷溶液,搅拌过夜,加二氯甲烷稀释,依次用饱和碳酸氢钠、1N稀盐酸、饱和氯化钠洗涤,无水硫酸钠干燥,蒸干,石油醚/乙酸乙酯=1:1柱层析纯化得化合物B1白色固体50mg,收率为%。1H NMR(400MHz,CDCl3)δ8.72(d,J=5.7Hz,2H(maj)),8.56(d,J=4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J=7.8Hz,1H(maj)),7.49(d,J=7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J=9.5,4.4Hz,1H(maj)),4.82(dd,J=13.2,5.1Hz,1H(min)),4.64(dd,J=8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J=13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J=13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H]+.
实施例(S)-B1:化合物(S)-B1的合成
2-5替换实施例B1中的1-5,得化合物(S)-B1白色固体50mg,收率为60%。1H NMR(400MHz,CDCl3)δ8.72(d,J=5.7Hz,2H(maj)),8.56(d,J=4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J=7.8Hz,1H(maj)),7.49(d,J=7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J=9.5,4.4Hz,1H(maj)),4.82(dd,J=13.2,5.1Hz,1H(min)),4.64(dd,J=8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J=13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J=13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H]+.
实施例(R)-B1:化合物(R)-B1的合成
3-5替换实施例B1中的1-5,得化合物(R)-B1白色固体50mg,收率为60%。1H NMR(400MHz,CDCl3)δ8.72(d,J=5.7Hz,2H(maj)),8.56(d,J=4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J=7.8Hz,1H(maj)),7.49(d,J=7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J=9.5,4.4Hz,1H(maj)),4.82(dd,J=13.2,5.1Hz,1H(min)),4.64(dd,J=8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J=13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J=13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H]+.
实施例B2:化合物B2的合成
化合物1-5溶于乙腈,加入碳酸钾,12-1回流过夜,蒸干,石油醚/乙酸乙酯=1:1柱层析纯化得化合物B2白色固体50mg,收率为%。1H NMR(400MHz,CDCl3)δ8.06(brs,1H),7.61(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J=7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J=16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H]+.
实施例(S)-B2:化合物(S)-B2的合成
化合物2-5替换实施例B2中的1-5,得(S)-B2。1H NMR(400MHz,CDCl3)δ8.06(brs,1H),7.61(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J=7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J=16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H]+.
实施例(R)-B2:化合物(R)-B2的合成
化合物3-5替换实施例B2中的1-5,得(R)-B2。1H NMR(400MHz,CDCl3)δ8.06(brs,1H),7.61(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J=7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J=16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H]+.
实施例B3:化合物B3的合成
用化合物13-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物B3。1H NMR(500MHz,CDCl3)δ9.54(t,J=2.4Hz,1H),7.64–7.58(m,1H),7.38–7.31(m,1H),7.17(ddd,J=8.1,7.4,1.0Hz,1H),7.14–7.07(m,2H),6.73(d,J=1.1Hz,1H),6.62(t,J=1.0Hz,1H),4.91(td,J=6.1,0.9Hz,1H),3.90–3.81(m,7H),3.78(ddd,J=11.5,7.3,5.0Hz,2H),3.60(ddd,J=12.1,6.5,4.1Hz,1H),3.40(ddd,J=11.7,7.4,5.1Hz,2H),3.08(dddd,J=14.7,6.4,4.1,0.9Hz,1H),2.94(dt,J=14.7,7.3Hz,1H),2.88–2.74(m,2H),2.52(dtd,J=12.6,7.3,6.0Hz,1H),2.44(p,J=6.5Hz,1H),2.25(dtd,J=12.6,7.3,6.1Hz,1H),1.93–1.82(m,2H),1.68(dddd,J=13.2,7.3,6.5,5.0Hz,2H).ESI-MS m/z449.2[M+H]+.
实施例(S)-B3:化合物(S)-B3的合成
用化合物13-1替换实施例B1中的11-1,合成方法参考化合物(S)-B1的合成,得到化合物(S)-B3。ESI-MS m/z 449.2[M+H]+.
实施例(R)-B3:化合物(R)-B3的合成
用化合物13-1替换实施例B1中的11-1,合成方法参考化合物(R)-B1的合成,得到化合物(R)-B3。ESI-MS m/z 449.2[M+H]+.
实施例B4:化合物B4的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物B4。1H NMR(400MHz,CDCl3)δ8.19(brs,1H(min)),8.15(brs,1H(maj)),7.61–7.54(m,1H),7.39–7.33(m,1H),7.24–7.00(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(maj)),5.66(dd,J=9.2,4.8Hz,1H(maj)),4.77(dd,J=7.1,7.1Hz,1H(min)),4.66(ddd,J=7.5,6.3,2.0Hz,1H(min)),4.27–4.05(m,2H),3.90–3.82(m,3H(min,maj)1H(maj)),3.81(s,3H(min)),3.65(s,3H(maj)),3.55(ddd,J=13.7,11.0,4.6Hz,1H(maj)),3.48(s,3H(maj)),3.32(s,3H(min)),3.21(ddd,J=13.3,11.5,4.9Hz,1H(min)),2.97–2.64(m,4H),2.35–2.10(m,2H).ESI-MS m/z 409.2[M+H]+.
实施例(S)-B4:化合物(S)-B4的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(S)-B1的合成,得到化合物(S)-B4。ESI-MS m/z 409.2[M+H]+.
实施例(R)-B4:化合物(R)-B4的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(R)-B1的合成,得到化合物(R)-B4。ESI-MS m/z 409.2[M+H]+.
实施例B5:化合物B5的合成
用化合物15-1替换实施例B2中的12-1,合成方法参考化合物B2的合成,得到化合物B5。1H NMR(400MHz,CDCl3)δ7.97(brs,1H),7.60(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.17(ddd,J=8.2,7.2,1.1Hz,1H),7.09(ddd,J=7.9,7.1,1.0Hz,1H),7.04(d,J=2.0Hz,1H),6.56(s,1H),6.37(s,1H),3.84(s,3H),3.78–3.70(m,4H),3.68(s,3H),3.48(dd,J=39.3,16.6Hz,2H),3.34(ddd,J=13.5,9.8,5.2Hz,1H),3.04(dt,J=9.7,5.2Hz,1H),3.00–2.87(m,2H),2.82(ddd,J=15.6,9.7,5.6Hz,1H),2.60(dt,J=16.5,4.5Hz,1H),2.27–2.15(m,1H),2.14–2.03(m,1H).ESI-MS m/z 409.2[M+H]+.
实施例(S)-B5:化合物(S)-B5的合成
用化合物15-1替换实施例B2中的12-1,合成方法参考化合物(S)-B2的合成,得到化合物(S)-B5。
实施例(R)-B5:化合物(R)-B5的合成
用化合物15-1替换实施例B2中的12-1,合成方法参考化合物(R)-B2的合成,得到化合物(R)-B5。
实施例B6:化合物B6的合成
用化合物16-1替换实施例B2中的12-1,合成方法参考化合物B2的合成,得到化合物B6。1H NMR(400MHz,CDCl3)δ7.94(brs,1H),7.61(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.21–7.14(m,1H),7.13–7.06(m,1H),7.02(s,1H),6.56(s,1H),6.37(s,1H),3.84(s,3H),3.72(s,3H),3.67(dd,J=8.4,4.1Hz,1H),3.43–3.31(m,1H),3.24(dq,J=15.4,9.5Hz,1H),3.11–2.81(m,5H),2.52(d,J=14.7Hz,1H),2.16(dt,J=13.9,7.0Hz,1H),2.10–1.98(m,1H).ESI-MS m/z 419.2[M+H]+.
实施例(S)-B6:化合物(S)-B6的合成
用化合物16-1替换实施例B2中的12-1,合成方法参考化合物(S)-B2的合成,得到化合物(S)-B6。ESI-MS m/z 419.2[M+H]+.
实施例(R)-B6:化合物(R)-B6的合成
用化合物16-1替换实施例B2中的12-1,合成方法参考化合物(R)-B2的合成,得到化合物(R)-B6。ESI-MS m/z 419.2[M+H]+.
实施例B7:化合物B7的合成
用化合物17-1替换实施例B2中的12-1,合成方法参考化合物B2的合成,得到化合物B7。1H NMR(400MHz,CDCl3)δ7.98(brs,1H),7.59(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.18(t,J=7.1Hz,1H),7.11(dd,J=11.0,3.9Hz,1H),6.99(s,1H),6.56(s,1H),6.46(s,1H),3.98(dd,J=11.4,2.9Hz,1H),3.84(s,3H),3.76(s,3H),3.63–3.47(m,1H),3.38(td,J=10.9,3.3Hz,2H),3.31–3.16(m,1H),3.05–2.67(m,4H),2.60–2.30(m,3H),2.24–1.96(m,2H),1.88–1.67(m,3H),1.28(m,1H).ESI-MS m/z 435.3[M+H]+.
实施例(S)-B7:化合物(S)-B7的合成
用化合物17-1替换实施例B2中的12-1,合成方法参考化合物(S)-B2的合成,得到化合物(S)-B7。ESI-MS m/z 435.3[M+H]+.
实施例(R)-B7:化合物(R)-B7的合成
用化合物17-1替换实施例B2中的12-1,合成方法参考化合物(R)-B2的合成,得到化合物(R)-B7。ESI-MS m/z 435.3[M+H]+.
实施例B8:化合物B8的合成
用化合物18-1替换实施例B2中的12-1,合成方法参考化合物B2的合成,得到化合物B8。1H NMR(400MHz,CDCl3)δ7.59(d,J=7.9Hz,1H),7.36(d,J=8.2Hz,1H),7.26(t,J=7.6Hz,1H),7.14(m,2H),6.56(s,1H),6.36(s,1H),4.77–4.58(m,2H),3.84(s,3H),3.73(s,3H),3.53(t,J=6.4Hz,2H),3.31–3.21(m,1H),3.18–3.06(m,2H),3.04–2.81(m,7H),2.38–2.15(m,1H),2.17–2.04(m,1H).ESI-MS m/z 443.2[M+H]+.
实施例(S)-B8:化合物(S)-B8的合成
用化合物18-1替换实施例B2中的12-1,合成方法参考化合物(S)-B2的合成,得到化合物(S)-B8。ESI-MS m/z 443.2[M+H]+.
实施例(R)-B8:化合物(R)-B8的合成
用化合物18-1替换实施例B2中的12-1,合成方法参考化合物(R)-B2的合成,得到化合物(R)-B8。ESI-MS m/z 443.2[M+H]+.
实施例B9:化合物B9的合成
用化合物19-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物B9。1H NMR(500MHz,CDCl3)δ9.55(t,J=2.4Hz,1H),7.61(dt,J=7.3,0.9Hz,1H),7.38–7.31(m,1H),7.17(ddd,J=8.1,7.4,1.0Hz,1H),7.14–7.06(m,2H),6.90(d,J=0.9Hz,1H),6.62(t,J=1.0Hz,1H),5.00(td,J=6.0,1.0Hz,1H),4.38(d,J=17.2Hz,1H),4.04(d,J=17.0Hz,1H),3.91(ddd,J=12.1,6.3,4.3Hz,1H),3.83(s,6H),3.75(ddd,J=11.9,6.2,4.2Hz,1H),2.98(s,3H),3.03–2.87(m,3H),2.81(dt,J=14.9,7.3Hz,1H),2.39(dtd,J=12.6,7.3,6.1Hz,1H),2.26(dtd,J=12.6,7.3,6.1Hz,1H).ESI-MS m/z 457.2[M+H]+
实施例(S)-B9:化合物(S)-B9的合成
用化合物19-1替换实施例B1中的11-1,合成方法参考化合物(S)-B1的合成,得到化合物(S)-B9。ESI-MS m/z 457.2[M+H]+.
实施例(R)-B9:化合物(R)-B9的合成
用化合物19-1替换实施例B1中的11-1,合成方法参考化合物(R)-B1的合成,得到化合物(R)-B9。ESI-MS m/z 457.2[M+H]+.
实施例B10:化合物B10的合成
1-5溶于THF中,加入20-1室温搅拌20h,DCM稀释,饱和碳酸氢钠、饱和氯化洗涤,无水硫酸钠干燥蒸干,石油醚/乙酸乙酯=1:1柱层析纯化得黄色油状物20mg,收率为58%。1HNMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.59(ddd,J=7.3,1.1,0.6Hz,1H),7.38–7.32(m,1H),7.17(td,J=7.7,1.1Hz,1H),7.15–7.07(m,2H),6.83(d,J=1.1Hz,1H),6.61(t,J=1.0Hz,1H),4.96(td,J=5.4,1.0Hz,1H),3.95(ddd,J=11.9,6.4,4.0Hz,1H),3.86–3.78(m,7H),3.12–2.98(m,2H),2.89–2.78(m,2H),2.42–2.25(m,2H).ESI-MS m/z433.2[M+H]+.
实施例(S)-B10:化合物(S)-B10的合成
用2-5替换实施例B10中的1-5,得化合物(S)-B10。ESI-MS m/z 433.2.
实施例(R)-B10:化合物(R)-B10的合成
用3-5替换实施例B10中的1-5,得化合物(R)-B10。ESI-MS m/z 433.2[M+H]+.
实施例B11:化合物B11的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到白色固体25mg,产率88%。1H NMR(400MHz,CDCl3)δ8.19(brs,1H(min)),8.15(brs,1H(maj)),7.61–7.54(m,1H),7.39–7.33(m,1H),7.24–7.00(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(maj)),5.66(dd,J=9.2,4.8Hz,1H(maj)),4.77(dd,J=7.1,7.1Hz,1H(min)),4.66(ddd,J=7.5,6.3,2.0Hz,1H(min)),4.27–4.05(m,2H),3.90–3.82(m,3H(min,maj)1H(maj)),3.81(s,3H(min)),3.65(s,3H(maj)),3.55(ddd,J=13.7,11.0,4.6Hz,1H(maj)),3.48(s,3H(maj)),3.32(s,3H(min)),3.21(ddd,J=13.3,11.5,4.9Hz,1H(min)),2.97–2.64(m,4H),2.35–2.10(m,2H).ESI-MS m/z 409.2[M+H]+.
实施例(S)-B11:化合物(S)-B11的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(S)-B1的合成,得(S)-B11。ESI-MS m/z 409.2[M+H]+.
实施例(R)-B11:化合物(R)-B11的合成
用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(R)-B1的合成,得(R)-B11。ESI-MS m/z 409.2[M+H]+.
实施例B12:化合物B12的合成
用溴乙烷替换实施例A2中的4-2,用化合物14-1替换实施例B1中的11-1,合成方法参考化合物B11的合成,得B12,产率85%。1H NMR(400MHz,CDCl3)δ8.17(brs,1H(min)),8.13(brs,1H(maj)),7.62–7.52(m,1H),7.41–7.32(m,1H),7.23–6.98(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.54(s,1H(min)),6.40(s,1H(maj)),5.64(dd,J=9.1,4.7Hz,1H(maj)),4.76(dd,J=7.6,6.7Hz,1H(min)),4.64(ddd,J=8.2,5.7,1.9Hz,1H(min)),4.20(q,J=13.6Hz,2H(maj)),4.06(s,2H(min)),3.89–3.78(m,3H(min,maj)1H(min)1H(maj)),3.55(ddd,J=13.5,10.8,4.4Hz,1H(maj)),3.48(s,3H(maj)),3.31(s,3H(min)),3.21(ddd,J=12.6,11.0,4.2Hz,1H(min)),3.03–2.61(m,4H),2.38–2.20(m,2H(maj)),2.18–2.08(m,2H(min)),1.44(t,J=7.0Hz,3H(min)),1.35(t,J=7.0Hz,3H(maj)).ESI-MSm/z 423.0[M+H]+.
实施例(S)-B12:化合物(S)-B12的合成
用溴乙烷替换实施例A2中的4-2,用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(S)-B11的合成,得(S)-B12。ESI-MS m/z 423.0[M+H]+.
实施例(R)-B12:化合物(R)-B12的合成
用溴乙烷替换实施例A2中的4-2,用化合物14-1替换实施例B1中的11-1,合成方法参考化合物(R)-B11的合成,得(R)-B12。ESI-MS m/z 423.0[M+H]+.
实施例B13:化合物B13的合成
中间体1-5溶于二氯甲烷,加入吡啶、46-1,室温搅拌1h,0.1N NaOH溶液淬灭反应,二氯甲烷萃取,1N稀盐酸洗涤,有机层干燥蒸干过柱得化合物B13。1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.55(dd,J=14.9,3.1Hz,1H),7.32(dd,J=15.0,3.1Hz,1H),7.23–7.12(m,2H),7.02–6.91(m,2H),6.87(s,1H),4.49(t,J=13.0Hz,1H),3.74(s,6H),3.42(dt,J=24.7,10.8Hz,1H),3.14(dt,J=24.7,10.8Hz,1H),2.94(s,3H),2.86–2.66(m,4H),2.12(td,J=15.7,13.1Hz,2H).ESI-MS m/z 415.2[M+H]+.
实施例(S)-B13:化合物(S)-B13的合成
2-5替换实施例B13中的1-5,得化合物(S)-B13。ESI-MS m/z 415.2[M+H]+.
实施例(R)-B13:化合物(R)-B13的合成
3-5替换实施例B13中的1-5,得化合物(R)-B13。ESI-MS m/z 415.2[M+H]+.
实施例B14:化合物B14的合成
中间体1-5溶于二氯甲烷,加入B14-1、三乙胺,室温搅拌2h,饱和氯化铵溶液淬灭反应,二氯甲烷萃取,饱和食盐水洗涤,有机层干燥蒸干过柱得化合物B14。1H NMR(500MHz,CDCl3)δ9.41(t,J=2.4Hz,1H),7.61(ddt,J=7.3,1.1,0.6Hz,1H),7.39–7.32(m,1H),7.21–7.13(m,1H),7.14–7.07(m,2H),6.64(t,J=1.0Hz,1H),6.50(d,J=1.1Hz,1H),5.09(td,J=5.4,1.0Hz,1H),4.03(ddd,J=11.9,6.2,4.2Hz,1H),3.83(d,J=2.4Hz,6H),3.64–3.53(m,5H),3.17–3.08(m,4H),3.04–2.87(m,3H),2.79–2.69(m,1H),2.50(dtd,J=12.6,7.3,5.3Hz,1H),2.28(dtd,J=12.6,7.3,5.4Hz,1H).ESI-MS m/z 450.2[M+H]+.
实施例(S)-B14:化合物(S)-B14的合成
2-5替换实施例B14中的1-5,得化合物(S)-B14。ESI-MS m/z 450.2[M+H]+.
实施例(R)-B14:化合物(R)-B14的合成
3-5替换实施例B14中的1-5,得化合物(R)-B14。ESI-MS m/z 450.2[M+H]+.
实施例B15:化合物B15的合成
氯甲酸甲酯替换实施例B14中的B14-1,得化合物B15。1H NMR(500MHz,CDCl3)δ7.62–7.56(m,1H),7.38–7.32(m,1H),7.20–7.11(m,2H),7.06(td,J=7.5,1.6Hz,1H),6.84(d,J=0.9Hz,1H),6.73(t,J=0.9Hz,1H),5.04(td,J=5.3,1.0Hz,1H),3.85–3.73(m,8H),3.68(s,2H),3.19(qt,J=14.8,7.3Hz,2H),2.92(ddd,J=6.2,5.0,1.1Hz,2H),2.47(dtd,J=12.7,7.3,5.3Hz,1H),2.39(dtd,J=12.7,7.3,5.4Hz,1H).ESI-MS m/z 395.2[M+H]+.
实施例(S)-B15:化合物(S)-B15的合成
2-5替换实施例B14中的1-5,氯甲酸甲酯替换实施例B15中的B14-1,参考实施例B15,得化合物(S)-B15。ESI-MS m/z 395.2[M+H]+.
实施例(R)-B15:化合物(R)-B15的合成
3-5替换实施例B14中的1-5,氯甲酸甲酯替换实施例B15中的B14-1,参考实施例B15,得化合物(R)-B15。ESI-MS m/z 395.2[M+H]+.
实施例B16:化合物B16的合成
溴乙烷替换实施例A2中的4-2,2-碘乙酰胺替换实施例B2中的12-1,参考实施例B2,得化合物B16。
实施例(S)-B16:化合物(S)-B16的合成
溴乙烷替换实施例A2中的4-2,2-碘乙酰胺替换实施例B2中的12-1,参考实施例B2,得化合物B16。
实施例(R)-B16:化合物(R)-B16的合成
溴乙烷替换实施例A2中的4-2,2-碘乙酰胺替换实施例B2中的12-1,参考实施例B2,得化合物B16。
实施例C1:化合物C1的合成
化合物23-3的合成:
23-2溶于二氯甲烷,加入四氯化锆,缓慢滴加23-1的二氯甲烷溶液,室温搅拌1h。加二氯甲烷稀释,水洗,有机层蒸干直接投下步。
化合物23-4的合成:
23-3溶于四氢呋喃/水=1:1溶剂中,加氢氧化锂,室温搅拌16h。加乙酸乙酯萃取,收集水层,1N稀盐酸调pH至酸性,乙酸乙酯萃取三遍,收集有机层,无水硫酸钠干燥,蒸干得棕色固体420mg,两步产率68%。1H NMR(500MHz,Methanol-d4)δ10.04(brs,1H)7.66(d,J=1.9Hz,1H),7.24(d,J=8.6Hz,1H),7.16(dd,J=8.6,1.9Hz,1H),7.08(s,1H),3.01(t,J=7.4Hz,2H),2.65(t,J=7.5Hz,2H).ESI-MS m/z 268.0[M+H]+
用化合物4-5替换实施例A1中的1-1,用化合物23-4替换实施例A1中的1-2,合成方法参考化合物A1的合成,得到化合物C1。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.19(s,2H(maj)),8.13(brs,1H(min)),7.77(s,1H(min)),7.70(s,1H(maj)),7.32–7.27(m,1H),7.26–7.23(m,1H),7.21(s,1H(min)),7.04(s,1H(maj)),6.56(s,1H(maj)),6.54(s,1H(min)),6.37(s,1H(maj)),6.33(s,1H(min)),5.40(dd,J=9.0,4.2Hz,1H(min)),4.67–4.61(m,1H(min)),4.58–4.54(m,1H(min)),4.54–4.48(m,1H(maj)),4.37(dd,J=9.2,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.73(dd,J=13.3,5.6Hz,1H(maj)),3.61(ddd,J=12.6,12.6,4.2Hz,1H(min)),3.10(ddd,J=12.6,12.6,4.8Hz,1H(maj)),2.96–2.63(m,4H),2.31–2.13(m,2H),1.98–1.70(m,6H),1.68–1.47(m,2H).ESI-MSm/z 497.1[M+H]+.
实施例(S)-C1:化合物(S)-C1的合成
参考实施例(S)-A2和实施例C1,得化合物(S)-C1,ESI-MS m/z 497.1[M+H]+.
实施例(R)-C1:化合物(R)-C1的合成
参考实施例(R)-A2和实施例C1,得化合物(R)-C1,ESI-MS m/z 497.1[M+H]+.
实施例C2:化合物C2的合成
用化合物24-1替换实施例C1中的23-1,合成方法参考化合物C1的合成,得到化合物C2。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.21(s,1H(maj)),8.02(brs,1H(maj)),7.95(brs,1H(min)),7.41(s,1H(maj)),7.35(s,1H(min)),7.31–7.22(m,1H),7.11(s,1H(min)),7.07–6.99(m,1H),6.99(s,1H(maj)),6.56(s,1H(maj)),6.54(s,1H(min)),6.40(s,1H(min)),6.38(s,1H(maj)),5.45(dd,J=8.1,5.6Hz,1H(min)),4.62–4.48(m,1H(maj,min),1H(maj)),4.42(dd,J=9.9,3.9Hz,1H(maj)),3.80(s,3H),3.73(dd,J=13.2,5.8Hz,1H(min)),3.62(ddd,J=13.3,11.9,4.4Hz,1H(min)),3.12(ddd,J=12.5,12.5,4.7Hz,1H(maj)),2.98–2.63(m,4H),2.46(s,3H(maj)),2.44(s,3H(min)),2.30–2.16(m,2H),1.91–1.68(m,6H),1.61–1.48(m,2H).ESI-MS m/z 433.2[M+H]+.
实施例(S)-C2:化合物(S)-C2的合成
用化合物24-1替换实施例C1中的23-1,参考化合物(S)-C1的合成,得化合物(S)-C2。ESI-MS m/z 433.2[M+H]+.
实施例(R)-C2:化合物(R)-C2的合成
用化合物24-1替换实施例C1中的23-1,参考化合物(R)-C1的合成,得化合物(R)-C2。ESI-MS m/z 433.2[M+H]+.
实施例C3:化合物C3的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物C1的合成,得到化合物C3。1H NMR(400MHz,CDCl3)δ8.27(s,1H(min)),8.19(s,1H(maj)),8.02(brs,1H(maj)),7.94(brs,1H(min)),7.51(d,J=8.0Hz,1H(maj)),7.45(d,J=8.0Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.06(s,1H(min)),6.99–6.90(m,1H(maj,min)1H(maj))6.56(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(min)),6.38(s,1H(maj)),5.44(dd,J=8.4,5.3Hz,1H(min)),4.61–4.47(m,1H(maj,min)1H(maj)),4.40(dd,J=9.4,4.1Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J=13.2,6.4Hz,1H(min)),3.62(dd,J=18.3,7.1Hz,1H(min)),3.11(ddd,J=12.4,4.6,4.6Hz,1H(maj)),2.97–2.58(m,4H),2.46(s,3H(maj)),2.45(s,3H(min)),2.32–2.13(m,2H),1.92–1.64(m,6H),1.65–1.45(m,2H).ESI-MS m/z433.2[M+H]+.
实施例(S)-C3:化合物(S)-C3的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(S)-C1的合成,得到化合物(S)-C3。ESI-MS m/z 433.2[M+H]+.
实施例(R)-C3:化合物(R)-C3的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(R)-C1的合成,得到化合物(R)-C3。ESI-MS m/z 433.2[M+H]+.
实施例C4:化合物C4的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物A3的合成,得到化合物C4。1H NMR(400MHz,CDCl3)δ8.27(s,1H(min)),8.18(s,1H(maj)),7.97(brs,1H(maj)),7.90(brs,1H(min)),7.50(d,J=8.1Hz,1H(maj)),7.44(d,J=8.0Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.05(s,1H(min)),6.95(m,1H(min,maj)1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.43(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J=8.5,5.3Hz,1H(min)),4.53(dd,J=13.1,5.7Hz,1H(min)),4.39(dd,J=9.6,4.2Hz,1H(maj)),3.83(s,3H),3.77–3.55(m,2H(min),2H(maj,min)),3.11(ddd,J=12.5,12.5,4.8Hz,1H(maj)),2.98–2.60(m,4H),2.47(s,3H(maj)),2.45(s,3H(min)),2.29–2.13(m,2H),0.67–0.54(m,2H),0.35–0.24(m,2H).ESI-MS m/z 419.2[M+H]+.
实施例(S)-C4:化合物(S)-C4的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(S)-A3的合成,得到化合物(S)-C4。ESI-MS m/z 419.2[M+H]+.
实施例(R)-C4:化合物(R)-C4的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(R)-A3的合成,得到化合物(R)-C4。ESI-MS m/z 419.2[M+H]+.
实施例C5:化合物C5的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物A1的合成,得到化合物C5。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.19(s,1H(maj)),7.97(brs,1H(maj)),7.89(brs,1H(min)),7.51(d,J=8.0Hz,1H(maj)),7.45(d,J=8.1Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.04(s,1H(min)),7.00–6.89(m,1H(min,maj)1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.43(s,1H(min)),6.40(s,1H(maj)),5.46(dd,J=7.3,6.3Hz,1H(min)),4.54(dd,J=13.2,6.1Hz,1H(min)),4.43(dd,J=9.8,3.8Hz,1H(maj)),3.83(s,3H),3.75(s,3H(maj)),3.78–3.68(m,3H(min,maj)1H(min)),3.62(ddd,J=12.2,12.2,4.2Hz,1H(min)),3.12(ddd,J=12.2,12.2,4.5Hz,1H(maj)),2.98–2.63(m,4H),2.46(s,3H(maj)),2.45(s,3H(min)),2.31–2.17(m,2H).ESI-MS m/z 379.2[M+H]+.
实施例(S)-C5:化合物(S)-C5的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(S)-A1的合成,得到化合物(S)-C5。ESI-MS m/z 379.2[M+H]+.
实施例(R)-C5:化合物(R)-C5的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(R)-A1的合成,得到化合物(R)-C5。ESI-MS m/z 379.2[M+H]+.
实施例C6:化合物C6的合成
用化合物29-1替换实施例C1中的23-1,合成方法参考化合物A1的合成,得到化合物C6。1H NMR(400MHz,CDCl3)δ8.29(s,1H(min)),8.20(s,1H(maj)),8.19(brs,1H(maj)),8.11(brs,1H(min)),7.51(dd,J=8.7,5.3Hz,1H(maj)),7.46(dd,J=8.7,5.3Hz,1H(min)),7.14–6.98(m,2H),6.94–6.81(m,2H),6.58(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J=8.5,5.3Hz,1H(min)),4.54(ddd,J=13.1,6.4,1.4Hz,1H(maj)),4.43(dd,J=7.0,7.0Hz,1H(maj)),3.84(s,3H(maj)),3.84(s,3H(min)),3.77(s,3H(maj)),3.76–3.68(m,4H(min)),3.62(ddd,J=13.4,11.9,4.5Hz,1H(min)),3.12(ddd,J=13.1,11.8,4.7Hz,1H(maj)),2.98–2.63(m,4H),2.30–2.15(m,2H).ESI-MS m/z 383.2[M+H]+.
实施例(S)-C6:化合物(S)-C6的合成
用化合物29-1替换实施例C1中的23-1,合成方法参考化合物(S)-A1的合成,得化合物(S)-C6。ESI-MS m/z 383.2[M+H]+.
实施例(R)-C6:化合物(R)-C6的合成
用化合物29-1替换实施例C1中的23-1,合成方法参考化合物(R)-A1的合成,得化合物(R)-C6。ESI-MS m/z 383.2[M+H]+.
实施例C7:化合物C7的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物A4的合成,得到化合物C7。1H NMR(400MHz,Chloroform)δ8.02(s,1H),7.60(s,1H),7.53(s,1H),7.25–7.16(m,3H),6.97(s,1H),6.88(s,1H),4.70(s,1H),4.13(s,2H),3.92(s,1H),3.75(s,3H),3.33(s,1H),2.91(d,J=15.0Hz,2H),2.76(s,1H),2.44(s,3H),2.26(s,2H),1.42(s,3H).ESI-MSm/z 393.2[M+H]+.
实施例(S)-C7:化合物(S)-C7的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(S)-A4的合成,得到化合物(S)-C7。ESI-MS m/z 393.2[M+H]+.
实施例(R)-C7:化合物(R)-C7的合成
用化合物25-1替换实施例C1中的23-1,合成方法参考化合物(R)-A4的合成,得到化合物(R)-C7。ESI-MS m/z 393.2[M+H]+.
实施例C8:化合物C8的合成
用化合物31-1替换实施例C1中的23-1,合成方法参考化合物A4的合成,得到化合物C8。1H NMR(400MHz,CDCl3)δ8.28(s,1H(min)),8.21(s,1H(maj)),8.03(brs,1H(maj)),7.96(brs,1H(min)),7.28(d,J=8.8Hz,1H(maj)),7.25(d,J=8.8Hz,1H(min)),7.11(s,1H(min)),7.03(d,J=2.3Hz,1H(maj)),7.00(d,J=2.0Hz,1H(min)1H(maj)),6.88(dd,J=8.8,2.4Hz,1H(maj)),6.84(dd,J=8.8,2.4Hz,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(maj)),6.42(s,1H(min)),5.45(dd,J=8.3,5.5Hz,1H(min)),4.53(ddd,J=13.0,6.3,1.7Hz,1H(maj)),4.43(dd,J=7.9,5.2Hz,1H(maj)),3.98–3.84(m,5H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J=12.9,6.1Hz,1H(min)),3.66–3.57(m,1H(min)),3.12(ddd,J=13.1,11.8,4.8Hz,1H(maj)),2.96–2.64(m,4H),2.28–2.16(m,2H),1.43–1.34(m,3H).ESI-MS m/z 409.2[M+H]+.
实施例(S)-C8:化合物(S)-C8的合成
用化合物31-1替换实施例C1中的23-1,合成方法参考化合物(S)-A4的合成,得到化合物(S)-C8。ESI-MS m/z 409.2[M+H]+.
实施例(R)-C8:化合物(R)-C8的合成
用化合物31-1替换实施例C1中的23-1,合成方法参考化合物(R)-A4的合成,得到化合物(R)-C8。ESI-MS m/z 409.2[M+H]+.
实施例C9:化合物C9的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物A1的合成,得到化合物C9。1H NMR(400MHz,CDCl3)δ8.32(brs,1H(maj)),8.18(s,1H(min)),8.16(brs,1H(min)),7.65(d,J=7.7Hz,1H(maj)),7.60(m,1H(min)1H(maj)),7.41(d,J=7.9Hz,1H(maj)),7.36(d,J=8.1Hz,1H(min)),7.28–7.07(m,2H),6.95(s,1H(maj)),6.93(s,1H(min)),6.70(s,1H(maj)),6.67(s,1H(maj)),6.57(s,1H(min)),6.34(s,1H(min)),5.69(dd,J=6.5Hz,1H(min)),4.74(dd,J=9.8,3.8Hz,1H(maj)),4.53(dd,J=13.0,4.4Hz,1H(maj)),3.91(s,3H(maj)),3.88(s,3H(maj)),3.87(s,3H(min)),3.64–3.54(m,4H(min)),3.48–3.13(m,3H),3.00–2.81(m,1H),2.77(dd,J=16.0,2.5Hz,1H(maj)),2.69(dd,J=16.2,2.3Hz,1H(min)).ESI-MS m/z 351.2[M+H]+.
实施例(S)-C9:化合物(S)-C9的合成
实施例(R)-C9:化合物(R)-C9的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(R)-A1的合成,得到化合物(R)-C9。ESI-MS m/z 351.2[M+H]+.
实施例C10:化合物C10的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物A4的合成,得到化合物C10。1H NMR(400MHz,CDCl3)δ8.27(brs,1H(maj)),8.15(s,1H(min)),8.11(brs,1H(min)),7.62(d,J=7.5Hz,1H(maj)),7.59–7.53(m,1H(min),1H(maj)),7.38(d,J=8.0Hz,1H(maj)),7.33(d,J=8.1Hz,1H(min)),7.25–7.04(m,2H),6.93(s,1H(maj)),6.93(s,1H(min)),6.71(s,1H(maj)),6.64(s,1H(maj)),6.55(s,1H(min)),6.37(s,1H(min)),5.66(t,J=6.5Hz,1H(min)),4.69(dd,J=9.8,3.8Hz,1H(maj)),4.49(ddd,J=13.1,6.2,2.1Hz,1H(maj)),4.07(qd,J=7.0,1.9Hz,2H(maj)),3.87(s,3H(maj)),3.83(s,3H(min)),3.81–3.65(m,2H(min)),3.54(ddd,J=13.0,6.0,1.7Hz,1H(min)),3.43–3.07(m,3H),2.97–2.58(m,2H),1.47(t,J=7.0Hz,3H(maj)),1.32(t,J=7.0Hz,3H(min)).ESI-MS m/z365.2[M+H]+.
实施例(S)-C10:化合物(S)-C10的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(S)-A1的合成,得到化合物(S)-C10。ESI-MS m/z 365.2[M+H]+.
实施例(R)-C10:化合物(R)-C10的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(R)-A1的合成,得到化合物(R)-C10。ESI-MS m/z 365.2[M+H]+.
实施例C11:化合物C11的合成
用化合物32-1替换实施例A1中的1-2,参考化合物B1的合成,得到化合物C11。1HNMR(400MHz,CDCl3)δ8.32(brs,1H(min)),8.08(brs,1H(maj)),7.67(m,1H),7.40(d,J=7.4Hz,1H(min)),7.33(d,J=8.1Hz,1H(maj)),7.24–7.05(m,2H),6.93(s,1H(min)),6.88(s,1H(maj)),6.64(s,1H(min)),6.58(s,1H(maj)),6.54(s,1H(min)),6.20(s,1H(maj)),5.79(dd,J=7.1,6.0Hz,1H(maj)),4.92(dd,J=8.6,5.7Hz,1H(min)),4.80(dd,J=12.6,5.7Hz,1H(min)),4.14(s,1H(maj)),3.87(s,3H(min)),3.84(s,3H(maj)),3.78(s,3H(min)),3.69(m,1H),3.49(s,3H(maj)),3.48–3.41(m,1H(min)),3.39(s,3H(maj)),3.37–3.15(m,3H),2.98(s,3H(min)),2.96–2.79(m,1H),2.77–2.63(m,1H).ESI-MS m/z 395.2[M+H]+.
实施例(S)-C11:化合物(S)-C11的合成
用化合物32-1替换实施例A1中的1-2,参考化合物(S)-B1的合成,得到化合物(S)-C11。ESI-MS m/z 395.2[M+H]+.
实施例(R)-C11:化合物(R)-C11的合成
用化合物32-1替换实施例A1中的1-2,参考化合物(R)-B1的合成,得到化合物(R)-C11。ESI-MS m/z 395.2[M+H]+.
实施例C12:化合物C12的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物B8的合成,得到化合物C12。1H NMR(400MHz,CDCl3)δ7.83(brs,1H),7.57(dd,J=14.9,3.0Hz,1H),7.33(dd,J=15.0,3.1Hz,1H),7.24–7.13(m,2H),7.05–6.93(m,2H),6.88(s,1H),3.96(t,J=14.0Hz,1H),3.84(dd,J=16.4,15.4Hz,1H),3.77–3.68(m,6H),3.55–3.23(m,4H),3.15–2.96(m,2H),2.84–2.66(m,5H),2.58(m,1H).ESI-MS m/z 429.2[M+H]+.
实施例(S)-C12:化合物(S)-C12的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(S)-B8的合成,得到化合物(S)-C12。ESI-MS m/z 429.2[M+H]+.
实施例(R)-C12:化合物(R)-C12的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(R)-B8的合成,得到化合物(R)-C12。ESI-MS m/z 429.2[M+H]+.
实施例C13:化合物C13的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例B9的合成,得到化合物C13。1H NMR(400MHz,CDCl3)δ8.37(brs,1H(min)),8.12(brs,1H(maj)),7.62(d,J=7.8Hz,1H(maj)),7.57(d,J=7.6Hz,1H(min)),7.39(d,J=7.8Hz,1H(min)),7.33(d,J=8.1Hz,1H(maj)),7.26–7.07(m,2H),7.02(s,1H(min)),6.87(s,1H(maj)),6.68(s,1H(min)),6.64(s,1H(min)),6.58(s,1H(maj)),6.19(s,1H(maj)),5.81(dd,J=6.8,6.8Hz,1H(maj)),5.01(dd,J=9.7,4.4Hz,1H(min)),4.74(dd,J=13.3,3.2Hz,1H(min)),4.09(q,J=14.4Hz,2H(maj)),3.87(s,3H(maj)),3.86(s,3H(min)),3.84(s,3H(maj)),3.74–3.64(m,1H(maj)),3.50(s,2H),2.99(s,3H),2.78(s,2H).ESI-MS m/z 443.2[M+H]+.
实施例(S)-C13:化合物(S)-C13的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-B9的合成,得到化合物(S)-C13。ESI-MS m/z 443.2[M+H]+.
实施例(R)-C13:化合物(R)-C13的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-B9的合成,得到化合物(R)-C13。ESI-MS m/z 443.2[M+H]+.
实施例C14:化合物C14的合成
用化合物32-1替换实施例A1中的1-2,参考实施例A4及实施例B8的合成,得到化合物C14。1H NMR(400MHz,CDCl3)δ8.13(brs,1H),7.58(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.20(t,J=7.3Hz,1H),7.13(t,J=7.3Hz,1H),6.98(s,1H),6.59(s,1H),6.36(s,1H),4.02–3.93(m,1H),3.92–3.74(m,5H),3.51–3.38(m,1H),3.20(m,2H),3.12–2.83(m,6H),2.55(d,J=15.6Hz,1H),2.41(s,3H),1.36(t,J=7.0Hz,3H).ESI-MS m/z 443.2[M+H]+.
实施例(S)-C14:化合物(S)-C14的合成
用化合物32-1替换实施例A1中的1-2,参考实施例(S)-A4及实施例(S)-B8的合成,得到化合物(S)-C14。ESI-MS m/z 443.2[M+H]+.
实施例(R)-C14:化合物(R)-C14的合成
用化合物32-1替换实施例A1中的1-2,参考实施例(R)-A4及实施例(R)-B8的合成,得到化合物(R)-C14。ESI-MS m/z 443.2[M+H]+.
实施例C15:化合物C15的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例A4及实施例B9的合成,得到化合物C15。1H NMR(400MHz,CDCl3)δ7.71(brs,1H),7.57(dd,J=7.5,1.4Hz,1H),7.33(dd,J=7.5,1.4Hz,1H),7.23–7.15(m,2H),7.02–6.94(m,2H),6.88(s,1H),5.66(t,J=7.1Hz,1H),4.35(s,2H),4.17–4.05(m,3H),3.75(s,3H),3.58(dd,J=12.4,7.1Hz,1H),3.49(dt,J=12.4,5.5Hz,1H),3.32(dd,J=12.5,7.0Hz,1H),2.98–2.84(m,5H),1.42(t,J=5.9Hz,3H).ESI-MS m/z 457.2[M+H]+.
实施例(S)-C15:化合物(S)-C15的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-A4及实施例(S)-B9的合成,得到化合物C15。ESI-MS m/z 457.2[M+H]+.
实施例(R)-C15:化合物(R)-C15的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-A4及实施例(R)-B9的合成,得到化合物(R)-C15。ESI-MS m/z 457.2[M+H]+.
实施例C16:化合物C16的合成
/>
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例A4及实施例B4的合成,得到化合物C16。1H NMR(400MHz,CDCl3)δ8.42(brs,1H(min)),8.14(brs,1H(maj)),7.66(d,J=7.1Hz,1H(min)),7.63(d,J=7.9Hz,1H(maj)),7.39(d,J=7.2Hz,1H(min)),7.33(d,J=8.1Hz,1H(maj)),7.25–7.05(m,2H),6.93(s,1H(min)),6.87(s,1H(maj)),6.63(s,1H(min)),6.60(s,1H(min)),6.57(s,1H(maj)),6.26(s,1H(maj)),5.78(dd,J=6.6,6.6Hz,1H(maj)),4.88(dd,J=9.0,4.8Hz,1H(min)),4.80(dd,J=12.7,5.2Hz,1H(min)),4.13(s,2H(maj)),3.99(dt,J=16.4,9.4Hz,2H(maj)),3.86(s,3H(min)),3.83(s,3H(maj)),3.78–3.57(m,1H(min)1H(maj)),3.48–3.13(m,3H(maj)3H(min,maj)2H(min)),2.95(s,3H(min)),2.76(m,2H),1.44(t,J=7.0Hz,3H(min)),1.28(t,J=7.0Hz,3H(maj)).ESI-MS m/z 409.2[M+H]+.
实施例(S)-C16:化合物(S)-C16的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-A4及实施例(S)-B4的合成,得到化合物(S)-C16。
实施例(R)-C16:化合物(R)-C16的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-A4及实施例(R)-B4的合成,得到化合物(R)-C16。
实施例C17:化合物C17的合成
化合物43-1的合成:
氩气保护下将24-1溶于无水四氢呋喃中,-78℃下搅拌缓慢滴加正丁基锂溶液,反应30min后,逐滴加入氯化锌的四氢呋喃溶液,升至室温下,加入15-1,搅拌24h。反应液倒入饱和氯化铵溶液,乙酸乙酯萃取三遍,有机层水洗、饱和氯化钠洗,无水硫酸钠干燥,蒸干石油醚/乙酸乙酯=10:1柱层析得黄色油状物(605mg,70%)。
化合物43-2的合成:
43-1溶于四氢呋喃/水=1:1溶剂中,加入氢氧化锂,室温搅拌16h。加乙酸乙酯萃取,收集水层,1N稀盐酸调pH至酸性,乙酸乙酯萃取三遍,收集有机层,无水硫酸钠干燥,蒸干得棕黄色固体g,产率95%。
用化合物43-2替换实施例A1中的1-2,参考实施例C10的合成方法,得到白色固体C17。1H NMR(400MHz,CDCl3)δ8.19(brs,1H(maj)),8.15(s,1H(min)),8.03(brs,1H(min)),7.57(s,1H(maj)),7.36(s,1H(maj)),7.29(s,1H(min)),7.27(d,J=7.5Hz,1H(maj)),7.21(d,J=8.3Hz,1H(min)),7.05(d,J=8.4Hz,1H(maj)),6.99(d,J=8.4Hz,1H(min)),6.88(s,1H(maj)),6.84(s,1H(min)),6.72(s,1H(maj)),6.64(s,1H(maj)),6.55(s,1H(min)),6.39(s,1H(min)),5.64(dd,J=6.3,6.3Hz,1H(min)),4.69(dd,J=9.8,4.0Hz,1H(maj)),4.47(ddd,J=13.3,6.3,2.2Hz,1H(maj)),4.07(qd,J=6.9,1.7Hz,2H(maj)),3.87(s,3H(maj)),3.84(s,3H(min)),3.83–3.68(m,2H(min)),3.54(ddd,J=13.3,6.3,2.3Hz,1H(min)),3.42–3.05(m,3H),2.96–2.78(m,1H),2.78–2.59(m,1H),2.49(s,3H(maj)),2.41(s,3H(min)),1.48(t,J=7.0Hz,3H(maj)),1.33(t,J=7.0Hz,3H(min)).ESI-MS m/z379.2[M+H]+.
实施例(S)-C17:化合物(S)-C17的合成
用化合物43-2替换实施例A1中的1-2,参考实施例(S)-C10的合成方法,得到白色固体(S)-C17。
实施例(R)-C17:化合物(R)-C17的合成
用化合物43-2替换实施例A1中的1-2,参考实施例(R)-C10的合成方法,得到白色固体(R)-C17。
实施例C18:化合物C18的合成
用化合物44-1替换实施例C17中的24-1,合成方法参考化合物C17的合成,得到白色固体C18。1H NMR(400MHz,CDCl3)δ8.17(s,1H(maj)1H(min)),8.00(brs,1H(min)),7.62(s,1H(maj)),7.27(d,J=8.9Hz,1H),7.21(d,J=8.8Hz,1H(maj)),7.00(d,J=2.4Hz,1H(min)),6.98(d,J=2.4Hz,1H(maj)),6.91(s,1H(maj)),6.88(dd,J=8.8,2.4Hz,1H(maj)),6.86(s,1H(min)),6.82(dd,J=8.7,2.4Hz,1H(min)),6.69(s,1H(maj)),6.63(s,1H(maj)),6.54(s,1H(min)),6.39(s,1H(min)),5.63(t,J=6.1Hz,1H(min)),4.68(dd,J=9.6,4.4Hz,1H(maj)),4.46(ddd,J=12.7,6.2,2.1Hz,1H(maj)),4.05(qd,J=6.9,2.3Hz,2H(maj)),3.87(s,3H(maj)),3.87(s,3H(min)),3.85–3.71(m,3H(min,maj)2H(min)),3.54(ddd,J=8.2,6.1,2.5Hz,1H(min)),3.37–3.08(m,3H),2.95–2.77(m,1H),2.77–2.56(m,1H),1.46(t,J=7.0Hz,3H(maj)),1.33(t,J=7.0Hz,3H(min)).ESI-MS m/z 395.2[M+H]+.
实施例(S)-C18:化合物(S)-C18的合成
用化合物44-1替换实施例C17中的24-1,合成方法参考化合物(S)-C17的合成,得到白色固体(S)-C18。
实施例(R)-C18:化合物(R)-C18的合成
用化合物44-1替换实施例C17中的24-1,合成方法参考化合物(R)-C17的合成,得到白色固体(R)-C18。
实施例C19:化合物C19的合成
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1,合成方法参考化合物A4的合成,得到化合物C19。
实施例(S)-C19:化合物(S)-C19的合成
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1,合成方法参考化合物(S)-A4的合成,得到化合物(S)-C19。
实施例(R)-C19:化合物(R)-C19的合成
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1,合成方法参考化合物(R)-A4的合成,得到化合物(R)-C19。
实施例C20:化合物C20的合成
用中间体C20-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C20。ESI-MS m/z 407.0[M+H]+.
实施例(S)-C20:化合物(S)-C20的合成
用中间体C20-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C20。1H NMR(500MHz,Chloroform-d)δ9.74(t,J=2.4Hz,1H),8.20(s,1H),7.48(dd,J=2.5,0.5Hz,1H),7.34(dt,J=2.7,0.6Hz,1H),7.08(ddd,J=8.4,2.2,0.6Hz,1H),6.93(dd,J=15.4,0.9Hz,1H),6.84–6.77(m,2H),6.65(dd,J=15.6,6.4Hz,1H),6.49(d,J=1.0Hz,1H),5.22(dt,J=6.4,0.9Hz,1H),4.20–4.03(m,2H),3.85(d,J=13.4Hz,5H),3.73(ddd,J=11.7,6.4,4.3Hz,1H),3.65(ddd,J=11.5,6.4,4.3Hz,1H),2.97(dddd,J=14.6,6.4,4.2,1.0Hz,1H),2.89(dddd,J=14.6,6.4,4.2,1.0Hz,1H),1.43(t,J=6.9Hz,3H).ESI-MS m/z 407.2[M+H]+.
实施例(R)-C20:化合物(R)-C20的合成
用中间体C20-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C20。ESI-MS m/z 407.0[M+H]+.
实施例C21:化合物C21的合成
用中间体C21-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C21。ESI-MS m/z 463.0[M+H]+.
实施例(S)-C21:化合物(S)-C21的合成
用中间体C21-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C21。1H NMR(500MHz,Chloroform-d)δ9.04(t,J=2.4Hz,1H),8.28(s,1H),7.28–7.22(m,1H),7.11–7.06(m,2H),6.83(d,J=1.0Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.63(t,J=1.0Hz,1H),4.66(dd,J=6.0,1.1Hz,1H),4.20–4.02(m,2H),3.84(d,J=10.1Hz,6H),3.68(ddd,J=11.7,6.3,4.4Hz,1H),3.50(ddd,J=11.7,6.3,4.4Hz,1H),3.42(p,J=5.9Hz,1H),2.99–2.84(m,2H),2.31(h,J=6.0Hz,1H),2.07–1.96(m,2H),1.82–1.70(m,4H),1.70–1.60(m,2H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 463.3[M+H]+.
实施例(R)-C21:化合物(R)-C21的合成
用中间体C21-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C21。ESI-MS m/z 463.3[M+H]+.
实施例C22:化合物C22的合成
用中间体C21-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C22。1H NMR(500MHz,CDCl3)δ8.29(s,1H),7.74(ddd,J=7.9,1.3,0.6Hz,1H),7.53–7.47(m,1H),7.37(td,J=7.7,1.3Hz,1H),7.21–7.14(m,1H),6.67(d,J=0.9Hz,1H),6.60(t,J=1.0Hz,1H),4.98–4.91(m,1H),4.20–4.03(m,2H),3.84(s,2H),3.73(ddd,J=11.5,6.2,4.2Hz,1H),3.56(ddd,J=11.7,6.4,4.3Hz,1H),3.04–2.83(m,3H),2.48–2.29(m,3H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 380.2[M+H]+./>
实施例(S)-C22:化合物(S)-C22的合成
用中间体C22-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C22。ESI-MS m/z 380.2[M+H]+.
实施例(R)-C22:化合物(R)-C22的合成
用中间体C22-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C22。ESI-MS m/z 380.2[M+H]+.
实施例C23:化合物C23的合成
用中间体C23-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C23。1H NMR(500MHz,CDCl3)δ8.28(s,1H),7.55–7.49(m,1H),7.44–7.37(m,1H),7.32–7.25(m,1H),7.18(ddd,J=7.9,7.3,1.1Hz,1H),6.67(d,J=0.9Hz,1H),6.60(t,J=1.0Hz,1H),6.47–6.42(m,1H),4.85(td,J=5.4,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.70(ddd,J=11.5,6.2,4.3Hz,1H),3.54(ddd,J=11.7,6.3,4.4Hz,1H),2.97–2.83(m,3H),2.62(dt,J=13.7,7.3Hz,1H),2.30–2.12(m,2H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 380.2[M+H]+.
实施例(S)-C23:化合物(S)-C23的合成
用中间体C23-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C23。ESI-MS m/z 380.0[M+H]+.
实施例(R)-C23:化合物(R)-C23的合成
用中间体C23-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C23。ESI-MS m/z 380.0[M+H]+.
实施例C24:化合物C24的合成
用中间体C24-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C24。1H NMR(500MHz,CDCl3)δ8.29(s,1H),7.77–7.67(m,2H),7.39–7.32(m,1H),7.16–7.06(m,2H),6.67(d,J=0.9Hz,1H),6.61(t,J=1.0Hz,1H),4.88(td,J=5.4,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.72(ddd,J=11.7,6.2,4.5Hz,1H),3.55(ddd,J=11.7,6.2,4.5Hz,1H),3.00–2.91(m,1H),2.94–2.84(m,2H),2.76(dt,J=13.7,7.3Hz,1H),2.24(ddtd,J=35.3,12.5,7.3,5.4Hz,2H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 396.2[M+H]+.
实施例(S)-C24:化合物(S)-C24的合成
用中间体C24-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C24。ESI-MS m/z 396.2[M+H]+.
实施例(R)-C24:化合物(R)-C24的合成
用中间体C24-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C24。ESI-MS m/z 396.2[M+H]+.
实施例C25:化合物C25的合成
/>
成路线,得化合物C25。1H NMR(500MHz,CDCl3)δ8.30(s,1H),7.38–7.25(m,2H),7.18–7.08(m,2H),6.70(d,J=1.9Hz,1H),6.65–6.59(m,2H),5.06(td,J=5.3,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.71(ddd,J=11.5,6.2,4.3Hz,1H),3.55(ddd,J=11.7,6.2,4.4Hz,1H),2.97–2.83(m,2H),2.77(dt,J=13.5,7.3Hz,1H),2.60(dt,J=13.7,7.4Hz,1H),2.26(dtd,J=12.6,7.3,5.3Hz,1H),2.16(dtd,J=12.5,7.2,5.3Hz,1H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 379.2[M+H]+.
实施例(S)-C25:化合物(S)-C25的合成
用中间体C25-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C25。ESI-MS m/z 379.2[M+H]+.
实施例(R)-C25:化合物(R)-C25的合成
用中间体C25-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C25。ESI-MS m/z 379.2[M+H]+.
实施例C26:化合物C26的合成
用中间体C26-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C26。1H NMR(500MHz,Chloroform-d)δ8.83–8.76(m,2H),8.30(s,1H),8.03–7.97(m,1H),7.34(dd,J=7.9,3.5Hz,1H),6.87–6.82(m,1H),6.65–6.60(m,2H),4.92(td,J=5.3,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.73(ddd,J=11.5,6.2,4.3Hz,1H),3.56(ddd,J=11.7,6.3,4.4Hz,1H),2.97–2.88(m,1H),2.92–2.84(m,1H),2.88–2.79(m,1H),2.47–2.30(m,2H),2.26(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 380.2[M+H]+
实施例(S)-C26:化合物(S)-C26的合成
用中间体C26-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C26。ESI-MS m/z 380.0[M+H]+.
实施例(R)-C26:化合物(R)-C26的合成
用中间体C26-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C26。ESI-MS m/z 380.0[M+H]+.
实施例C27:化合物C27的合成
合成路线,得化合物C27。1H NMR(500MHz,CDCl3)δ8.24(s,1H),6.86(d,J=1.1Hz,1H),6.61(t,J=1.0Hz,1H),4.86(td,J=5.4,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,2H),3.69(ddd,J=11.7,6.3,4.4Hz,1H),3.51(ddd,J=11.7,6.4,4.4Hz,1H),2.97–2.82(m,2H),2.01(dtd,J=12.8,7.4,5.3Hz,1H),1.77(dtd,J=12.8,7.5,5.4Hz,1H),1.66–1.38(m,11H),1.35–1.12(m,7H).ESI-MS m/z 346.2[M+H]+.
实施例(S)-C27:化合物(S)-C27的合成
用中间体C27-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C27。ESI-MS m/z 346.2[M+H]+.
实施例(R)-C27:化合物(R)-C27的合成
用中间体C27-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C27。ESI-MS m/z 346.2[M+H]+.
实施例C28:化合物C28的合成
用中间体C28-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C28。1H NMR(500MHz,Chloroform-d)δ8.24(s,1H),6.95(d,J=0.9Hz,1H),6.62(t,J=1.0Hz,1H),4.72(td,J=5.4,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,3H),3.87–3.79(m,1H),3.76(t,J=6.0Hz,4H),3.49(ddd,J=11.7,6.2,4.5Hz,1H),2.95–2.83(m,2H),2.72(dt,J=11.9,7.2Hz,1H),2.58–2.42(m,5H),2.06(dtd,J=12.6,7.3,5.3Hz,1H),1.92(dtd,J=12.6,7.3,5.5Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 349.2[M+H]+.
实施例(S)-C28:化合物(S)-C28的合成
用中间体C28-1替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C28。ESI-MS m/z 349.2[M+H]+.
实施例(R)-C28:化合物(R)-C28的合成
用中间体C28-1替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C28。ESI-MS m/z 349.2[M+H]+.
实施例C29:化合物C29的合成
用
中间体C29-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C29。1HNMR(500MHz,CDCl3)δ8.48–8.38(m,2H),8.27(s,1H),7.46(dt,J=7.9,2.1Hz,1H),7.19(dd,J=7.8,3.5Hz,1H),6.63(t,J=1.0Hz,1H),6.55(d,J=1.1Hz,1H),4.77(td,J=5.3,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,2H),3.76(ddd,J=11.7,6.3,4.4Hz,1H),3.54(ddd,J=11.7,6.4,4.3Hz,1H),2.96–2.80(m,3H),2.66(dt,J=13.9,7.3Hz,1H),2.27(dtd,J=12.6,7.3,5.3Hz,1H),2.15(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MSm/z 341.2[M+H]+.
实施例(S)-C29:化合物(S)-C29的合成
用中间体C29-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物(S)-C29。ESI-MS m/z 341.2[M+H]+.
实施例(R)-C29:化合物(R)-C29的合成
用中间体C29-1替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物(R)-C29。ESI-MS m/z 341.2[M+H]+.
实施例C30:化合物C30的合成
C30-1溶于无水二氯甲烷,冰浴下滴加氯乙酰氯、三乙胺,移至室温反应1h,加水淬灭,DCM萃取干燥蒸干柱层析得C30-2。C30-3溶于乙腈,加碳酸铯,室温搅拌2h,氮气保护下加C30-2,搅拌18h,饱和氯化铵淬灭,乙酸乙酯萃取,饱和食盐水洗涤,干燥蒸干柱层析得C30-4。以C30-4替换实施例A1中的1-3,参考A4的合成,得化合物C30。1H NMR(500MHz,Chloroform-d)δ9.86(dd,J=2.6,2.1Hz,1H),8.28(s,1H),7.46–7.39(m,2H),7.16(dd,J=2.5,0.6Hz,1H),6.81(dd,J=8.4,2.7Hz,1H),6.74(d,J=1.0Hz,1H),6.62(t,J=1.0Hz,1H),5.23(td,J=5.4,1.0Hz,1H),4.70(dd,J=10.5,5.4Hz,1H),4.61(dd,J=10.6,5.5Hz,1H),4.18–4.02(m,2H),3.84(d,J=11.7Hz,5H),3.67(ddd,J=11.7,6.4,4.2Hz,1H),3.57(ddd,J=11.7,6.5,4.2Hz,1H),2.97(dddd,J=14.6,6.4,4.2,1.1Hz,1H),2.87(dddd,J=14.5,6.2,4.1,1.0Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 411.2[M+H]+.
实施例(S)-C30:化合物(S)-C30的合成
以C30-4替换实施例A1中的1-3,参考(S)-A4的合成,得化合物(S)-C30。ESI-MS m/z 411.2[M+H]+.
实施例(R)-C30:化合物(R)-C30的合成
以C30-4替换实施例A1中的1-3,参考(R)-A4的合成,得化合物(R)-C30。ESI-MS m/z 411.2[M+H]+.
实施例C31:化合物C31的合成
以
C31-1替换实施例C30中的C30-3,参考C30的合成,得化合物C31。1H NMR(500MHz,Chloroform-d)δ9.99(dd,J=2.6,2.0Hz,1H),8.21(s,1H),7.57(dd,J=2.5,0.5Hz,1H),7.47(ddd,J=8.4,2.2,0.5Hz,1H),7.35–7.30(m,1H),6.81(dd,J=8.4,2.7Hz,1H),6.67(d,J=1.1Hz,1H),6.61(t,J=1.0Hz,1H),5.22(td,J=4.1,1.0Hz,1H),4.20–4.03(m,2H),3.85(d,J=17.0Hz,5H),3.75(dd,J=13.5,4.1Hz,1H),3.66(ddd,J=11.7,6.1,4.6Hz,1H),3.56(dd,J=13.5,4.1Hz,1H),3.42(ddd,J=11.7,6.2,4.4Hz,1H),2.94–2.81(m,2H),1.43(t,J=6.9Hz,3H).ESI-MS m/z 427.2[M+H]+.
实施例(S)-C31:化合物(S)-C31的合成
以C31-1替换实施例C30中的C30-3,参考(S)-C30的合成,得化合物(S)-C31。ESI-MS m/z 427.2[M+H]+.
实施例(R)-C31:化合物(R)-C31的合成
以C31-1替换实施例C30中的C30-3,参考(R)-C30的合成,得化合物(R)-C31。ESI-MS m/z 427.2[M+H]+.
实施例C32:化合物C32的合成
以C32-1替换实施例C30中的C30-3,参考C30的合成,得化合物C32。1H NMR(500MHz,Chloroform-d)δ9.43(t,J=2.4Hz,1H),8.26(s,1H),7.45–7.39(m,1H),7.22(ddd,J=14.8,2.6,0.6Hz,2H),6.80(dd,J=8.4,2.7Hz,1H),6.64(t,J=1.1Hz,1H),6.53(d,J=1.0Hz,1H),4.64(td,J=4.7,1.0Hz,1H),4.10(q,J=6.9Hz,2H),3.84(d,J=17.0Hz,5H),3.66(ddd,J=11.7,6.4,4.3Hz,1H),3.60–3.47(m,3H),3.48–3.40(m,2H),2.95(dddd,J=14.6,6.4,4.2,1.0Hz,1H),2.87(dddd,J=14.6,6.4,4.2,1.0Hz,1H),2.82(d,J=4.8Hz,2H),2.75(t,J=5.3Hz,4H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 479.3[M+H]+.
实施例(S)-C32:化合物(S)-C32的合成
以C32-1替换实施例C30中的C30-3,参考(S)-C30的合成,得化合物(S)-C32。ESI-MS m/z 479.3[M+H]+.
实施例(R)-C32:化合物(R)-C32的合成
以C32-1替换实施例C30中的C30-3,参考(R)-C30的合成,得化合物(R)-C32。ESI-MS m/z 479.3[M+H]+.
实施例C33:化合物C33的合成
/>
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2,参考化合物A4的合成路线,得化合物C33。
实施例(S)-C33:化合物(S)-C33的合成
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2,参考化合物(S)-A4的合成路线,得化合物(S)-C33。
实施例(R)-C33:化合物(R)-C33的合成
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2,参考化合物(R)-A4的合成路线,得化合物(R)-C33。
实施例C34:化合物C34的合成
C33-1替换实施例A1中的1-5,参考化合物B9的合成,得化合物C34。1H NMR(500MHz,Chloroform-d)δ6.94(t,J=1.0Hz,1H),6.74(t,J=1.0Hz,1H),4.54(d,J=0.9Hz,2H),4.18(s,1H),4.11(q,J=7.0Hz,2H),3.84(s,2H),3.82–3.68(m,2H),2.95(s,2H),2.89(td,J=5.3,1.0Hz,2H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 328.1[M+H]+.
实施例C35:化合物C35的合成
以3-氨基吲哚替换实施例C30中的C30-3,参考C30的合成,得化合物C35。
实施例(S)-C35:化合物(S)-C35的合成
以3-氨基吲哚替换实施例C30中的C30-3,参考(S)-C30的合成,得化合物(S)-C35。
实施例(R)-C35:化合物(R)-C35的合成
以3-氨基吲哚替换实施例C30中的C30-3,参考(R)-C30的合成,得化合物(R)-C35。
实施例C36:化合物C36的合成
中间体C36-1,3-吲哚丙酸与EDCI、HOBT、TEA在二氯甲烷中室温反应过夜得C36-2。C36-2经HCl-二氧六环溶液反应两小时得C36-3。C36-3于甲酸乙酯中回流过夜,经石油醚、乙酸乙酯体系过柱纯化得C36。
实施例(S)-C36:化合物(S)-C36的合成
以(S)-C36-1替换中间体C36-1,参考C36的合成得(S)-C36。
实施例(R)-C36:化合物(R)-C36的合成
以(R)-C36-1替换中间体C36-1,参考C36的合成得(R)-C36。
实施例C37:化合物C37的合成
用化合物C37-1替换实施例A1中的2-1,合成方法参考化合物A1,得化合物C37。1HNMR(400MHz,DMSO):δ10.86,10.74(2×s,1H),8.18,8.15(2×s,1H),7.42–7.22(m,2H),7.08–6.90(m,2H),6.81–6.73(m,1H),6.65–6.52(m,2H),5.55–5.46,5.06–4.96(2×m,1H),3.71–3.63,3.41–3.25(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.21–3.10,3.06–2.94(2×m,1H),2.80–2.57(m,4H),2.08–1.68(m,4H).ESI-MS m/z 379.2[M+H]+HR-MS:(ESI,m/z)calcd for C23H26N2O3+[M+H]+379.2016,found:379.2027.
实施例(S)-C37:化合物(S)-C37的合成
用化合物C37-1替换实施例A1中的2-1,合成方法参考化合物(S)-A1,得化合物(S)-C37。1H NMR(400MHz,DMSO):δ10.87,10.74(2×s,1H),8.18,8.15(2×s,1H),7.43–7.23(m,2H),7.08–6.90(m,2H),6.82–6.72(m,1H),6.64–6.52(m,2H),5.55–5.46,5.06–4.95(2×m,1H),3.73–3.63,3.41–3.24(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.22–3.10,3.09–2.94(2×m,1H),2.81–2.57(m,4H),2.08–1.71(m,4H).ESI-MS m/z 379.2[M+H]+HR-MS:(ESI,m/z)calcd for C23H26N2O3+[M+H]+379.2016,found:379.2027.
实施例(R)-C37:化合物(R)-C37的合成
用化合物C37-1替换实施例A1中的2-1,合成方法参考化合物(R)-A1,得化合物(R)-C37。1H NMR(400MHz,DMSO):δ10.86,10.74(2×s,1H),8.18,8.15(2×s,1H),7.44–7.24(m,2H),7.08–6.90(m,2H),6.82–6.73(m,1H),6.65–6.52(m,2H),5.55–5.46,5.06–4.96(2×m,1H),3.71–3.63,3.41–3.25(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.21–3.10,3.06–2.94(2×m,1H),2.80–2.57(m,4H),2.08–1.68(m,4H).ESI-MS m/z 379.2[M+H]+C23H26N2O3+[M+H]+:379.1943,found:379.2008.
实施例C38:化合物C38的合成
/>
用化合物32-1替换实施例A1中的1-2,用乙酰氯替换实施例B14中的B14-1,合成方法参考化合物B14的合成,得到化合物C38。1H NMR(500MHz,CDCl3)δ8.89,8.59(2×s,1H),7.63,7.58(2×d,J=31.9,7.8Hz,1H),7.34(2×d,J=37.5,7.9Hz,1H),7.22–7.03(m,2H),6.87,6.83(2×s,1H),6.64,6.58(2×s,1H),,6.20(s,1H),5.85–5.23(m,1H),4.92,4.81(2×dd,J=5.52,6.32,5.92,6.32Hz,1H),3.86,3.83(2×s,3H),3.80(s,1H),3.68–3.48(m,1H),3.46(s,2H),3.36–3.26(m,1H),3.25–3.16(m,2H),2.96–2.77(m,1H),2.75–2.64(m,1H),2.15,1.54(2×s,3H).ESI-MS m/z 365.1[M+H]+.HR-MS:(ESI,m/z)calcd forC22H23N2O3+[M+H]+365.1787,found 365.1863.
实施例(S)-C38:化合物(S)-C38的合成
用化合物32-1替换实施例A1中的1-2,用乙酰氯替换实施例B14中的B14-1,合成方法参考化合物(S)-B14的合成,得到化合物(S)-C38。1H NMR(500MHz,CDCl3)δ8.88,8.57(2×s,1H),7.64,7.58(2×d,J=31.9,7.8Hz,1H),7.34(2×d,J=37.5,7.9Hz,1H),7.22–7.03(m,2H),6.87,6.83(2×s,1H),6.64,6.57(2×s,1H),6.20(s,1H),5.85–5.23(m,1H),4.92,4.81(2×dd,J=5.52,6.32,5.92,6.32Hz,1H),3.86,3.83(2×s,3H),3.80(s,1H),3.68–3.48(m,1H),3.46(s,2H),3.36–3.26(m,1H),3.25–3.16(m,2H),2.96–2.77(m,1H),2.74–2.64(m,1H),2.14,1.52(2×s,3H).ESI-MS m/z 365.1[M+H]+.HR-MS:(ESI,m/z)calcd forC22H23N2O3+[M+H]+365.1787,found 365.1867.
实施例C39:化合物C39的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物B1的合成,得到化合物C39。1H NMR(400MHz,CDCl3)δ8.63,8.50(2×s,1H),8.35,8.18(2×s,1H),7.70,7.63(2×s,1H),7.39(dd,J=8.1,3.9Hz,1H),7.22(td,J=7.2,3.5Hz,1H),7.09–6.96(m,1H),6.89(d,J=1.9Hz,1H),6.71,6.60(2×s,1H),6.42(dd,J=16.8,11.8Hz,1H),6.00(t,J=6.8Hz,1H),4.93,4.82(2×dd,J=5.83,6.97,5.83,5.51Hz,1H),4.14(q,J=7.1Hz,1H),3.90(d,J=13.8Hz,3H),3.77(s,1H),3.64(d,J=9.5Hz,1H),3.56–3.35(m,2H),3.27–3.06(m,2H),2.92–2.73(m,1H),2.07(s,1H).ESI-MS m/z428.1[M+H]+.HR-MS:(ESI,m/z)calcd forC20H25N3O3+[M+H]+428.1896,found 428.1971.
实施例C40:化合物C40的合成
/>
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物B14的合成,得到化合物C40。1H NMR(500MHz,CDCl3)δ8.26(s,1H),7.67(d,J=7.6Hz,1H),7.36(d,J=7.9Hz,1H),7.17(dt,J=21.1,7.1Hz,2H),6.95(s,1H),6.61(s,1H),6.41(s,1H),5.20–5.11(m,1H),3.85(s,3H),3.67(s,3H),3.52–3.38(m,3H),3.30(dd,J=14.5,8.6Hz,1H),3.19(ddd,J=20.5,10.7,5.0Hz,3H),3.06–2.97(m,2H),2.96–2.88(m,1H),2.71(ddd,J=27.6,13.4,3.5Hz,3H).ESI-MS m/z 436.1[M+H]+.HR-MS:(ESI,m/z)calcd for C25H29N3O4+[M+H]+436.2158,found 436.2241.
实施例(S)-C40:化合物(S)-C40的合成
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(S)-B14的合成,得到化合物(S)-C40。1H NMR(500MHz,CDCl3)δ8.26(s,1H),7.67(d,J=7.6Hz,1H),7.36(d,J=7.9Hz,1H),7.17(dt,J=21.1,7.1Hz,2H),6.95(s,1H),6.61(s,1H),6.41(s,1H),5.20–5.11(m,1H),3.85(s,3H),3.67(s,3H),3.52–3.38(m,3H),3.30(dd,J=14.5,8.6Hz,1H),3.19(ddd,J=20.5,10.7,5.0Hz,3H),3.06–2.97(m,2H),2.96–2.88(m,1H),2.71(ddd,J=27.6,13.4,3.5Hz,3H).ESI-MS m/z 436.1[M+H]+.HR-MS:(ESI,m/z)calcd for C25H29N3O4+[M+H]+436.2158,found 436.2236.
实施例C41:化合物C41的合成
用化合物32-1替换实施例A1中的1-2,用化合物13-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物C41。1H NMR(500MHz,CDCl3)δ8.35,8.13(2×s,1H),7.81–7.58(m,1H),7.43–7.29(m,1H),7.33(d,J=8.1Hz,6H),7.25(d,J=3.1Hz,1H),7.15,7.07(dt,J=15.1,15.1Hz,1H),6.94,6.87(2×s,1H),6.77,6.65(2×s,1H),6.57–5.83(m,1H),5.07,4.83(2×dd,J=10.5,3.0,12.9,5.1,Hz,1H),4.04–3.96(m,1H),3.94(s,2H),3.88(s,2H),3.84(s,1H),3.81–3.67(m,1H),3.50–3.43(m,2H),3.41–3.12(m,3H),3.02–2.65(m,3H).ESI-MS m/z 436.1[M+H]+.HR-MS:(ESI,m/z)calcd for C25H30N3O4+[M+H]+435.2206,found 435.2290.
实施例(S)-C41:化合物(S)-C41的合成
用化合物32-1替换实施例A1中的1-2,用化合物13-1替换实施例B1中的11-1,合成方法参考化合物(S)-B1的合成,得到化合物(S)-C41。1H NMR(500MHz,CDCl3)δ9.12,8.63(2×d,J=32.9,30.9Hz,1H),7.76,7.57(2×d,J=5.12,8.47Hz,1H),7.39,7.30(2×d,,J=7.13,9.13Hz,1H),7.25–7.20(m,1H),7.13,7.04(2×t,J=13.8,14.4Hz,1H),6.92,6.86(2×s,1H),6.80,6.66(2×s,1H),6.58,6.22,5.85(2×s,t,J=6.5Hz,1H),5.09,4.85(2×d,J=10.0,7.7Hz,1H),4.02–3.78(m,6H),3.72–3.52(m,1H),3.46–3.27(m,3H),2.96–2.70(m,3H),2.09–1.87(m,2H),1.76–1.40(m,3H),1.36–1.12(m,2H).ESI-MS m/z 435.1[M+H]+.HR-MS:(ESI,m/z)calcd for C25H30N3O4+[M+H]+435.2206,found 435.2279.
实施例C42:化合物C42的合成
用化合物32-1替换实施例A1中的1-2,用化合物C42-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物C42。1H NMR(400MHz,CDCl3)δ8.09,7.90(2×d,J=12.4,2.5Hz,1H),7.90(2×d,J=7.7,3.1Hz,1H),7.57–7.52(m,1H),7.34–7.25(m 1H),7.23–7.15(m,1H),7.12–7.08(m,1H),7.05–6.95(m,1H),6.84–6.78(m,1H),6.62(d,J=16.6Hz,1H),6.34,6.08(2×s,1H),5.93,4.77(2×dd,J=8.3,5.4,13.4,3.7Hz,1H),3.85(d,J=7.1Hz,3H),3.83–3.76(m,1H),3.56(s,1H),3.54–3.44(m,1H),3.44–3.37(m,2H),3.28(dd,J=14.2,6.7Hz,1H),3.10–3.00(m,1H),2.89–2.73(m,1H),1.66(s,2H).ESI-MSm/z 434.9[M+H]+.HR-MS:(ESI,m/z)calcd for C24H24N3O3S+[M+H]+434.1460,found434.1546.
实施例(S)-C42:化合物(S)-C42的合成
用化合物32-1替换实施例A1中的1-2,用化合物C42-1替换实施例B1中的11-1,合成方法参考化合物B1的合成,得到化合物(S)-C42。1H NMR(500MHz,CDCl3)δ8.07(d,J=20.6Hz,1H),7.73,7.67(3×d,J=3.2,7.9,6.1Hz,1H),7.54(t,J=6.1Hz,2H),7.38–7.21(m,1H),7.17–7.07(m,1H),7.03–6.90(m,1H),6.81(dd,J=11.8,4.5Hz,1H),6.65,6.60(2×s,1H),6.34,6.09(2×s,1H),5.30–4.73(m,1H),3.95–3.77(m,3H),3.56(s,2H),3.52–3.41(m,1H),3.42–3.37(m,2H),3.34–3.25(m,1H),3.12–2.99(m,1H),2.89–2.73(m,1H),2.62(s,1H).ESI-MS m/z 434.1[M+H]+.HR-MS:(ESI,m/z)calcd for C24H24N3O3S+[M+H]+434.1460,found 434.1542.
实施例C43:化合物C43的合成
用化合物32-1替换实施例A1中的1-2,用化合物15-1替换实施例B2中的12-1,合成方法参考化合物B2的合成,得到化合物C43。1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.59(d,J=7.7Hz,1H),7.35(d,J=8.0Hz,1H),7.14(ddd,J=14.9,14.0,7.0Hz,2H),6.94(d,J=2.0Hz,1H),6.56(s,1H),5.96(s,1H),4.14–4.05(m,1H),3.83(s,3H),3.67(s,3H),3.54(q,J=16.7Hz,2H),3.38(s,3H),3.05(dd,J=14.4,7.9Hz,2H),2.87(ddd,J=16.4,10.4,6.0Hz,1H),2.61(dd,J=12.3,3.8Hz,1H),1.40(t,J=7.3Hz,1H).ESI-MS m/z 395.2[M+H]+.HR-MS:(ESI,m/z)calcd for C23H27N2O3+[M+H]+395.1893,found395.1971.
实施例C44:化合物C44的合成
用化合物C44-1替换实施例A1中的1-2,合成方法参考化合物A1的合成,得到化合物C44。1H NMR(400MHz,CDCl3)δ9.05,8.80(2×s,1H),8.13,7.52(2×s,1H),7.48,7.43(2×d,J=8.7,8.3Hz,1H),7.33,7.29(2×d,J=1.3,1.4Hz,1H),7.10,7.01(2×dd,J=8.4,1.7,8.5,1.7Hz,1H),6.89,6.84(2×d,J=1.6,1.7Hz,1H),6.67,6.64(2×s,1H),6.30,6.61(s,t,J=6.5Hz 1H),4.67,4.48(2×dd,J=9.9,3.8,12.1,5.5Hz,1H),3.87(d,J=2.2Hz,3H),3.84(s,1H),3.57,3.46(2×s,3H),3.39–3.00(m,2H),2.96–2.60(m,2H),1.35(t,J=7.3Hz,1H).ESI-MS m/z 385.1[M+H]+.HR-MS:(ESI,m/z)calcd for C21H22ClN2O3+[M+H]+385.1241,found 385.2241.
实施例(S)-C44:化合物(S)-C44的合成
用化合物C44-1替换实施例A1中的1-2,合成方法参考化合物(S)-A1的合成,得到化合物(S)-C44。1H NMR(500MHz,CDCl3)δ8.48,8.27(2×s,1H),8.15,7.57(2×s,1H),7.47(dd,J=18.5,8.4Hz,1H),7.34(dd,J=19.3,1.6Hz,1H),7.09(2×dd,J=1.8,1.8,1.9,1.7Hz,1H),6.92,6.87(2×s,1H),6.65(d,J=9.2Hz,1H),6.56,6.32(2×s,1H),4.68–4.46(m,1H),3.94–3.83(m,4H),3.59(s,1H),3.58–f3.34(m,1H),3.26(dd,J=11.3,5.2Hz,1H),3.23–3.10(m,1H),2.96–2.77(m,1H),2.79–2.61(m,1H),2.06(d,J=16.5Hz,1H),1.80(s,1H).ESI-MS m/z 385.1[M+H]+.HR-MS:(ESI,m/z)calcd for C21H22ClN2O3+[M+H]+385.1241,found385.1323.
实施例C45:化合物C45的合成
用化合物C45-1替换实施例A1中的1-2,合成方法参考化合物A1的合成,得到化合物C45。1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.64–7.53(m,2H),7.33(d,J=8.2Hz,1H),7.18(dt,J=14.8,7.0Hz,1H),7.08,6.80(m,1H),6.65(2×s,1H),6.55,6.26,5.64(2×s,t,J=6.4Hz,1H),4.72–4.47(m,1H),3.88(s,1H),3.85(d,J=2.1Hz,3H),3.75(s,1H),3.71(s,1H),3.60–3.53(m,1H),3.52(s,1H),3.38–3.07(m,3H),2.96–2.79(m,1H),2.79–2.63(m,1H),1.72(s,2H).ESI-MS m/z 365.1[M+H]+.HR-MS:(ESI,m/z)calcd for C22H25N2O3+[M+H]+365.1787,found 365.1868.
实施例C46:化合物C46的合成
用化合物32-1替换实施例A1中的1-2,用化合物溴苄替换实施例A2中的4-2,合成方法参考化合物A2的合成,得到化合物C46。1H NMR(400MHz,CDCl3)δ8.36,8.17(2×s,1H),7.55(dd,J=17.0,8.6Hz,2H),7.47(d,J=7.3Hz,1H),7.38(dd,J=12.8,3.9Hz,1H),7.31(d,J=7.4Hz,1H),7.26(t,J=7.2Hz,2H),7.17(m,1H),6.87,6.73(2×s,1H),6.69(d,J=4.5Hz,1H),6.58,6.32(2×s,1H),5.58(t,3H),5.15(s,1H),4.79(dd,J=39.4,12.5Hz,1H),4.56(m,1H),4.15(q,J=7.1Hz,1H),3.92,3.87(2×s,3H),3.61–3.29(m,1H),3.27–3.02(m,2H),2.98–2.79(m,1H),2.79–2.61(m,1H),2.07(s,1H).ESI-MS m/z 427.1[M+H]+.HR-MS:(ESI,m/z)calcd for C27H27N2O3+[M+H]+427.1943,found 427.2025.
实施例(S)-C47:化合物(S)-C47的合成
用苯磺酰氯替换实施例B13中的甲磺酰氯,合成方法参考化合物(S)-C8和B13的合成,得到化合物(S)-C47。1H NMR(500MHz,Chloroform-d)δ7.96(s,1H),7.72(d,J=7.8Hz,2H),7.41(t,J=7.4Hz,1H),7.30(t,J=7.7Hz,2H),7.27–7.23(m,1H),7.12(d,J=2.2Hz,1H),7.01(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),6.29(d,J=2.3Hz,2H),5.01(dd,J=9.4,4.2Hz,1H),3.95(dt,J=14.3,4.5Hz,1H),3.85(s,3H),3.85–3.80(m,2H),3.73(s,3H),3.56–3.46(m,1H),2.98–2.86(m,2H),2.40(dt,J=6.2,3.8Hz,2H),2.23(dtd,J=14.6,8.6,5.9Hz,1H),2.13(qd,J=9.0,8.4,3.8Hz,1H),1.36(t,J=7.0Hz,3H).
实施例(S)-C48:化合物(S)-C48的合成
用环丙基磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C48。1H NMR(500MHz,Chloroform-d)δ7.84(s,1H),7.25(s,1H),7.12(d,J=2.0Hz,1H),7.03(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),6.56(s,1H),6.30(s,1H),4.78(dd,J=9.9,3.8Hz,1H),4.02(dd,J=14.8,6.8Hz,1H),3.85(s,3H),3.85(q,J=7.0Hz,2H),3.82(s,3H),3.54(ddd,J=14.8,12.0,5.1Hz,1H),3.11–3.00(m,1H),3.00–2.90(m,2H),2.68(dd,J=16.7,5.0Hz,1H),2.24(ddt,J=14.2,8.3,4.3Hz,1H),2.15–2.03(m,2H),1.36(t,J=7.0Hz,3H),1.22–1.16(m,1H),1.07(ddt,J=10.2,6.8,4.9Hz,1H),0.82(qd,J=7.9,4.8Hz,1H),0.72(dt,J=9.6,6.0Hz,1H).
实施例(S)-C49:化合物(S)-C49的合成
用环己基磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C49。1H NMR(500MHz,Chloroform-d)δ7.67(s,1H),7.22(d,J=7.5Hz,1H),7.13(s,1H),7.04(s,1H),6.96(s,1H),6.70(d,J=7.5Hz,1H),6.26(s,1H),4.61(dq,J=12.3,7.9Hz,1H),4.19(s,1H),4.06(dq,J=12.5,8.1Hz,1H),3.89(d,J=15.0Hz,6H),3.62–3.50(m,2H),3.42(dt,J=16.9,7.1Hz,1H),3.26(dt,J=12.5,7.0Hz,1H),2.88–2.72(m,2H),2.50–2.39(m,3H),2.02–1.85(m,6H),1.78–1.66(m,1H),1.61–1.31(m,6H).
实施例(S)-C50:化合物(S)-C50的合成
用3-氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C50。1H NMR(500MHz,Chloroform-d)δ7.98–7.94(m,1H),7.47(td,J=7.9,1.7Hz,2H),7.30–7.23(m,2H),7.13–7.08(m,2H),7.01(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.33(s,1H),6.29(s,1H),4.97(dd,J=9.3,4.3Hz,1H),3.98–3.93(m,1H),3.86(s,3H),3.83(t,J=7.0Hz,2H),3.75(s,3H),3.58–3.51(m,1H),2.98–2.86(m,2H),2.49–2.43(m,2H),2.24(dtd,J=14.6,8.2,6.0Hz,1H),2.17–2.08(m,1H),1.36(t,J=7.0Hz,3H).
实施例(S)-C51:化合物(S)-C51的合成
用3,4-二氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C51。1H NMR(500MHz,Chloroform-d)δ7.95(s,1H),7.56(ddd,J=9.5,7.2,2.2Hz,1H),7.44(ddd,J=8.7,3.8,1.8Hz,1H),7.26(d,J=2.5Hz,1H),7.12(d,J=2.1Hz,1H),7.06(td,J=9.3,7.5Hz,1H),7.01(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.34(s,1H),6.29(s,1H),4.95(dd,J=9.3,4.3Hz,1H),3.97–3.90(m,1H),3.86(s,3H),3.83(q,J=7.0Hz,2H),3.76(s,3H),3.55(ddd,J=14.5,11.0,5.7Hz,1H),2.98–2.87(m,2H),2.51–2.39(m,2H),2.24(dtd,J=14.5,8.4,6.0Hz,1H),2.18–2.10(m,1H),1.37(t,J=7.0Hz,3H).
实施例(S)-C52:化合物(S)-C52的合成
用2,4-二氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C52。1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.95–7.88(m,1H),7.24(d,J=8.7Hz,1H),7.07(d,J=2.2Hz,1H),6.98(d,J=2.4Hz,1H),6.91–6.87(m,1H),6.85(dd,J=8.8,2.5Hz,1H),6.69(ddd,J=10.6,8.5,2.4Hz,1H),6.39(s,1H),6.32(s,1H),5.04(dd,J=9.3,4.4Hz,1H),4.05–3.97(m,1H),3.85(d,J=2.7Hz,4H),3.83(q,J=7.0Hz,2H),3.77(s,3H),3.57(ddd,J=14.3,9.5,7.0Hz,1H),2.95–2.81(m,2H),2.55–2.48(m,2H),2.24(dtd,J=14.6,8.9,5.7Hz,1H),2.17–2.08(m,1H),1.36(t,J=7.0Hz,3H).
实施例(S)-C53:化合物(S)-C53的合成
用乙基磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C53。1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.24(d,J=8.7Hz,1H),7.10(d,J=2.3Hz,1H),7.02(d,J=2.4Hz,1H),6.84(dd,J=8.8,2.4Hz,1H),6.57(s,1H),6.32(s,1H),4.77(dd,J=9.4,4.2Hz,1H),4.03–3.95(m,1H),3.84(s,3H),3.83(q,J=7.0Hz,2H),3.82(s,3H),3.54(ddd,J=14.6,11.8,5.0Hz,1H),3.01–2.78(m,5H),2.68(ddd,J=16.8,5.0,1.9Hz,1H),2.25(dtd,J=14.6,8.7,5.8Hz,1H),2.11(dtd,J=14.3,8.1,4.2Hz,1H),1.36(t,J=7.0Hz,3H),1.26(t,J=7.4Hz,3H).
实施例(S)-C54:化合物(S)-C54的合成
用三氟乙酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C54。1H NMR(500MHz,Chloroform-d)δ8.32(d,J=9.0Hz,1H),7.31(d,J=2.4Hz,1H),7.03–6.93(m,2H),6.61(s,1H),6.52(s,1H),5.59(dd,J=9.6,4.5Hz,1H),4.09–3.97(m,2H),3.93–3.80(m,8H),3.67(tdd,J=11.3,9.2,5.0Hz,1H),2.99(ddd,J=16.7,11.3,5.6Hz,1H),2.89–2.67(m,3H),2.38–2.16(m,2H),1.41(t,J=7.0Hz,3H).
实施例(S)-C55:化合物(S)-C55的合成
用吡啶-3-磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C55。1H NMR(500MHz,Chloroform-d)δ8.99(d,J=2.2Hz,1H),8.64–8.57(m,1H),8.03(s,1H),7.92(dt,J=8.1,2.0Hz,1H),7.26(s,1H),7.20(dd,J=8.1,4.9Hz,1H),7.14(d,J=2.0Hz,1H),7.01(d,J=2.3Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),6.30(s,1H),6.26(s,1H),4.97(dd,J=9.4,4.2Hz,1H),4.01(ddd,J=14.7,7.0,2.4Hz,1H),3.86(s,3H),3.82(q,J=7.0Hz,2H),3.74(s,3H),3.57(ddd,J=14.6,11.0,5.8Hz,1H),2.94(q,J=7.1,6.3Hz,2H),2.53–2.40(m,2H),2.25(dddd,J=14.8,13.2,9.6,5.7Hz,1H),2.15(dtd,J=14.3,7.9,4.4Hz,1H),1.36(t,J=6.9Hz,3H).
实施例(S)-C56:化合物(S)-C56的合成
用3-氟-4-溴磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C56。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.51–7.43(m,2H),7.31(dd,J=8.3,2.0Hz,1H),7.11(d,J=2.3Hz,1H),7.01(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.33(s,1H),6.29(s,1H),4.96(dd,J=9.3,4.4Hz,1H),3.93(ddd,J=14.7,6.4,2.9Hz,1H),3.86(s,3H),3.83(q,J=6.9Hz,2H),3.76(s,3H),3.55(ddd,J=14.5,10.6,6.0Hz,1H),2.92(td,J=7.9,4.7Hz,2H),2.46(dq,J=11.4,6.3,4.8Hz,2H),2.24(dtd,J=14.5,8.3,6.0Hz,1H),2.14(dtd,J=14.4,7.8,4.3Hz,1H),1.37(t,J=7.0Hz,3H).
实施例(S)-C57:化合物(S)-C57的合成
用2-氟磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C57。1H NMR(500MHz,Chloroform-d)δ7.99–7.94(m,1H),7.94–7.90(m,1H),7.45–7.39(m,1H),7.17(td,J=7.7,1.1Hz,1H),7.07(d,J=2.3Hz,1H),7.00–6.93(m,2H),6.84(dd,J=8.8,2.4Hz,1H),6.36(s,1H),6.31(s,1H),5.07(dd,J=9.4,4.3Hz,1H),4.04(ddd,J=14.5,6.2,2.7Hz,1H),3.85(s,3H),3.83(q,J=7.0Hz,2H),3.75(s,3H),3.56(ddd,J=14.3,10.9,5.6Hz,1H),2.93–2.81(m,2H),2.57–2.46(m,2H),2.24(dtd,J=14.6,9.1,5.5Hz,1H),2.12(dddd,J=13.9,8.9,7.1,4.4Hz,1H),1.36(t,J=7.0Hz,3H).
实施例(S)-C58:化合物(S)-C58的合成
用4-氟磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C58。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.73–7.67(m,2H),7.12(d,J=2.3Hz,1H),7.01(d,J=2.4Hz,1H),6.96(t,J=8.6Hz,2H),6.86(dd,J=8.7,2.4Hz,1H),6.30(s,1H),6.28(s,1H),4.98(dd,J=9.5,4.1Hz,1H),3.94(ddd,J=14.4,7.0,2.2Hz,1H),3.85(s,3H),3.83(q,J=6.9Hz,2H),3.74(s,3H),3.52(ddd,J=14.5,11.3,5.5Hz,1H),2.99–2.88(m,2H),2.46–2.32(m,2H),2.23(dtd,J=14.5,8.7,5.7Hz,1H),2.16–2.09(m,1H),1.37(t,J=7.0Hz,3H).
实施例(S)-C59:化合物(S)-C59的合成
用二氟乙酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C59。1H NMR(500MHz,Chloroform-d)δ7.61(s,1H),7.22(d,J=7.5Hz,1H),7.14(d,J=1.0Hz,1H),7.04(s,1H),6.79(d,J=1.6Hz,1H),6.70(dd,J=7.5,1.5Hz,1H),6.23–6.16(m,1H),4.95(s,1H),4.57(dq,J=12.3,7.9Hz,1H),4.40–4.26(m,1H),3.89(m,8H),3.56(dt,J=12.5,7.1Hz,1H),3.38(dtd,J=14.1,7.0,1.0Hz,1H),2.95–2.76(m,2H),2.54(ddd,J=12.5,9.9,6.5Hz,1H),2.16–2.06(m,2H),1.46(t,J=8.0Hz,3H).
实施例(S)-C60:化合物(S)-C60的合成
用4-甲氧基磺酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C60。1H NMR(500MHz,Chloroform-d)δ7.92(s,1H),7.63(d,J=8.8Hz,2H),7.12(d,J=1.8Hz,1H),7.01(d,J=2.4Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.79–6.74(m,2H),6.31(d,J=11.7Hz,2H),4.98(dd,J=9.3,4.3Hz,1H),3.94–3.88(m,1H),3.85(s,3H),3.83(q,J=7.0Hz,2H),3.77(s,3H),3.75(s,3H),3.50(dt,J=14.4,8.8Hz,1H),2.92(q,J=7.7,7.0Hz,2H),2.45–2.39(m,2H),2.21(ddd,J=14.7,10.1,5.9Hz,1H),2.16–2.08(m,1H),1.36(t,J=7.0Hz,3H).
实施例(S)-C61:化合物(S)-C61的合成
用61-1替换实施例(S)-A1中的1-2,合成方法参考化合物(S)-A1的合成,得到化合物(S)-C61。1H NMR(500MHz,Chloroform-d)δ8.28(2×s,1H),7.86–7.83(2×m,1H),7.71(2×dd,J=6.7,2.0Hz,1H),7.45–7.37(2×m,2H),7.22(2×s,1H),6.60(2×s,1H),6.47(2×s,1H),4.51(2×dd,J=9.4,4.7Hz,1H),3.84(2×s,3H),3.74(2×s,3H),3.60(2×m,1H),3.04(2×dd,J=15.4,7.9Hz,1H),2.94–2.90(2×m,3H),2.71(2×ddd,J=16.2,4.8,2.1Hz,1H),2.26(2×m,2H).
实施例(S)-C62:化合物(S)-C62的合成
用甲氧基乙酰氯替换实施例(S)-C47中的苯磺酰氯,合成方法参考化合物(S)-C47的合成,得到化合物(S)-C62。1H NMR(500MHz,Chloroform-d)δ7.82(2×s,1H),7.39(2×d,J=2.3Hz,1H),7.22(2×d,J=7.5Hz,1H),7.16(2×d,J=0.9Hz,1H),7.10(2×d,J=1.7Hz,1H),6.70(2×dd,J=7.5,1.5Hz,1H),5.02(2×dd,J=7.6,6.6Hz,1H),4.93(2×d,J=12.5Hz,1H),4.66(2×d,J=12.3Hz,1H),4.35(2×dq,J=12.3,7.9Hz,1H),4.04–3.85(2×m,8H),3.64(2×dt,J=12.5,7.1Hz,1H),3.36–3.26(2×m,1H),3.25(2×s,3H),3.01(2×dt,J=12.5,7.9Hz,1H),2.89–2.71(2×m,2H),2.15–2.07(2×m,2H),1.46(2×t,J=8.0Hz,3H).
实施例(S)-C63:化合物(S)-C63的合成
用63-1替换实施例(S)-A1中的1-1,合成方法参考化合物(S)-A1和(S)-C8的合成,得到化合物(S)-C63。ESI-MS m/z 449.2。
实施例(S)-C64:化合物(S)-C64的合成
用64-1替换实施例(S)-C63中的63-1,合成方法参考化合物(S)-C63的合成,得到化合物(S)-C64。ESI-MS m/z 431.2。
实施例(S)-C65:化合物(S)-C65的合成
用65-1替换实施例(S)-C8中的31-1,合成方法参考化合物(S)-C8的合成,得到化合物(S)-C65。ESI-MS m/z 404.2。
实施例(S)-C66:化合物(S)-C66的合成
用66-1替换实施例(S)-C63中的63-1,合成方法参考化合物(S)-C63的合成,得到化合物(S)-C66。ESI-MS m/z 423.1。
实施例(S)-C67:化合物(S)-C67的合成
用67-1替换实施例(S)-C63中的63-1,合成方法参考化合物(S)-C63的合成,得到化合物(S)-C67。ESI-MS m/z 423.1。
实施例(S)-C68:化合物(S)-C68的合成
化合物(S)-C66溶于甲醇中,加入1M NaOH室温搅拌2小时,1M盐酸溶液中和至中性,乙酸乙酯萃取,柱层析分离得到化合物(S)-C68。ESI-MS m/z 409.2。
实施例(S)-C69:化合物(S)-C69的合成
化合物(S)-C68溶于二氯甲烷中,加入2当量甲胺四氢呋喃溶液,1.5当量HATU和2当量三乙胺室温搅拌过夜,加入二氯甲烷,水洗,有机相干燥后柱层析分离得到化合物(S)-C69。ESI-MS m/z 422.2。
实施例(S)-C70:化合物(S)-C70的合成
化合物(S)-C68溶于二氧六环中,加入2当量碳酸氢铵,2当量BOC酸酐,5当量吡啶,室温搅拌过夜,加入二氯甲烷,水洗,有机相干燥后柱层析分离得到化合物(S)-C70。ESI-MSm/z 408.2。
实施例(S)-C71:化合物(S)-C71的合成
用71-1替换实施例(S)-C63中的63-1,合成方法参考化合物(S)-C63的合成,得到化合物(S)-C71。ESI-MS m/z 415.2。
实施例(S)-C72:化合物(S)-C72的合成
用二氟碘甲烷替换实施例(S)-B2中的12-1,合成方法参考化合物(S)-B2的合成,得到化合物(S)-C72。ESI-MS m/z 431.2。
实施例(S)-C73:化合物(S)-C73的合成
用73-1替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C73。ESI-MS m/z 447.2。
实施例(S)-C74:化合物(S)-C74的合成
用5-二氟甲基吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C74。ESI-MS m/z 429.2。
实施例(S)-C75:化合物(S)-C75的合成
用吲哚-5-甲酸甲酯替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C75。ESI-MS m/z 437.2。
实施例(S)-C76:化合物(S)-C76的合成
用5-三氟甲氧基吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C76。ESI-MS m/z 463.2。
实施例(S)-C77:化合物(S)-C77的合成
用5-二氟甲氧基吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C77。ESI-MS m/z 445.2。
实施例(S)-C78:化合物(S)-C78的合成
用5-氟吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C78。ESI-MS m/z 397.2。
实施例(S)-C79:化合物(S)-C79的合成
用79-1替换实施例(S)-C63中的63-1,合成方法参考化合物(S)-C63的合成,得到化合物(S)-C79。ESI-MS m/z 409.20。
实施例(S)-C80:化合物(S)-C80的合成
用6-氯-5-甲氧基吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C80。ESI-MS m/z 443.2。
实施例(S)-C81:化合物(S)-C81的合成
用5-氟-6-氯吲哚替换实施例(S)-C65中的65-1,合成方法参考化合物(S)-C65的合成,得到化合物(S)-C81。ESI-MS m/z 431.1。
实施例(S)-C82:化合物(S)-C82的合成
用5-氟吲哚替换实施例(S)-C62中的5-甲氧基吲哚,合成方法参考化合物(S)-C62的合成,得到化合物(S)-C82。ESI-MS m/z 441.2。
实施例(S)-C83:化合物(S)-C83的合成
用1-氯-2-(甲基磺酰基)乙烷替换实施例(S)-C72中的二氟碘甲烷,合成方法参考化合物(S)-C72的合成,得到化合物(S)-C83。ESI-MS m/z 487.2。
生物学活性实验例部分
实验例B1.化合物对PDE4的分子酶活抑制测定
采用临近闪烁实验(Scintillation Proximity Assay,SPA)方法测定化合物对PDE4D催化结构域的酶活抑制效果。人源PDE4D催化结构域蛋白质通过在大肠杆菌中表达和纯化获得,阳性化合物Apremilast购于陶素生化,微孔板闪烁计数仪(MicroBeta2,PerkinElmer),恒温水浴锅(DK420,上海医疗器械厂),微样震荡仪(XW-80A,上海精科实业有限公司)为放射性实验室公用仪器,分步移液器(Multipette Plus,Eppendorf)及配套枪头购于艾本德生物技术公司,3.5.[3H]-cAMP,闪烁微珠(RPNQ0150,Perkin Elmer),96孔闪烁微孔板(Isoplate-96,Perkin Elmer)购于Perkin Elmer公司。10x SPA buffer于实验室配制(500mM Tris pH7.5,83mM MgCl2,17mM EGTA)。
在实验中,在总体积为100μl的反应体积中,加入60μl水,10μl反应液并使各组分终浓度分别为50mM Tris-HCl、pH7.5、8.3mM MgCl2、1.7mM EGTA,10μl化合物和10μl酶(0.1ng/ul),最后统一加入10μl[3H]-cAMP(0.005μCi/μl),30℃水浴锅孵育30min,加入50μl SPA beads终止反应,适当振摇,静置20min,微孔板闪烁计数器读数。
表B1为化合物对PDE4D酶活抑制率及IC50值
表B1
/>
aMan HW,et al.J.Med.Chem.2009,52:1522-1524b拆分得到
结论:通过对化合物在1μM浓度时对PDE4的抑制率测定后,进而对抑制效率高的化合物测定测定其对PDE4抑制活性的IC50值。其中14个化合物的IC50值达百纳摩尔,3个化合物(C10、(S)-C10和(S)-C8)IC50值低于百纳摩尔,与阳性对照化合物Apremilast的IC50值相当。
实验例2.化合物对PBMC中TNF-α分泌的抑制活性测定
PDE4诸多功能中被研究的最多的是抗炎症效应。免疫***中单核细胞和巨噬细胞是TNF-α的重要生产者,PDE4在这些细胞中是主要酶,现有靶向PDE4抑制剂的抗炎症效应密切关联着免疫***中TNF-α表达量。我们根据人体血液中细胞密度的差异,通过淋巴细胞分离液梯度离心法直接分离纯化得到PBMC(peripheral blood mononuclear cell,PBMC),其细胞类型为血液里单个核的细胞,主要包括淋巴细胞(T/B)、单核细胞、巨噬细胞、树突状细胞和其他少量细胞类型,其中淋巴细胞占很大一部分,从而能够很直接地模拟体外的血液免疫环境。脂多糖(Lipopolysaccharide,LPS)是革兰氏阴性菌胞壁的成份,可通过MAPK等多种信号通路显著激发致炎因子TNF-α的表达,从而评价PDE4部分抑制剂的细胞活性,模拟体外炎症效应。PDE4部分抑制剂对人PBMC细胞TNF-α表达的抑制效应主要参照GeorgeW.Muller等人的工作。
实验过程中,阳性化合物Apremilast购自陶素生化科技有限公司。健康人的全血由上海市血液中心提供;胎牛血清(Fetal Bovine Serum,FBS)购自Hyclone(South Logan,UT,USA);RPMI-1640培养基及人源TNF-αELISA检测试剂盒购自Invitrogen(San Diego,CA,USA);细菌脂多糖LPS购自Sigma(L9764,St.Louis,MO,USA)。
将从人血中分离获得的PBMC细胞以2*105/ml植入96孔板内;加入梯度化合物,每个梯度至少设三个重复;于37℃,5% CO2孵育1个小时后加LPS(终浓度为10ug/ml)刺激PBMC表达TNF-α;37℃,5%CO2孵育18-20h收集96孔板。另设无刺激剂本底对照及刺激对照孔,总体积为200μl。离心收取培养上清,ELISA法检测培养上清中TNF-α的表达水平。
表2为化合物对PBMC中炎症因子TNF-α分泌的抑制实验结果
表2
/>
a Man HW,et al.J.Med.Chem.2009,52:1522-1524b拆分得到
结论:分子水平抑制酶活效率较优的化合物对PBMC中TNF-α分泌抑制的效果也较好,其IC50值在个位数微摩尔左右,而活性最优的化合物(S)-C8的IC50值达26纳摩尔,优于阳性对照化合物Apremilast。
实验例B3.化合物对RAW 264.7细胞分泌肿瘤坏死因子-α的抑制活性测定
肿瘤坏死因子-α作为炎症、自身免疫病等疾病发展过程中重要的炎症介质,主要由活化的单核/巨噬细胞产生,可介导多种炎症反应的发生,加速恶化疾病进程。小鼠单核/巨噬细胞白血病细胞株RAW 264.7细胞是常用的炎症细胞模型之一,在细菌脂多糖(LPS)诱导激活后,可释放肿瘤坏死因子-α等多种炎症介质的释放;同时磷酸二酯酶PDE4在巨噬细胞中有表达,通过检测肿瘤坏死因子-α的分泌可反映化合物对磷酸二酯酶PDE4的抑制活性。
(1)化合物对RAW 264.7细胞毒性检测:受试化合物对RAW 264.7细胞的细胞毒性通过CCK-8法检测,小鼠RAW 264.7细胞购自American Type Culture Collection(Manassas,VA,USA)培养于含10%胎牛血清(Hyclone,South Logan,UT,USA)的DMEM培养液(Hyclone,South Logan,UT,USA)中,临用前收集细胞并计数,(1×105/孔)接种于96孔板(Corning,NY,USA)中,细胞孵育24h后,加入不同浓度的化合物,另设相应的溶媒对照及培养液本底对照,总体积为200μl。于37℃,5% CO2培养箱中培养4h。培养结束前30min加入20μl CCK-8溶液(Dojindo,Kumamoto,Japan),至培养结束,于酶标仪(Molecular Devices,Sunnyvale,CA,USA)450nm(参比650nm)处测定吸光度OD值。化合物对RAW 264.7细胞的毒性作用以待测样品OD值除以细胞对照孔OD值计算,标记为细胞存活率(%)。
(2)化合物对RAW 264.7细胞肿瘤坏死因子-α分泌的抑制活性:RAW 264.7细胞(1×105/孔)接种于96孔板,孵育24h后,加入不同浓度的化合物孵育30min,在1μg/ml LPS(L5886,Sigma,St.Louis,MO,USA)刺激作用下,于37℃,5% CO2培养箱中培养4h。另设无刺激剂本底对照及刺激对照孔,总体积为200μl。离心收取培养上清,采用酶联免疫吸附法检测培养上清中肿瘤坏死因子-α的分泌水平,肿瘤坏死因子-α检测试剂盒购自BDPharmingen(San Diego,CA,USA)。
表B3为化合物对RAW 264.7细胞炎症因子肿瘤坏死因子-α分泌的抑制实验结果表B3
/>
表B4为部分化合物对RAW 264.7细胞毒性(CC50)及分泌肿瘤坏死因子-α的抑制(IC50)实验结果
表B4
a CC50为致半数细胞毒性所需药物浓度;b IC50为有效抑制50%肿瘤坏
死因子-α时药物浓度;c SI为CC50/IC50。
结论:通过检测受试化合物对RAW 264.7细胞肿瘤坏死因子-α分泌的抑制活性,发现了部分抑制活性较好的化合物,结合化合物对PDE4D催化结构域的抑制活性以及PBMCs生物活性结果,选取了化合物(S)-A1、(S)-C5、(S)-C6、(S)-C8、(S)-C7检测了化合物RAW264.7细胞细胞毒性及肿瘤坏死因子-α抑制活性,实验结果见表B3和表B4。与阳性化合物Apremilast相比,化合物(S)-C5、(S)-C8具有相当或更强的肿瘤坏死因子-α抑制活性。
实验例B4.化合物(S)-C5、(S)-C8对小鼠背部气囊急性炎症模型的治疗效果
小鼠背部气囊急性炎症模型作为候选化合物体内抗炎活性评价的经典模型,可行性高,且重复性好。实验第1天,小鼠背部皮下注射3ml空气,第3天背部皮下注射1.5ml空气,第6天背部皮下注射1ml 2%角叉菜胶(Sigma-Aldrich,St.Louis,MO,USA)溶液致敏,致敏后4h使用磷酸盐缓冲液灌洗空气囊中分泌物,灌洗液用于白细胞计数以及炎症因子检测。其中阳性药物Apremilast、受试药物(S)-C5、(S)-C8以0.5%羧甲基纤维素钠(Sigma-Aldrich,St.Louis,MO,USA)+0.25%吐温-80(购自国药集团)进行分散,药物分别在致敏前24h、1h灌胃口服给药(5mg/kg),肿瘤坏死因子-α、白介素-6检测试剂盒购自BD Pharmingen(San Diego,CA,USA)。
结论:如图1所示,受试化合物(S)-C5、(S)-C8灌胃口服给药可明显降低小鼠背部气囊急性炎症模型的炎症反应,降低灌洗液中白细胞浸润数目、肿瘤坏死因子-α以及白介素-6分泌水平。
实验例5:大鼠药代动力学试验
1.实验步骤:
健康大鼠6只,雄性,体重150-200g,随机分成2组,每组3只。分别灌胃和静脉注射给予本发明的化合物14、16、17、18、22和29,给药体积为10mL/kg,药物以DMSO/吐温80/生理盐水(5:5:90,v/v/v)配制。试验前禁食12h,自由饮水。给药后2h统一进食。
2.采血时间点及样品处理:
灌胃给药:给药后0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h;
静脉给药:给药后5min,0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h;
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml,置肝素化试管中,11000rpm离心5min,分离血浆,于–20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。采用DAS 3.0软件的非房室模型计算给药后的药代动力学参数。
4.实验结果:
表B5为化合物(S)-C7和(S)-C8在大鼠体内药代动力学实验结果
表B5
化合物(S)-C7:大鼠灌胃给予20mg/kg化合物(S)-C7后,血浆浓度达峰时间Tmax为1h,达峰浓度Cmax为2383.6ng/ml;药时曲线下面积AUC0-t为9232.3ng·h/ml;末端消除半衰期t1/2为1h。静脉注射给予10mg/kg化合物(S)-C7后,AUC0-t为6761.8ng·h/ml;经剂量标准化后,大鼠灌胃给予20mg/kg化合物(S)-C7后的绝对生物利用度为68.3%。
化合物(S)-C8:大鼠灌胃给予20mg/kg化合物(S)-C8后,血浆浓度达峰时间Tmax为1.33h,达峰浓度Cmax为491ng/ml;药时曲线下面积AUC0-t为508ng·h/ml;末端消除半衰期t1/2为1.03h。静脉注射给予10mg/kg化合物(S)-C7后,AUC0-t为2640ng·h/ml;经剂量标准化后,大鼠灌胃给予20mg/kg化合物(S)-C8后的绝对生物利用度为9.30%。
实验结论:从以上实验结果可以看出,在大鼠药代动力学实验中,化合物(S)-C7表现出较好的生物利用度,达到68.3%。
实验例6:比格犬药代动力学试验
1.实验步骤:
健康比格犬6只,雄性,体重9-11kg,随机分成2组,每组3只。分别灌胃和静脉注射给予本发明的化合物(S)-C8,给药体积分别为5mL/kg和1mL/kg,灌胃给药以0.5%CMC-Na+0.25% Tween 80配制,静脉给药以5% DMSO/40% PEG400/55%生理盐水配制。
2.采血时间点及样品处理:
灌胃给药:给药后0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h;
静脉给药:给药后5min,0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h;
在以上设定时间点经四肢静脉取静脉血1ml,置EDTA-2K抗凝管中,3500rpm离心10min,分离血浆,于–20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定比格犬血浆中化合物(S)-C8的浓度。
采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
4.实验结果:
表B6为化合物(S)-C8在比格犬体内的药物动力学实验结果
表B6
比格犬灌胃给予10mg/kg化合物(S)-C8后,血浆浓度达峰时间Tmax为0.5h,达峰浓度Cmax为4685ng/ml;药时曲线下面积AUC0-t为16601ng·h/ml;末端消除半衰期t1/2为2.92h。静脉注射给予3mg/kg化合物(S)-C8后,AUC0-t为9610ng·h/ml;经剂量标准化后,比格犬灌胃给予10mg/kg化合物(S)-C8后的绝对生物利用度为52.3%。
实验结论:从以上实验结果可以看出,在比格犬药代动力学实验中,化合物(S)-C8表现出良好的绝对生物利用度.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (14)
1.一种通式(I)所示的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
手性碳原子C*独立地为S型、R型,或其组合;
n=1;
X为-CH2-;
Y选自连接基团:C1~C6直链或支链亚烷基、-CH2O-、-CH2NH-、
R1、R2各自独立地选自下组:羟基、取代或未取代的C1~C6直链或支链烷氧基、取代或未取代的C3~C7环烷氧基、取代或未取代的C3~C7环烷基甲氧基、苄氧基、羧基取代的C2~C8直链烷氧基、N,N-二甲基氨基取代的C2~C8直链烷氧基,-COOR5或-CONR5R6;所述取代基选自氘或者卤素;
R3选自未被取代或者被1-3个取代基取代的以下基团:-C(O)-5~7元杂芳基、-C(O)-4~7元杂环基、-C1~C4酰基、-CHO、R7SO2-、NH2(CH2)m SO2-、R7SO2(CH2)m-、R7O(CH2)mCO-、R7OCO(CH2)m-、二氟甲基、三氟甲基、C1~C4亚磺酰基、苯磺酰基、5-7元杂芳基磺酰基;其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、C1~C6直链或支链烷氧羰基、羟基、氨基、羟甲基、三氟甲基、C1~C4酰胺基、C0~C4磺酰基;
R5、R6、R7各自独立地选自氢、取代或未取代的C1~C4直链或支链烷基、取代或未取代的C3~C8环烷基、取代或未取代的C6-C10芳基;所述取代基选自氘或者卤素;
m选自0、1、2、3或者4;
R4选自未被取代或者被1-3个取代基取代的以下基团:5~12元杂芳基;其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷基、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR5。
2.如权利要求1所述的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,通式(I)中:
R1、R2各自独立地选自下组:取代或未取代的C1~C6直链或支链烷氧基、取代或未取代的C3~C7环烷氧基、取代或未取代的C3~C7环烷基甲氧基、羧基取代的C2~C8直链烷氧基、N,N-二甲基氨基取代的C2~C8直链烷氧基,COOR5或CONR5R6;所述取代基选自氘或者卤素。
3.如权利要求2所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,通式(I)中:
Y选自下组:-CH2-、-CH2-CH2-、
R4选自未被取代或者被1-3个取代基取代的以下基团:苯并5~7元杂芳基。
4.如权利要求2所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,所述基团中的杂环和杂芳环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
5.根据权利要求3所述的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,通式(I)中:
R3选自未被取代或者被1-3个取代基取代的以下基团:C1~C4酰基,R7SO2-、NH2(CH2)mSO2-、R7O(CH2)mCO-、C1~C3亚磺酰基、苯磺酰基;其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自氘、卤素、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、C1~C6直链或支链烷氧羰基、羟基、氨基、羟甲基、三氟甲基、C1~C4酰胺基、C1~C4磺酰基;
R7选自氢、C1~C4直链或支链烷基;
m选自0、1或者2。
6.如权利要求1所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,通式(I)中:
手性碳原子C*为S型。
7.如权利要求1所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其中,所述四氢异喹啉类化合物选自以下化合物:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
8.一种选自下组的四氢异喹啉类化合物,其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
/>
9.一种如权利要求1所述通式(I)所示的化合物的制备方法,包括步骤:
(1)在惰性溶剂中,在缩合剂存在下,用式II化合物和式Ic化合物反应,得到式Id化合物;
(2)在惰性溶剂中,用式Id化合物进行Bischler–Napieralski关环反应,得到式Ie化合物;
(3)在惰性溶剂中,用式Ie化合物进行还原反应,得到式If化合物;
(4)在惰性溶剂中,用式If化合物进行成缩合反应或N-烷基化反应或Buchwald–Hartwig反应,得到式(I)化合物;
上述各式中,各基团的定义如权利要求1-7任一所述。
10.如权利要求9所述的方法,其特征在于,所述的方法还包括选自下组的一个或多个特征:
所述的步骤(1)中,缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐);
所述的步骤(2)中,所述的关环反应在三氯氧磷存在下进行;
所述的步骤(3)中,所述的还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂。
11.一种药物组合物,其特征在于,所述的药物组合物包括:治疗有效量的一种或多种权利要求1所述通式(I)所示化合物,或其药学上可接受的盐。
12.如权利要求1所述的通式(I)的用途,其特征在于,用于制备预防、治疗或辅助治疗与PDE4活性或表达量相关的疾病的药物组合物。
13.如权利要求12所述的用途,其特征在于,所述的疾病为与PDE4活性或表达量相关的免疫和炎症性疾病。
14.如权利要求12所述的用途,其特征在于,所述的与PDE4活性或表达量相关的疾病选自下组:银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、***性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症、和精神***症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018101180387 | 2018-02-06 | ||
CN201810118038.7A CN110117271A (zh) | 2018-02-06 | 2018-02-06 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
PCT/CN2019/074704 WO2019154395A1 (zh) | 2018-02-06 | 2019-02-03 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111712491A CN111712491A (zh) | 2020-09-25 |
CN111712491B true CN111712491B (zh) | 2023-11-17 |
Family
ID=67519958
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810118038.7A Pending CN110117271A (zh) | 2018-02-06 | 2018-02-06 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
CN201980012210.3A Active CN111712491B (zh) | 2018-02-06 | 2019-02-03 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810118038.7A Pending CN110117271A (zh) | 2018-02-06 | 2018-02-06 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20210040066A1 (zh) |
EP (1) | EP3750886A4 (zh) |
JP (1) | JP7125495B2 (zh) |
KR (1) | KR102556482B1 (zh) |
CN (2) | CN110117271A (zh) |
AU (2) | AU2019217408B2 (zh) |
CA (1) | CA3090598C (zh) |
WO (1) | WO2019154395A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117126134A (zh) * | 2022-05-20 | 2023-11-28 | 中国科学院上海药物研究所 | 新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
CN114957221B (zh) * | 2022-05-30 | 2023-05-12 | 广西师范大学 | 一种喹喔啉衍生物及其制备方法和应用 |
CN115260094B (zh) * | 2022-06-16 | 2024-04-05 | 珠海润都制药股份有限公司 | 一种新的盐酸去甲乌药碱的合成方法 |
CN117510512A (zh) * | 2022-07-29 | 2024-02-06 | 中国科学院上海药物研究所 | 一类多取代的四氢异喹啉化合物及制备方法、药物组合物和用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4292320A (en) * | 1973-07-30 | 1981-09-29 | Fujisawa Pharmaceutical Company, Limited | 1,2,3,4-Tetrahydroisoquinoline derivatives and the preparation thereof |
WO2001064647A1 (en) * | 2000-02-28 | 2001-09-07 | Sanofi-Synthelabo | Isoquinoline derivatives as pde4 inhibitors |
CN1764647A (zh) * | 2003-03-26 | 2006-04-26 | 埃科特莱茵药品有限公司 | 四氢异喹啉基乙酰胺衍生物作为阿立新受体拮抗剂的应用 |
CN105793250A (zh) * | 2013-12-05 | 2016-07-20 | 奇斯药制品公司 | 用于治疗呼吸病的杂芳基衍生物 |
CN106831577A (zh) * | 2016-12-05 | 2017-06-13 | 华南农业大学 | 一种c3取代的四氢异喹啉衍生物及其制备方法和应用 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3326923A (en) * | 1964-09-14 | 1967-06-20 | Warner Lambert Pharmaceutical | Cis-indolomorphinanones and process for their production |
ES2252230T3 (es) * | 2000-05-11 | 2006-05-16 | Bristol-Myers Squibb Company | Analogos de tetrahidroisoquinolina utiles como secretores de la hormona del crecimiento. |
AU2002357692A1 (en) * | 2001-11-09 | 2003-05-26 | Bristol-Myers Squibb Company | Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity |
AU2005250077B2 (en) | 2004-03-01 | 2011-06-09 | Idorsia Pharmaceuticals Ltd | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
EP1998775B1 (en) | 2006-03-17 | 2010-05-19 | Université de Liège | Bis1,2,3,4-tetrahydroisoquinoline derivatives and their uses as pharmaceuticals |
AU2009306026A1 (en) | 2008-09-19 | 2010-04-29 | Ranbaxy Laboratories Limited | Phosphodiestarase inhibitors |
MX2012003693A (es) | 2009-10-01 | 2012-04-19 | Alcon Res Ltd | Composiciones de olopatadine y usos de las mismas. |
WO2016036873A1 (en) | 2014-09-05 | 2016-03-10 | Genentech, Inc. | Therapeutic compounds and uses thereof |
US10195189B2 (en) * | 2014-12-15 | 2019-02-05 | Prosetta Antiviral, Inc. | 2-phenethenyltetrahydro isoquinolines useful as anti-HIV compounds |
-
2018
- 2018-02-06 CN CN201810118038.7A patent/CN110117271A/zh active Pending
-
2019
- 2019-02-03 AU AU2019217408A patent/AU2019217408B2/en active Active
- 2019-02-03 KR KR1020207025606A patent/KR102556482B1/ko active IP Right Grant
- 2019-02-03 EP EP19750381.6A patent/EP3750886A4/en active Pending
- 2019-02-03 CN CN201980012210.3A patent/CN111712491B/zh active Active
- 2019-02-03 JP JP2020542635A patent/JP7125495B2/ja active Active
- 2019-02-03 CA CA3090598A patent/CA3090598C/en active Active
- 2019-02-03 WO PCT/CN2019/074704 patent/WO2019154395A1/zh unknown
- 2019-02-03 US US16/967,721 patent/US20210040066A1/en active Pending
-
2022
- 2022-04-13 AU AU2022202463A patent/AU2022202463A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4292320A (en) * | 1973-07-30 | 1981-09-29 | Fujisawa Pharmaceutical Company, Limited | 1,2,3,4-Tetrahydroisoquinoline derivatives and the preparation thereof |
WO2001064647A1 (en) * | 2000-02-28 | 2001-09-07 | Sanofi-Synthelabo | Isoquinoline derivatives as pde4 inhibitors |
CN1764647A (zh) * | 2003-03-26 | 2006-04-26 | 埃科特莱茵药品有限公司 | 四氢异喹啉基乙酰胺衍生物作为阿立新受体拮抗剂的应用 |
CN105793250A (zh) * | 2013-12-05 | 2016-07-20 | 奇斯药制品公司 | 用于治疗呼吸病的杂芳基衍生物 |
CN106831577A (zh) * | 2016-12-05 | 2017-06-13 | 华南农业大学 | 一种c3取代的四氢异喹啉衍生物及其制备方法和应用 |
Non-Patent Citations (8)
Title |
---|
Aporphine alkaloid synthesis and diversification via direct arylation,Marc Lafrance 等,European Journal of Organic Chemistry;Marc Lafrance 等;《European Journal of Organic Chemistry》;第5卷;第811-825页,尤其是第813页表2 * |
Chemical and Pharmacological Studies on Derivatives of Benzo[de]quinoline. II;BORGULYA Janos 等;《Helvetica Chimica Acta》;19771231;第60卷(第2期);第600页化合物11,第603页化合物31 * |
egioselectivity of Pictet-Spengler Cyclization: Synthesis of Halotetrahydroisoquinolines;CHO Sudong 等;《Tetrahedron Letters》;20010903;第42卷(第36期);第6251-6252页化合物4i * |
Piperazine-substituted Isoquinoline Derivatives;HROMATKA,O. 等;《Monatshefte fuer Chemie》;19661231;第97卷(第1期);第21页化合物IXa~c * |
Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability;David A. Perrey 等;《ACS Chemical Neuroscience》;第9卷(第3期);第587-602页,化合物13a-b,CAS登记号2243744-83-2的化合物 * |
Synthesis of 5,6,6a,7,7a,12a-hexahydro-4H-benzo[d,e]benzothieno[2,3-g]quinolines and of 8-phenyl-2,3,7,8,9,9a-hexahydro-1H-benzo[d,e]quinolines;COPP,F.C. 等;《J. Chem. Soc. Perkin Trans. 1》;19831231;第5卷;第911页左栏第6段化合物1 * |
Zum Mechanismus der 1,2-Dihydroisochinolinumlagerung Dihydroisochinolinumlagerung, 21. Mitt;KNABE,J. 等;《Archiv der Pharmazie》;19741231;第307卷(第9期);第728页化合物2 * |
取代四氢异喳琳衍生物的合成及其生物活性;黄文龙 等;《药学学报》;第25卷(第11期);第815-823页,尤其是第816页化合物8 * |
Also Published As
Publication number | Publication date |
---|---|
EP3750886A1 (en) | 2020-12-16 |
US20210040066A1 (en) | 2021-02-11 |
AU2019217408A1 (en) | 2020-09-24 |
EP3750886A4 (en) | 2021-11-24 |
CA3090598A1 (en) | 2019-08-15 |
CN111712491A (zh) | 2020-09-25 |
RU2020129199A (ru) | 2022-03-09 |
AU2022202463A1 (en) | 2022-05-05 |
WO2019154395A1 (zh) | 2019-08-15 |
AU2019217408B2 (en) | 2022-04-28 |
RU2020129199A3 (zh) | 2022-03-09 |
CA3090598C (en) | 2024-01-09 |
JP2021513530A (ja) | 2021-05-27 |
JP7125495B2 (ja) | 2022-08-24 |
KR102556482B1 (ko) | 2023-07-18 |
KR20200118145A (ko) | 2020-10-14 |
CN110117271A (zh) | 2019-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111712491B (zh) | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 | |
CN113651814B (zh) | Kras突变蛋白抑制剂 | |
JP5926727B2 (ja) | 置換イミダゾ[1,2−b]ピリダジン | |
Cao et al. | Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives | |
Cao et al. | Design, synthesis and in vitro and in vivo antitumor activities of novel β-carboline derivatives | |
Shi et al. | Design, synthesis and in vitro and in vivo antitumor activities of novel bivalent β-carbolines | |
CN109310675A (zh) | 治疗性抑制化合物 | |
CN107759587A (zh) | [1,2,4]***并[1,5‑a]吡啶类化合物及其制备方法和医药用途 | |
CN104902959A (zh) | Irak抑制剂和其用途 | |
WO2020035020A1 (zh) | 咪唑并吡啶类衍生物及其制备方法和其在医药上的用途 | |
CN108721298A (zh) | 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用 | |
WO2005035537A2 (en) | Substituted tricyclic heterocycles and their uses | |
ES2850023T3 (es) | Compuesto de anillo heterocíclico nítrico de seis miembros sustituido con amino y preparación y uso del mismo | |
NO971687L (no) | Diazepinoindoler som forsfodiesterase IV-inhibitorer | |
WO2004103974A1 (ja) | 置換2-オキソキノリン化合物およびその医薬用途 | |
BR112017016278B1 (pt) | Uso de um composto com atividade inibitória de btk ou um sal deste para produzir um agente preventivo e/ou terapêutico para a prevenção ou tratamento de uma doença imune | |
CN106588913A (zh) | 具有咪唑并吡啶类衍生物,其制备及其在医药上的应用 | |
RU2792034C2 (ru) | Тетрагидроизохинолиновое соединение, способ его получения, фармацевтическая композиция, содержащая такое соединение, и его применение | |
CN116239594B (zh) | 6-(咪唑并[1,2-a]吡啶-6-基)喹唑啉衍生物及用途 | |
CN114671861B (zh) | 一种汉黄芩素衍生物及其制备方法与应用 | |
EP4279485A1 (en) | Bridged heterocyclyl-substituted pyrimidine compounds, preparation method and medical use thereof | |
CN115197206B (zh) | 吲哚3-位取代的四氢-γ-咔啉化合物、其药物组合物及用途 | |
KR100888468B1 (ko) | 항암활성을 갖는1'-알킬피페리딘-4'-스피로-2-6-(아미도)-2h-벤조피란유도체 | |
CN105461733B (zh) | (2,4-二羟基-5-异丙基苯基)(4,6-二氢-5H-噻吩并[2,3-c]吡咯-5-基)甲酮类衍生物及其制备和应用 | |
CN116462688A (zh) | 芳香稠合环类衍生物及其制备方法和用途 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |