CN109867627B - 一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 - Google Patents
一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN109867627B CN109867627B CN201810122219.7A CN201810122219A CN109867627B CN 109867627 B CN109867627 B CN 109867627B CN 201810122219 A CN201810122219 A CN 201810122219A CN 109867627 B CN109867627 B CN 109867627B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- substituted
- smu
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims description 14
- 150000002989 phenols Chemical class 0.000 title abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- -1 R3Is substituted H Chemical group 0.000 claims abstract description 6
- 229940125400 channel inhibitor Drugs 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000004344 phenylpropyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 claims description 5
- 239000004593 Epoxy Substances 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 4
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 4
- 229920002866 paraformaldehyde Polymers 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 229940126214 compound 3 Drugs 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 abstract description 14
- 102100039360 Toll-like receptor 4 Human genes 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 206010019280 Heart failures Diseases 0.000 abstract description 3
- 239000002671 adjuvant Substances 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 2
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 108091006146 Channels Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 102000002689 Toll-like receptor Human genes 0.000 description 8
- 108020000411 Toll-like receptor Proteins 0.000 description 8
- 101001009079 Homo sapiens Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 Proteins 0.000 description 7
- 102100027391 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 Human genes 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 5
- 108010048829 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Proteins 0.000 description 5
- 102000009453 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 208000004296 neuralgia Diseases 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 208000021722 neuropathic pain Diseases 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- PXPUTDXELSBHAY-UHFFFAOYSA-N 1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazole Chemical compound N1=C(C)C=C(C)N1CC1=CC=CC=C1Cl PXPUTDXELSBHAY-UHFFFAOYSA-N 0.000 description 2
- UHZNZGTWJIZDBS-UHFFFAOYSA-N 1-[[1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]-4-(4-methylphenoxy)butan-2-ol Chemical compound ClC1=C(CN2N=C(C(=C2C)CN(CC(CCOC2=CC=C(C=C2)C)O)C)C)C=CC=C1 UHZNZGTWJIZDBS-UHFFFAOYSA-N 0.000 description 2
- GTBWKPOQACBRJC-UHFFFAOYSA-N 1-[[3,5-dimethyl-1-[(2-methylphenyl)methyl]pyrazol-4-yl]methyl-methylamino]-4-(4-ethoxyphenoxy)butan-2-ol Chemical compound CC1=NN(C(=C1CN(CC(CCOC1=CC=C(C=C1)OCC)O)C)C)CC1=C(C=CC=C1)C GTBWKPOQACBRJC-UHFFFAOYSA-N 0.000 description 2
- RDSYUTANYRPEEV-UHFFFAOYSA-N 2-(4-ethoxyphenyl)oxirane Chemical compound C1=CC(OCC)=CC=C1C1OC1 RDSYUTANYRPEEV-UHFFFAOYSA-N 0.000 description 2
- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 2
- HXDOZKJGKXYMEW-UHFFFAOYSA-N 4-ethylphenol Chemical compound CCC1=CC=C(O)C=C1 HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 101001032038 Homo sapiens Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 Proteins 0.000 description 2
- 102100038718 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 Human genes 0.000 description 2
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 description 2
- 102000008233 Toll-Like Receptor 4 Human genes 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 230000002102 hyperpolarization Effects 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 244000000010 microbial pathogen Species 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- 102000007863 pattern recognition receptors Human genes 0.000 description 2
- 108010089193 pattern recognition receptors Proteins 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 210000001013 sinoatrial node Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 description 1
- MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 description 1
- JTMAFGVUZGHBEG-UHFFFAOYSA-N 1-[[1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]-4-(4-ethoxyphenoxy)butan-2-ol Chemical compound ClC1=C(CN2N=C(C(=C2C)CN(CC(CCOC2=CC=C(C=C2)OCC)O)C)C)C=CC=C1 JTMAFGVUZGHBEG-UHFFFAOYSA-N 0.000 description 1
- JZOBOJVGFIIVSE-UHFFFAOYSA-N 1-[[1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]-4-(4-fluorophenoxy)butan-2-ol Chemical compound ClC1=C(CN2N=C(C(=C2C)CN(CC(CCOC2=CC=C(C=C2)F)O)C)C)C=CC=C1 JZOBOJVGFIIVSE-UHFFFAOYSA-N 0.000 description 1
- IAVLXWDMCZAZMR-UHFFFAOYSA-N 1-[[1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]-4-(4-propylphenoxy)butan-2-ol Chemical compound ClC1=C(CN2N=C(C(=C2C)CN(CC(CCOC2=CC=C(C=C2)CCC)O)C)C)C=CC=C1 IAVLXWDMCZAZMR-UHFFFAOYSA-N 0.000 description 1
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DAPOWOXIWLWSRD-UHFFFAOYSA-N 4-(4-ethoxyphenoxy)-1-[[1-[(2-fluorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]butan-2-ol Chemical compound C(C)OC1=CC=C(OCCC(CN(C)CC=2C(=NN(C=2C)CC2=C(C=CC=C2)F)C)O)C=C1 DAPOWOXIWLWSRD-UHFFFAOYSA-N 0.000 description 1
- JSQLJURQKGBHPZ-UHFFFAOYSA-N 4-(4-tert-butylphenoxy)-1-[[1-[(2-chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]butan-2-ol Chemical compound C(C)(C)(C)C1=CC=C(OCCC(CN(C)CC=2C(=NN(C=2C)CC2=C(C=CC=C2)Cl)C)O)C=C1 JSQLJURQKGBHPZ-UHFFFAOYSA-N 0.000 description 1
- KLSLBUSXWBJMEC-UHFFFAOYSA-N 4-Propylphenol Chemical compound CCCC1=CC=C(O)C=C1 KLSLBUSXWBJMEC-UHFFFAOYSA-N 0.000 description 1
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 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
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000010429 evolutionary process Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 108091005434 innate immune receptors Proteins 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000012241 membrane hyperpolarization Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种取代苯酚β‑氨基醇类衍生物，其结构如下式所示：
其中R1为取代的卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代，R2分别独立的选自苯基、苄基、取代的苄基、苯乙基、取代的苯乙基、苯丙基、以及取代的苯丙基，R3为取代的H，卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代。本发明还公开了其作为HCN通道抑制剂或TLR4抑制剂的用途，以及制备佐剂、抗炎、镇痛、心力衰竭的药物中的应用。
Description
技术领域
本发明涉及医药领域，具体涉及TLR4，HCN抑制活性的一系列化合物，可用于科研，医疗等领域。
背景技术
天然免疫系统通过机体自身的模式识别受体识别潜在的微生物和非致病性共生菌群。其中Toll样受体实验就比较清楚的模式识别受体，同时也是识别病原微生物中最具代表性的一类。Toll样受体(以下简称TLR)是一类进化上高度保守且古老的天然免疫受体家族，它识别病原微生物在漫长的进化过程中保留下来的、对生存必不可少的特异性保守成分和机体在应激和损伤时放出的结构成分之后，TLRs构象发生改变，从而招募细胞质中特异的接头蛋白分子以激活信号级联反应。另外，TLRs信号过度活化或活化不足也会导致机体功能的异常和疾病的发生，因此机体采取了一系列正向或负向调控策略来调节TLRs介导的信号转导通路，使之维持适度的活化水平。
超极化激活的环核苷酸门控(HCN)通道被膜超极化激活，并进行混合的Na+/K+电流，从而促进起搏器去极化，从而在窦房结细胞和自发活动的神经元中产生节律活性。HCN通道的一个显着特征是它们被电压超极化和细胞内cAMP双重激活。迄今为止，已经鉴定了四种哺乳动物HCN通道异构体(HCN1-4)，每种具有不同的生物物理和调节性质以及不同的组织分布。HCN2在中枢及神经胶质细胞中表达较高。HCN2通道被抑制能明显缓解炎性痛和神经病理性痛的不良反应,成为可以缓解疼痛发生的新靶点。
发明内容
本发明的目的在于提供取代苯酚β-氨基醇类衍生物，如式I所示，所述多种化合物能抑制TLR4受体活性，有HCN通道抑制作用，降低一系列疾病的发生与发展，如感染性疾病、AS、哮喘、心脏病、肝病、肾病、肠炎、癌症、肥胖症(I型和II型)、RA、阿尔茨海默病、震颤性麻痹、多重性硬化和非菌性炎症反应。该系列化合物还可抑制HCN通道亚型，并对HCN2通道具有较高的亲和力，抑制效果强大。从而为这些的治疗疼痛提供一种新的手段和途径，该通道的特异性药物也将为广大患者带来新的福音，具有重要的研发价值和开发意义。
本发明提供了式I所示化合物在TLR4，HCN等方面应用。
本发明所述的化合物SMU-XYC系列，能进行结构修饰，获得活性更好的化合物，并用于治疗TLR4相关疾病。
具体的，本发明一个方面提供了式I所示的化合物或其可药用的盐。
其中，
R1为卤素、氨基、硝基、C1-6烷基、C1-6烷氧基、被1个或多个取代基取代的C1-6烷基；
R2为H，卤素、氨基、硝基、C1-6烷基、C1-6烷氧基、被1个或多个取代基取代的C1-6烷基、苯基、苄基、取代的苄基、苯乙基、取代的苯乙基、苯丙基、以及取代的苯丙基；
R3为H，卤素、氨基、硝基、C1-6烷基、C1-6烷氧基、被1个或多个取代基取代的C1-6烷基中任意一个或多个取代基所取代。
其中，R1、R2和R3中的卤素独立地选自F、Cl、Br、I；R1、R2和R3中的C1-6烷基独立地选自甲基、乙基、丙基、丁基、戊基或己基；R1、R2和R3中C1-6烷氧基独立地选自甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。
其中，R1为2位、3位或4位。
具体化合物如下表所示
本发明另一个方面提供了式I所示化合物的制备方法，包括下述步骤：
1)将4-溴-1-丁烷与mCPBA反应获得环氧溴丁烷；
2)化合物
与环氧溴丁烷通过取代反应得到化合物
3)将化合物
和化合物
通过取代反应得到化合物
4)化合物e在多聚甲醛和甲胺盐酸盐条件下反应获得化合物
5)化合物b和化合物f回流反应得到式I所示化合物；
R1、R2、R3分别如前所述。
本发明再一个方面提供了一种药物组合物，其包括式I所述化合物或其药可用的盐，其还包括药学上可接受的载体或辅料。
本发明再一个方面提供了式I化合物在制备佐剂，抗炎，TLR4抑制剂，HCN通道抑制剂，抗肿瘤，心力衰竭的药物中的用途。
本发明再一个方面提供了一种在体外、体内调节TLR4碱性磷酸酶活性或HCN通道抑制水平的方法，其方法为给予受试者本发明式I化合物。
本发明提供了化合物SMU-XYC系列的制备方法，其包括以下步骤：
1)将4-溴-1-丁烷逐滴加入到mCPBA的CH2Cl2溶液中。将反应混合物搅拌24小时，在此期间形成白色沉淀。然后加入NaOH并分离各相。用4M NaOH洗涤有机层一次，随后用水洗涤直至洗涤水溶液达到pH7。有机相用Na2SO4干燥，减压除去溶剂，得到环氧溴丁烷。
2)向丙酮中加入4-乙氧基苯酚(取代苯酚)，无水碳酸钾和环氧溴丁烷，混合溶液回流20小时。将混合物冷却至室温，减压浓缩滤液。将得到的油状物溶解在甲苯中，依次用水，5％NaOH水溶液洗涤，然后用Na2SO4干燥，减压浓缩。得到2-(4-乙氧基苯基)环氧乙烷；
3)1-(2-氯苄基)-3,5-二甲基-1H-吡唑的制备。
将3,5-二甲基-1H-吡唑和KOH溶于DMSO中，并将得到的非均相溶液在80℃下搅拌1.5h，然后冷却至室温。然后在15分钟内加入6M DMSO溶液的邻氯氯苄，并将反应混合物再搅拌2.5小时。TLC观察监测反应是否完全。将反应物溶于水，水相用CHCl3萃取。合并有机层用100ml水洗涤，用无水Na2SO4干燥并减压浓缩。残留物经硅胶快速色谱纯化，用20％乙酸乙酯的石油醚溶液洗脱。得到1-(2-氯苄基)-3,5-二甲基-1H-吡唑(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole)，为黄色油状物。
4)1-1-(2-氯苄基)-3,5-二甲基-1H-4-吡唑-N-甲基甲胺的制备。将多聚甲醛和甲胺盐酸盐溶于乙醇中搅拌1h，然后加入1-(2-氯苄基)-3,5-二甲基-1H-吡唑，并将反应混合物回流搅16小时。混合物液体冷却至室温，用NaHCO3中和。有机层用Na2SO4干燥并减压浓缩。通过硅胶快速色谱法用10％甲醇的乙酸乙酯溶液纯化残余物。得到1-1-(2-氯苄基)-3,5-二甲基-1H-4-吡唑-N-甲基甲胺(1-(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine)，为黄色油状物。
5)2-(4-乙氧基苯基)环氧乙烷和1-1-(2-氯苄基)-3,5-二甲基-1H-4-吡唑-N-甲基甲胺加入到乙醇中，混合溶液回流24小时。将混合物冷却至室温，减压浓缩。同样方法得到式I中多种化合物。
上述所示的部分化合物能剂量依赖性的抑制TLR4受体，抑制HCN等通道亚型。
本发明所述的化合物SMU-XYC系列可用于制成TLR4相关佐剂、药物等。结合现代常用药物制剂手段，可将所述化合物制成注射剂、片剂、粉剂、颗粒剂、胶囊，从而采用比较方便的给药形式，其中本发明化合物在所述药物中的质量百分比含量为1～20％。
上述各种剂型的药物均可按照药学领域的常规方法制备。
附图说明
图1为SMU-XYC1的1H NMR谱图。
图2为SMU-XYC2的1H NMR谱图。
图3为SMU-XYC3的1H NMR谱图。
图4为SMU-XYC4的1H NMR谱图。
图5为SMU-XYC5的1H NMR谱图。
图6为SMU-XYC6的1H NMR谱图。
图7为SMU-XYC7的1H NMR谱图。
图8为SMU-XYC8的1H NMR谱图。
图9为SMU-XYC9的1H NMR谱图。
图10 SMU-XYC5呈浓度依赖的抑制TLR4活性。
图11为SMU-XYC5阻断HCN4电流的电生理特性。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
实施例1：SMU-XYC1：
1)
的制备。
将4-溴-1-丁烯(1000mg，7.41mmol)滴加到mCPBA(1948mg，11.11mmol)的50mlCH2Cl2溶液中。搅拌反应混合物24小时，在此期间形成白色沉淀。之后加入1M NaOH并将相用乙酸乙酯萃取。用NaOH(4M，50ml)洗涤有机层一次，随后用水洗涤直到洗涤水溶液到pH＝7。有机相用Na2SO4干燥，减压除去溶剂，得到澄清液状的
2)
的制备；
向丙酮中加入4-氟苯酚(200mg，1.78mmol)，无水碳酸钾(494mg，3.57mmol)和环氧溴丁烷(1078mg，7.14mmol)，并将得到的非均相溶液回流20小时。将混合物冷却至室温，通过硅藻土垫过滤，减压浓缩滤液。依次用水，5％NaOH水溶液和水洗涤得到的油，然后用Na2SO4干燥，减压浓缩。得到的液体使用快速柱色谱法用含20％乙酸乙酯的石油醚进行纯化，得到
为澄清液体。
3)
的制备。
将3,5-二甲基-1H-吡唑(1000mg，10.40mmol)和KOH(1675mg，10.40mmol)溶于DMSO中，并将得到的非均相溶液在80℃下搅拌1.5h，然后冷却至室温。然后在15分钟内加入6MDMSO溶液的邻氯氯苄(876mg，15.61mmol)，并将反应混合物再搅拌2.5小时。TLC观察监测反应是否完全。将反应物溶于水，水相用CHCl3萃取。合并有机层用100ml水洗涤，用无水Na2SO4干燥并减压浓缩。残留物经硅胶快速色谱纯化，用20％乙酸乙酯的石油醚溶液洗脱。得到
为黄色油状物。
4)
的制备。
将多聚甲醛(820mg，27.2mmol)和甲胺盐酸盐(920mg，13.6mmol)溶于乙醇中搅拌1h，然后加入
(1000mg，4.53mmol)加入并将反应混合物回流搅16小时。混合物液体冷却至室温，用NaHCO3中和。有机层用Na2SO4干燥并减压浓缩。通过硅胶快速色谱法用10％甲醇的乙酸乙酯溶液纯化残余物。得到
为黄色油状物。
5)
的制备
1H NMR(CDCl3,400MHz)δ7.37(d,J＝7.6Hz,1H),7.22–7.12(m,2H),7.04–6.92(m,2H),6.90–6.82(m,2H),6.53–6.50(m,1H),5.32(s,2H),4.21–4.06(m,2H),4.01–3.91(m,1H),3.54–3.48(m,1H),3.37–3.26(m,1H),2.51–2.45(m,1H),2.39–2.31(m,1H),2.28–2.24(m,6H),2.13(s,3H),1.96–1.87(m,1H),1.85–1.75(m,1H).13C NMR(CDCl3,101MHz)δ154.94,147.75,138.40,135.05,131.71,129.20,128.55,127.36,127.21,115.79,115.56,115.45,115.37,113.41,65.30,64.05,62.84,62.83,51.40,50.04,41.56,34.52,12.10,9.56.ESI-MS:m/z calc’d for C24H29ClFN3O2(M+H+)445.2,found 445.4.
实施例2：化合物2-9的制备
实施例2中分别制备了化合物2-9。化合物2-9制备步骤与实施例1中相同，除了所用原料有所区别。不同之处如下面的表2所示：
表1化合物2-9与实施例1的区别
| 化合物编号 | 与实施例1步骤不同之处 |
| 2 | 将4-氟苯酚替换为4-甲基苯酚 |
| 3 | 将4-氟苯酚替换为4-乙基苯酚 |
| 4 | 将4-氟苯酚替换为4-丙基苯酚 |
| 5 | 将4-氟苯酚替换为4-叔丁基苯酚 |
| 6 | 将4-氟苯酚替换为4-甲氧基苯酚 |
| 7 | 将邻氯氯苄替换为邻氟氯苄 |
| 8 | 将邻氯氯苄替换为4-甲基氯苄 |
| 9 | 将邻氯氯苄替换为4-氯氯苄 |
实施例3：化合物1-9的结构验证
[SMU-XYC1]
1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(4-fluorophenoxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.37(d,J＝7.6Hz,1H),7.22–7.12(m,2H),7.04–6.92(m,2H),6.90–6.82(m,2H),6.53–6.50(m,1H),5.32(s,2H),4.21–4.06(m,2H),4.01–3.91(m,1H),3.54–3.48(m,1H),3.37–3.26(m,1H),2.51–2.45(m,1H),2.39–2.31(m,1H),2.28–2.24(m,6H),2.13(s,3H),1.96–1.87(m,1H),1.85–1.75(m,1H).ESI-MS:m/z calc’d forC24H29ClFN3O2(M+H+)445.2,found 445.3.
[SMU-XYC2]
1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(p-tolyloxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.38(d,J＝8.0Hz,1H),7.25–7.13(m,2H),7.09(d,J＝7.6Hz,2H),6.83(d,J＝8.4Hz,2H),6.52(d,J＝7.6Hz,1H),5.33(s,2H),4.15–4.11(m,2H),3.99(s,1H),3.56–3.50(m,1H),3.36–3.31(m,1H),2.53–2.48(m,1H),2.42–2.37(m,1H),2.32–2.24(m,9H),2.14(s,3H),1.98–1.79(m,2H).ESI-MS:m/z calc’d for C25H32ClN3O2(M+H+)441.2,found 441.4.
[SMU-XYC3]
1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(p-tolyloxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.38(d,J＝7.6Hz,1H),7.22–7.16(m,2H),7.10(d,J＝8.0Hz,2H),6.85(d,J＝8.4Hz,2H),6.53(d,J＝7.6Hz,1H),5.33(s,2H),4.14(t,J＝7.6Hz,2H),4.03(s,1H),3.58(s,1H),3.39(s,1H),2.72–2.54(m,3H),2.45–2.41(m,1H),2.28(s,6H),2.16(s,3H),1.97–1.83(m,2H),1.23(t,J＝7.6Hz,3H).ESI-MS:m/z calcd forC26H34ClN3O2(M+H+)455.3,found 455.4.
[SMU-XYC4]
1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(4-propylphenoxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.38(d,J＝7.6Hz,1H),7.23–7.13(m,2H),7.10(d,J＝8.4Hz,2H),6.84(d,J＝8.4Hz,2H),6.52(d,J＝7.6Hz,1H),5.33(s,2H),4.16–4.11(m,2H),4.02–3.94(m,1H),3.56–3.50(m,1H),3.36–3.30(m,1H),2.54(t,J＝7.6Hz,2H),2.49–2.45(m,1H),2.41–2.35(m,1H),2.28–2.25(m,5H),2.14(s,3H),1.97–1.77(m,2H),1.66–1.59(m,2H),1.29–1.24(m,1H),0.95(t,J＝7.3Hz,3H).ESI-MS:m/z calc’d for C27H36ClN3O2(M+H+)469.3,found 469.4.
[SMU-XYC5]
4-(4-(tert-butyl)phenoxy)-1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.39(d,J＝6.8Hz,1H),7.31(d,J＝8.4Hz,2H),7.22–7.15(m,2H),6.86(d,J＝8.8Hz,2H),6.52(d,J＝7.6Hz,1H),5.33(s,2H),4.15(t,J＝5.2Hz,2H),4.01(s,1H),3.58–3.52(m,1H),3.40–3.34(m,1H),2.54(s,1H),2.42(s,1H),2.28(s,6H),2.15(s,3H),1.95–1.83(m,2H),1.32(s,9H).ESI-MS:m/z calc’d for C28H38ClN3O2(M+H+)483.2,found483.3.
[SMU-XYC6]
1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(4-ethoxyphenoxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.37(d,J＝8.0Hz,1H),7.23–7.11(m,2H),6.84(d,J＝1.6Hz,4H),6.52–6.48(m,1H),5.32(s,2H),4.13-3.91(m,5H),3.53–3.25(m,2H),2.48–2.31(m,2H),2.27(s,3H),2.23(s,3H),2.12(s,3H),1.93–1.78(m,2H),1.42–1.37(m,3H).ESI-MS:m/z calc’d for C26H34ClN3O3(M+H+)471.2,found 471.2.
[SMU-XYC7]
4-(4-ethoxyphenoxy)-1-(((1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.27–7.22(m,1H),7.11–7.01(m,2H),6.85(s,5H),5.29(s,2H),4.10(t,J＝6.4Hz,2H),4.00(q,J＝7.2Hz,3H),3.56–3.50(m,1H),3.36–3.30(m,1H),2.52(s,1H),2.42–2.36(m,1H),2.26(s,6H),2.18(s,3H),1.91–1.80(m,2H),1.41(t,J＝7.0Hz,3H).ESI-MS:m/z calc’d for C26H34FN3O3(M+H+)455.3,found 455.6.
[SMU-XYC8]
1-(((3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(4-ethoxyphenoxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.17(d,J＝8.4Hz,2H),7.12–7.08(m,1H),6.85(s,4H),6.45(d,J＝7.2Hz,1H),5.21(s,2H),4.14–4.08(m,2H),4.00(q,J＝7.2Hz,3H),3.56–3.50(m,1H),3.36–3.30(m,1H),2.55–2.47(m,1H),2.40(s,1H),2.35(s,3H),2.27(s,6H),2.12(s,3H),1.97–1.80(m,2H),1.41(t,J＝7.2Hz,3H).ESI-MS:m/z calc’d for C27H37N3O3(M+H+)451.3,found451.6.
[SMU-XYC9]
1-(((3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl)methyl)(methyl)amin o)-4-(4-ethoxyphenoxy)butan-2-ol.
1H NMR(CDCl3,400MHz)δ7.30(s,1H),7.28(s,1H),7.00(d,J＝8.0Hz,2H),6.85(s,4H),5.20(s,2H),4.12–4.08(m,2H),4.00(q,J＝6.8Hz,3H),3.56–3.50(m,1H),3.36–3.30(m,1H),2.55–2.46(m,1H),2.41–2.35(m,1H),2.26(s,6H),2.14(s,3H),1.97–1.75(m,2H),1.41(t,J＝6.8Hz,3H).ESI-MS:m/z calc’d for C26H34ClN3O3(M+H+)471.2,found 471.3.
实施例4SMU-XYC5的TLR4抑制活性检测
TLR4抑制活性采用TLR4HEK BLUE细胞进行检测。TLR4HEK BLUE细胞培养于含10％胎牛血清，1％青霉素、链霉素的DMEM培养基中，置于含5％CO2的37℃细胞培养箱中培养。
HEK BLUE TLR4细胞以40000个/孔铺于96孔板中，37℃，5％CO2中培养24小时，每孔50μL。待细胞长势良好时，加入100μM浓度的化合物并倍比稀释9个浓度梯度。再于CO2培养箱中放置24小时。新96孔板中加入50μL上清，避光加入50μL Quanti-blue溶液，在620nm吸光度下15分钟为单位读数3次，以检测细胞上清中SEAP的信号强度。
如图10所示，SMU-XYC5能显著抑制TLR4碱性磷酸酶(SEAP)信号强度，在低浓度的抑制剂SMU-XYC5(0.39μM)时，其不能显著抑制TLR4碱性磷酸酶信号强度，而在高浓度的抑制剂SMU-XYC5(30μM)时，其能显著抑制TLR4碱性磷酸酶信号强度。
该结果显示该系列化合物具有很好的TLR4抑制活性，具有良好的开发潜力。由于TLR4与心脏疾病相关，同时HCN4在心脏窦房结中表达较多，与心律失常，心力衰竭等多种疾病相关。HCN2在中枢神经中表达较为广泛，所以HCN2抑制剂可以作为抗炎，止痛的新靶点来应用。
实施例5SMU-XYC5化合物的HCN抑制活性检测
首先测试了SMU-XYC5对HCN2通道在-50到-140mV不同电压下的抑制作用。10μMSMU-XYC5显着降低了所有测试电压下的HCN2电流，并将电压依赖性激活急剧地移向更超极化的方向，V1/2从-89.93±0.90移动到-120.70±0.67mV。此外，SMU-XYC5在-120mV(对照：242.90±24.02vs 4e：1598.00±154.40ms)显着减慢激活速度，而对去激活过程没有影响。进一步的剂量-反应曲线显示SMU-XYC5在HCN2通道上的IC50为3.42±1.02μM。
最近的研究报道HCN2通道调节伤害性感觉神经元的发放频率，并在炎症和神经性疼痛两者中起着核心作用。这一系列化合物可以抑制HCN通道的外周阻滞引起的炎症和神经性疼痛。这些抑制剂的发现可能是未来抑制剂开发的有希望的先导化合物。可以发挥缓解神经疼痛，抗心绞痛的作用。具体结果参见图11和表2。
表2：SMU-XYC系列对HCN2通道(神经疼痛方面)的抑制效果。
将化合物均匀地偶联到10μM，并在保持电位为-40mV时从2s超极化脉冲引起电流流动。紧接着，将测试脉冲以10mV的增量施加至-140至-50mV的电位，并且将750ms的去极化电流重新调整至+50mV以记录尾电流。I0是在对照条件下-120mV时HCN2的内向整流电流的幅度，而I是在相应的化合物存在下10μM时HCN2的内向整流电流的幅度。
Claims (4)
1.化合物在制备HCN通道抑制剂的用途，所述化合物为式I所示的化合物或其可药用的盐：
其中，
R1为卤素、氨基、硝基、C1-6烷基、C1-6烷氧基；
R2为H，卤素、氨基、硝基、C1-6烷基、C1-6烷氧基、苯基、苄基、苯乙基、苯丙基；
R3为H，卤素、氨基、硝基、C1-6烷基、C1-6烷氧基；
所述化合物的制备方法，包括下述步骤：
1)将4-溴-1-丁烯与mCPBA反应获得环氧溴丁烷；
2)化合物
与环氧溴丁烷通过取代反应得到化合物
3)将化合物
和化合物
通过取代反应得到化合物
4)化合物e在多聚甲醛和甲胺盐酸盐条件下反应获得化合物
5)化合物b和化合物f回流反应得到式I所示化合物。
2.根据权利要求1所述的化合物在制备HCN通道抑制剂的用途，其中，R1、R2和R3中的卤素独立地选自F、Cl、Br、I；R1、R2和R3中的C1-6烷基独立地选自甲基、乙基、丙基、丁基、戊基或己基；R1、R2和R3中C1-6烷氧基独立地选自甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。
3.根据权利要求1或2任一项所述的化合物在制备HCN通道抑制剂的用途，其中，R2为2位、3位或4位。
4.根据权利要求1或2任一项所述的化合物在制备HCN通道抑制剂的用途，化合物，或其可药用的盐，其选自如下化合物：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810122219.7A CN109867627B (zh) | 2018-02-07 | 2018-02-07 | 一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810122219.7A CN109867627B (zh) | 2018-02-07 | 2018-02-07 | 一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109867627A CN109867627A (zh) | 2019-06-11 |
| CN109867627B true CN109867627B (zh) | 2021-05-07 |
Family
ID=66915348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810122219.7A Active CN109867627B (zh) | 2018-02-07 | 2018-02-07 | 一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109867627B (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009074247A1 (de) * | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Neue 2-aryl-thiazol-4-carbonsäureamid-derivate, deren herstellung und verwendung als arzneimittel |
| WO2011038152A2 (en) * | 2009-09-23 | 2011-03-31 | The Regents Of The University Of Colorado, A Body Corporate | Toll-like receptor modulators and uses thereof |
| WO2013136070A1 (en) * | 2012-03-13 | 2013-09-19 | University Court Of The University Of Dundee | A sik inhibitor for use in a method of treating an inflammatory and/or immune disorder |
| CN105051018A (zh) * | 2012-11-16 | 2015-11-11 | 爱尔兰詹森科学公司 | 用于治疗病毒性感染的杂环的经取代的2-氨基-喹唑啉衍生物 |
| CN106163526A (zh) * | 2014-01-29 | 2016-11-23 | 维奥姆生物科学有限公司 | 抗性痤疮的治疗 |
-
2018
- 2018-02-07 CN CN201810122219.7A patent/CN109867627B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009074247A1 (de) * | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Neue 2-aryl-thiazol-4-carbonsäureamid-derivate, deren herstellung und verwendung als arzneimittel |
| WO2011038152A2 (en) * | 2009-09-23 | 2011-03-31 | The Regents Of The University Of Colorado, A Body Corporate | Toll-like receptor modulators and uses thereof |
| WO2013136070A1 (en) * | 2012-03-13 | 2013-09-19 | University Court Of The University Of Dundee | A sik inhibitor for use in a method of treating an inflammatory and/or immune disorder |
| CN105051018A (zh) * | 2012-11-16 | 2015-11-11 | 爱尔兰詹森科学公司 | 用于治疗病毒性感染的杂环的经取代的2-氨基-喹唑啉衍生物 |
| CN106163526A (zh) * | 2014-01-29 | 2016-11-23 | 维奥姆生物科学有限公司 | 抗性痤疮的治疗 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109867627A (zh) | 2019-06-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102538307B1 (ko) | Alk 단백질 분해제 및 암 치료에서의 이의 용도 | |
| EP3286183B1 (en) | Isoxazolyl substituted benzimidazoles | |
| CN109422752B (zh) | 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 | |
| EP2903998B1 (en) | Iap antagonists | |
| JP2798095B2 (ja) | 特定アミノメチルフェニルイミダゾール誘導体、新種のドーパミン受容体サブタイプの特定リガンド | |
| JP6525422B2 (ja) | リジン特異的なデメチラーゼ−１の阻害剤 | |
| CA2924705A1 (en) | Quinazoline derivative and preparation method therefor | |
| CA3183948A1 (en) | Heteroalkyl dihydroquinoline sulfonamide compounds | |
| TW201920221A (zh) | 作為納通道調節劑之吡啶酮醯胺之前藥 | |
| AU2006236622B2 (en) | Compositions of novel opioid compounds and method of use thereof | |
| EA026723B1 (ru) | Терапевтически активные соединения и способы их применения | |
| AU2017346454A1 (en) | Pharmaceutical compounds | |
| JPS63502031A (ja) | ヒドロキシおよびアミノチオゾリル−ベンゾジアジノン化合物、これを含む強心性組成物、およびその使用 | |
| KR20060100412A (ko) | 비만, 당뇨, 우울증 및 불안증을 치료하기 위한 ｍｃｈｒ１ 길항제로서의 3-(4-아미노페닐)티에노피리미드-4-온유도체 | |
| EP3929185A1 (en) | Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof | |
| US11826350B2 (en) | Proline-based neuropeptide FF receptor modulators | |
| EA026380B1 (ru) | Соединения хроманов | |
| CN109867627B (zh) | 一种取代苯酚β-氨基醇类衍生物及其制备方法和用途 | |
| CN108947912B (zh) | 一种靶向Neddylation通路的抗肿瘤化合物 | |
| EP3036219A2 (en) | Novel beta lactams as modulators of glutamate uptake and methods for use thereof | |
| WO1999006383A1 (en) | Piperazine derivatives active on the lower urinary tract | |
| WO2018096401A1 (en) | New naphtho[2,3-b]furan derivatives | |
| EP2142518B1 (en) | 3,4-dihydroquinazoline derivatives | |
| WO2011007899A1 (en) | Glycine transporter inhibitors | |
| CN109867662B (zh) | 一种咔唑β-氨基醇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 |