CN118084884A - 含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 - Google Patents
含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 Download PDFInfo
- Publication number
- CN118084884A CN118084884A CN202410088664.1A CN202410088664A CN118084884A CN 118084884 A CN118084884 A CN 118084884A CN 202410088664 A CN202410088664 A CN 202410088664A CN 118084884 A CN118084884 A CN 118084884A
- Authority
- CN
- China
- Prior art keywords
- compound
- dmso
- nmr
- acid
- pharmaceutically acceptable
- 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.)
- Pending
Links
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 title claims abstract description 38
- 206010061218 Inflammation Diseases 0.000 title claims abstract description 18
- 230000004054 inflammatory process Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 title claims abstract 5
- 239000003112 inhibitor Substances 0.000 title claims description 19
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims description 17
- 125000006615 aromatic heterocyclic group Chemical group 0.000 title claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 7
- 235000010290 biphenyl Nutrition 0.000 title description 8
- 239000004305 biphenyl Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 24
- 230000003287 optical effect Effects 0.000 claims abstract description 15
- 206010034674 peritonitis Diseases 0.000 claims abstract description 7
- -1 aliphatic alkyne Chemical class 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 230000004913 activation Effects 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 201000005569 Gout Diseases 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 208000007882 Gastritis Diseases 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 206010003757 Atypical pneumonia Diseases 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 230000002159 abnormal effect Effects 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 230000000737 periodic effect Effects 0.000 claims description 4
- 238000006268 reductive amination reaction Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 230000009529 traumatic brain injury Effects 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 208000030767 Autoimmune encephalitis Diseases 0.000 claims description 3
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 3
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000023652 chronic gastritis Diseases 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 230000001594 aberrant effect Effects 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000004067 aliphatic alkene group Chemical group 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 claims 1
- 239000005906 Imidacloprid Substances 0.000 claims 1
- 108091008099 NLRP3 inflammasome Proteins 0.000 claims 1
- 208000002353 alcoholic hepatitis Diseases 0.000 claims 1
- 229940056881 imidacloprid Drugs 0.000 claims 1
- 230000037081 physical activity Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 15
- 102000003777 Interleukin-1 beta Human genes 0.000 abstract description 8
- 108090000193 Interleukin-1 beta Proteins 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 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 abstract description 4
- 241000699670 Mus sp. Species 0.000 abstract description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 229960004580 glibenclamide Drugs 0.000 abstract description 3
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 224
- 238000005160 1H NMR spectroscopy Methods 0.000 description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 50
- 238000010189 synthetic method Methods 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- 239000000203 mixture Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 239000002158 endotoxin Substances 0.000 description 13
- 229920006008 lipopolysaccharide Polymers 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 238000009472 formulation Methods 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- HUUSXLKCTQDPGL-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea Chemical compound CC(C)(O)C1=COC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 HUUSXLKCTQDPGL-UHFFFAOYSA-N 0.000 description 8
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CRZNXLNLEMYCCI-UHFFFAOYSA-N 5-chloro-2-propoxybenzaldehyde Chemical compound CCCOC1=CC=C(Cl)C=C1C=O CRZNXLNLEMYCCI-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- ONHDMXPUMFGTRN-UHFFFAOYSA-N 5-bromo-n-propylthiophene-2-sulfonamide Chemical compound CCCNS(=O)(=O)C1=CC=C(Br)S1 ONHDMXPUMFGTRN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 5
- 229960004889 salicylic acid Drugs 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- HFHYZJDMVOCWSV-UHFFFAOYSA-N 4-bromo-n-propylbenzamide Chemical compound CCCNC(=O)C1=CC=C(Br)C=C1 HFHYZJDMVOCWSV-UHFFFAOYSA-N 0.000 description 4
- STYQHICBPYRHQK-UHFFFAOYSA-N 4-bromobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Br)C=C1 STYQHICBPYRHQK-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229940127107 NLRP3 inflammasome inhibitor Drugs 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 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
- 238000011161 development Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 3
- 229940012189 methyl orange Drugs 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-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
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108090000426 Caspase-1 Proteins 0.000 description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 2
- NHEULQMXMXIOJY-UHFFFAOYSA-N Cl[PH2]=O Chemical compound Cl[PH2]=O NHEULQMXMXIOJY-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 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
- 230000002378 acidificating effect Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 229930016911 cinnamic acid Natural products 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000019189 interleukin-1 beta production Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant 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
- 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
- 239000001993 wax Substances 0.000 description 2
- DIRRKLFMHQUJCM-UHFFFAOYSA-N (2-aminophenyl)boronic acid Chemical compound NC1=CC=CC=C1B(O)O DIRRKLFMHQUJCM-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 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 description 1
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 description 1
- RCNOGGGBSSVMAS-UHFFFAOYSA-N 2-thiophen-3-ylacetic acid Chemical compound OC(=O)CC=1C=CSC=1 RCNOGGGBSSVMAS-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
- 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
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- WGYBIEOLAFYDEC-UHFFFAOYSA-N 5-bromothiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)S1 WGYBIEOLAFYDEC-UHFFFAOYSA-N 0.000 description 1
- FUGKCSRLAQKUHG-UHFFFAOYSA-N 5-chloro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Cl)C=C1C=O FUGKCSRLAQKUHG-UHFFFAOYSA-N 0.000 description 1
- WRSDJJXJDSEUSQ-UHFFFAOYSA-N 5-oxo-5-phenylmethoxypentanoic acid Chemical compound OC(=O)CCCC(=O)OCC1=CC=CC=C1 WRSDJJXJDSEUSQ-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000011594 Autoinflammatory disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 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
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 102100037387 Gasdermin-A Human genes 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
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101001026276 Homo sapiens Gasdermin-A Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 231100000757 Microbial toxin Toxicity 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 102400001018 Proadrenomedullin N-20 terminal peptide Human genes 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- NXIUTNQGRDQRHA-UHFFFAOYSA-N [2-(aminomethyl)phenyl]boronic acid Chemical compound NCC1=CC=CC=C1B(O)O NXIUTNQGRDQRHA-UHFFFAOYSA-N 0.000 description 1
- CWLNHPXWZRALFS-UHFFFAOYSA-N [3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(B(O)O)=C1 CWLNHPXWZRALFS-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000005038 alkynylalkyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- OIRDTQYFTABQOQ-UHFFFAOYSA-N ara-adenosine Natural products Nc1ncnc2n(cnc12)C1OC(CO)C(O)C1O OIRDTQYFTABQOQ-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical compound NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- RVAUVEOTZNLMQL-UHFFFAOYSA-N cyclohexanesulfinic acid Chemical compound OS(=O)C1CCCCC1 RVAUVEOTZNLMQL-UHFFFAOYSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-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
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000007794 irritation Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940127285 new chemical entity Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 231100000847 severe hepatotoxicity Toxicity 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种如通式（I）所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物及其制备方法和应用。本发明提供的通式（I）化合物表现出了显著的抑制NLRP3炎症小体的活性，且部分化合物都在几百个纳摩尔，优于已报道的同类型的化合物格列本脲、JC124。此外，在体内抗炎实验中代表性化合物A20和A28能显著抑制LPS诱导的小鼠急性腹膜炎中的IL‑1β的释放，而不影响另一炎症因子TNF‑α的释放，表明化合物能特异性的抑制NLRP3炎症小体，具有一定的选择性。
Description
技术领域
本发明涉及化学合成药物技术领域，具体涉及一种含联苯或苯基取代芳杂环母核的NLRP3炎症小体抑制剂及其制备方法和应用。
背景技术
NLRP3炎症小体是一种胞浆多蛋白复合物，是先天免疫***的重要组成部分。NLRP3炎症小体的异常活化与多种疾病的发生发展密切相关(Int J Mol Sci,2020,21,5758)例如：冷吡啉相关周期性综合症(又称NLRP3相关自身炎症性疾病)、阿尔兹海默症、帕金森症、痛风、类风湿性关节炎、炎症性肠病、非典型肺炎、动脉粥样硬化、非酒精性脂肪性肝炎、多发性硬化和慢性阻塞性肺病、创伤性脑伤、心力衰竭、冠状动脉疾病、骨关节炎等(Nat Rev Immunol.2017,17,208-214)。开发NLRP3炎症小体抑制剂被认为是治疗上述疾病的潜在策略，受到学术界和制药工业界的广泛关注和青睐(J Med Chem.2021,64,101-122)。NLRP3炎症小体主要包含三部分，分别是传感蛋白(NLRP3)、衔接蛋白(ASC)，和效应蛋白Pro-caspase-1(Trends Biochem Sci,2016,41(12):1012-1021)。NLRP3炎症小体可以被很多因素激活，包括病毒RNA、微生物毒素和细菌表面成分等外源性病原相关分子模式(Pathogen associated molecular patterns，PAMPs)以及尿酸晶体、ATP、铝佐剂和β-淀粉样肽等内源性损伤相关分子模式(Damage associated molecular patterns，DAMPs)，典型的NLRP3炎症小体激活途径包括启动和激活两部分。在启动阶段，一些Toll样受体诱导核转录因子NF-κB活化，导致NLRP3、Pro-IL-18、Pro-IL-1β基因表达上调，为炎症小体组装积累物料；一旦NLRP3炎症小体被激活，即迅速组装成一个大分子复合物诱导Pro-caspase-1自裂解，导致促炎因子IL-1β、IL-18成熟和释放，并且还会切割Gasdermin D，使其在细胞膜上穿孔，导致促炎因子由胞质释放至胞外，最终导致细胞焦亡(Adv Immunol.2020,145,55-93)。
经过近10年来的研究，已发现了一些针对NLRP3炎症小体通路的小分子抑制剂，约有10个候选分子进入临床阶段，这类分子基本都是磺酰脲类化合物MCC950类似物，目前尚无抑制剂药物上市(J Med Chem.2023,66,14447-14473；J Med Chem.2023,66,12966-12989)。分析已经报道的化合物，存在结构骨架单一，活性不够突出的不足。苯磺酰脲类化合物MCC950是迄今为止发现的活性最高的NLRP3炎症小体抑制剂，抑制IL-1β产生的IC50为7.5nM，但是它对类风湿性关节炎的II期临床因其严重的肝毒性而终止(Nat Rev DrugDiscov.2018,17,588-606)，之后大量的MCC950类似物被报道，虽然它们的活性与MCC950相当，但是存在结构不稳定、易分解和半衰期短的不足，重要的是，它们可能存在与MCC950类似的人体肝毒性，在临床前研究中难以预测，为此类分子的开发带来了挑战(ACSOmega.2022,7,8158-8162)。目前已报道的NLRP3炎症小体抑制剂结构骨架单一，绝大多数活性较好的化合物都是MCC950类似物，结构同质化严重。而除了磺酰脲类化合物活性在几十纳摩尔，其他大部分化合物都在微摩尔级别，活性有待进一步提高(Eur J MedChem.2020,185,111822)。因此，急需寻找结构多样、活性更高、安全性更高的NLRP3炎症小体抑制剂，为治疗NLRP3炎症小体相关疾病提供更优的策略。
发明内容
针对上述问题，本发明第一目的在于提供一种表现出优异的NLRP3炎症小体抑制作用，并有良好的治疗NLRP3相关疾病作用的抑制剂。
本发明的第二目的在于提供一种上述NLRP3炎症小体抑制剂化合物的制备方法，该方法以价格低廉、易得的原料、较高的产率合成所需化合物，并且化合物的性质稳定。
本发明的第三目的在于提供上述化合物用于制备NLRP3炎症小体抑制剂及治疗NLRP3-相关疾病的用途。
为了研发潜在的NLRP3炎症小体抑制剂并用于治疗NLRP3炎症小体相关疾病，本发明在深入研究当前NLRP3炎症小体抑制剂不足的基础上，设计和成了一类母核为联苯或苯基芳杂环的NLRP3炎症小体抑制剂，并在体外实验中验证了这类化合物能够抑制NLRP3炎症小体的激活介导的IL-1β的释放，从而可以治疗与NLRP3炎症小体激活相关的疾病，比如：神经性疾病及脑损伤，如阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤、亨廷顿病；炎症性疾病，如炎症性肠病、急性肺炎、非典型肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急，慢性胃炎、急，慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染休克；代谢性疾病，如痛风、非酒精性脂肪肝、II型糖尿病；心血管疾病，包括心衰、动脉粥样硬化、急性心肌梗塞、冠状动脉疾病；肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷卟啉相关周期性综合症和***性红斑狼疮。
第一方面，本发明提供了一种以联苯或苯基芳杂环为母核的NLRP3炎症小体抑制剂，其特征在于，所述抑制剂具有如通式(1)所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物：
其中，选自/>
其中n＝0-1；
其中R1取代基选自其中A选自C1～C8的脂肪族烷烃、C2～C8的脂肪族炔烃、C2～C8的脂肪族烯烃、C3～C12的环烷烃、五元芳杂环或苯环或六元芳杂环；
R2和R3取代基在联苯或苯基取代芳杂环骨架上的位置不定，其中R2选自H、 其中X3选自O、S；其中n＝0-1；其中R4取代基为H、卤素、羟基、甲氧基；
其中R3选自H、
其中R5取代基为H、OH、 卤素、C1～C6烷基，其中n＝0-6；
其中R6取代基为H、卤素；
其中R7取代基为H、CF3、CN、NO2、OH、卤素。
在一些技术方案中，所述R1优选为其中n＝0-6；
进一步优选为：R1为其中n＝0-6；
最优选：R1为
在一些技术方案中，所述R2优选自其中X1选自O、S，其中n＝0-1；
优选：R2为
最优选：R2为
在一些技术方案中，所述R3优选H、
其中R5取代基为H、
其中R6取代基为H、卤素；
进一步优选：R3为
最优选，R3为
在一些具体的技术方案中，所述的化合物结构式如下：
除非特别定义，本发明中提供的化合物和盐还可以包含存在于中间体或最终化合物中的原子的所有同位素。同位素包括具有相同的原子序数但是具有不同的质量数的那些原子。
如本发明中所使用的，“卤素”是指F、Cl、Br或I。在一些实施方案中，卤素为F、Cl或Br。在一些实施方案中，卤素为F。在一些实施方案中，卤素为Cl。在一些实施方案中，卤素为Br。在一些实施方案中，卤素为I。
卤烷基中卤素的个数和种类不限，如三氟甲基、二氟甲基、三氟乙基等。
脂肪族烷基优选C1～C6烷基，如直链烷基、直链烷基、螺环烷基、桥环烷基、烯烷基、炔烷基、环烷基、环烯基、环炔基。
C1-C6取代的烷基优选为脂肪族烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基等。
芳香族烷基非限制性的包括：取代或非取代的苯甲基、苯乙基、苯异丙基、苯环丙基。
芳环非限制性的选自取代的或未取代的苯环、萘环、联苯环等。
芳杂环非限制性的选自取代的或未取代的噻吩环、呋喃环、吡啶环、吡咯环喹啉环、异喹啉环、苯并呋喃环等。
在本发明中使用短语“药学上可接受的”以指如下的那些化合物、材料、组合物和/或剂型，其在合理的医学判断的范围内，适合用于与人类和动物的组织接触而没有过度的毒性、刺激、过敏反应或者其它问题或并发症，与合理的获益/风险比相称。
其中药学上可接受的盐是指所公开的化合物的衍生物，其中通过将现有的酸或碱部分转化为其盐形式来修饰母体化合物。药学上可接受的盐的实例包括但不限于例如胺等碱性残基的无机酸盐或有机酸盐；和例如羧酸等酸性残基的碱金属盐或有机盐等。本发明的药学上可接受的盐包括例如由无毒的无机酸或有机酸形成的母体化合物的常规的无毒盐,主要包括无机酸盐如硫酸、硝酸、氢溴酸、磷酸、盐酸、硼酸、氨基磺酸等；或有机酸如乙酸、丙酸、丁酸、丙戊酸、樟脑酸、癸酸、己酸、辛酸、辛二酸、碳酸、肉桂酸、羟基乙酸、三氟乙酸、己二酸、丙酮酸、水杨酸、甲磺酸、海藻酸、2-羟基丙酸、2-氧代丙酸、硬脂酸、乳酸、柠檬酸、草酸、丙二酸、琥珀酸、焦谷氨酸、抗坏血酸、天冬氨酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、羟基马来酸、棕榈酸、肉桂酸、异丁酸、月桂酸、扁桃酸,、马来酸、富马酸、苹果酸、酒石酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、2-羟基-1,2,3-丙三酸、葡糖酸、葡萄糖醛酸、谷氨酸、戊二酸、甲酸、反丁烯二酸、粘酸、龙胆酸、乙基磺酸、苯甲磺酸、对甲苯磺酸、环己基亚磺酸、羟乙基磺酸、乙烷二磺酸、4-(笏甲氧羰基氨基)丁酸、二氯乙酸、1，2-乙烷二磺酸、樟脑-10-磺酸、2，4-二羟基苯甲酸、α-酮戊二酸、1-羟基-2-萘甲酸、对乙酰氨基苯甲酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸、全反式维甲酸。可以通过常规的化学方法从包含碱性或酸性部分的母体化合物合成本申请的药学上可接受的盐。通常，可以通过使这些化合物的游离酸或碱形式与化学计量量的适当的碱或酸在水中或在有机溶剂中或者在二者的混合物中反应来制备这样的盐；通常，非水性介质如醚、乙酸乙酯、醇类(例如，甲醇、乙醇、异丙醇或丁醇)或乙腈(MeCN)是优选的。
第二方面，本发明还提供了如上所述的通式(1)的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物的制备方法，包括以下步骤：
(1)当R1为时，通式(I)所示的化合物或其药学上可接受的盐的制备方法包括以下步骤：
以化合物1为起始原料，与氨基化合物反应得到中间体2；中间体2在四(三苯基膦)钯的催化下与取代或非取代的硼酸芳环或芳杂环类似物发生铃木反应得到中间体3；进一步中间体3与取代醛基化合物发生还原胺化反应生成中间体4；最后中间体4与取代羧酸发生缩合反应得到目标化合物5(通式(I)化合物)。
(2)当R1为时，通式(I)所示的化合物或其药学上可接受的盐的制备方法包括以下步骤：
以化合物6为起始原料，与氨基化合物发生缩合反应得到中间体7；中间体7在四(三苯基膦)钯的催化下与取代或非取代的硼酸芳环或芳杂环类似物发生铃木反应得到中间体8；进一步中间体8与取代醛基化合物发生还原胺化反应生成中间体9；最后中间体9与取代羧酸发生缩合反应得到目标化合物10。
第三方面，本发明还提供了一种药物组合物，其包含如上所述的通式(I)所示的化合物或其光学异构体、或其药学上可接受的盐、氘代物以及药学上可接受的稀释剂或载体。所述化合物或其光学异构体、或其药学上可接受的盐、溶剂合物、氘代物、或前药的含量为0.1-99.9wt％。
第四方面，本发明提供了如上所述的通式(I)的化合物或其光学异构体、或其药学上可接受的盐、氘代物在制备NLRP3炎症小体抑制剂中的用途。
第五方面，本发明还提供了如上所述的通式(I)的化合物或其光学异构体、或其药学上可接受的盐、氘代物在制备与NLRP3炎症小体异常活化相关的疾病的药物中的用途。
所述与NLRP3炎症小体异常活化相关疾病包括阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤、亨廷顿病等神经性疾病及脑损伤；炎症性肠病、急性肺炎、非典型肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急，慢性胃炎、急，慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染休克等炎症性疾病；痛风、非酒精性脂肪肝、II型糖尿病等代谢性疾病；心力衰竭、动脉粥样硬化、急性心肌梗塞、冠状动脉疾病等心血管疾病；肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷吡啉相关周期性综合症或***性红斑狼疮。
本发明的有益效果：本发明的有益效果在于基于NLRP3炎症小体抑制剂的药物设计，为治疗NLRP3炎症小体异常活化相关疾病提供新的化学实体。
1、本发明在现有技术的基础上，针对现有NLRP3炎症小体抑制剂的不足，提供了一种母核为联苯或苯基取代芳杂环的全新骨架的NLRP3炎症小体抑制剂。
2、本发明中提供的化合物对NLRP3炎症小体激活介导的IL-1β释放具有显著的抑制活性，且部分化合物的IC50在几百个纳摩尔，优于已报道的同类型的化合物格列本脲、JC124。同时代表性化合物A20、A28能显著的抑制LPS诱导的小鼠急性腹膜炎中的炎症因子IL-1β的生成，而对另一个炎症因子TNF-α无抑制作用，表明化合物A20、A28选择性抑制NLRP3炎症小体通路。
附图说明
图1是化合物A20(10mg/kg)、A28(10mg/kg)及MCC950(10mg/kg)对LPS诱导的C57BL/6小鼠产生IL-1β的影响图。
图2是化合物A20(10mg/kg)、A28(10mg/kg)及MCC950(10mg/kg)对LPS诱导的C57BL/6小鼠产生TNF-α的影响图。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本发明中使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
本发明包含含有治疗量本发明化合物的药物，和一种或多种药学上可接受载体和/或赋形剂的药物组合物。载体包括如盐水，缓冲盐水，葡萄糖，水，甘油，乙醇和它们的结合物，下文更详细地论述。如果需要，该组合物还可以包含较小量的润湿剂或乳化剂，或pH缓冲剂。该组合物可以是液体，悬浮液，乳剂，片剂，丸剂，胶囊，持续释放制剂或粉末。该组合物可以用传统的黏合剂和载体如三酸甘油酯配制成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，纤维素和碳酸镁等等。视需要制剂而定，配制可以设计混合，制粒和压缩或溶解成分。在另一个途径中，该组合物可以配制成纳米颗粒或肠溶性的微丸。
使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖，石膏粉，蔗糖，滑石，凝胶，琼脂，果胶，***胶，硬脂酸镁，硬脂酸等等。固体载体可以包括一种或多种可能同时作为增香剂，润滑剂，增溶剂，悬浮剂，填料，助流剂，压缩助剂，粘合剂或片剂崩解剂的物质；它还可以是包封材料。在粉末中，载体为精细粉碎的固体，它与精细粉碎的活性成分的混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合，以需要的形状和大小压缩。粉末和片剂优选包含至多99％活性成分。合适的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，糖，乳糖，糊精，淀粉，凝胶，纤维素，甲基纤维素，羧甲基纤维素钠盐，聚乙烯吡咯烷酮烷酮，低熔点蜡或离子交换树脂。
典型的液体载体包括糖浆，花生油，橄榄油，水等等。液体载体用于制备溶液，悬浮液，乳剂，糖浆，酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可接受的液体载体如水，有机溶剂，二者的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，增甜剂，增香剂，悬浮剂，增稠剂，颜料，粘度调节剂，稳定形或渗透压调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠盐溶液)，醇(包括一元醇和多元醇，例如乙二醇)和它们的衍生物，和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来，例如，静脉内，肌内，腹膜内或皮下注射。注射时可单次推入或逐渐注入，如30分钟的静脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料，如单硬脂酸甘油酯或二硬脂酸甘油酯，还可包括蜡，乙基纤维素，羟丙基甲基纤维素，异丁烯酸甲酯等等。当制剂用于口服时，公认PHOSALPG-50(磷脂(phospholipid)与1,2-丙二醇浓缩，A.Nattermann&Cie.GmbH)中的0.01％吐温80用于其他化合物的可接受的口服制剂的配制，可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体，制剂可以为肠溶性胞衣片剂，被放入硬胶囊中肠溶性微丸或锭剂或糖锭形式。固体载体的量在很大程度上变化，但是优选从约25mg到约1.0g。如果使用液体载体，制剂可以为糖浆，乳剂，软胶囊，在安瓿或小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
各种释放***是已知的并且可以用于化合物或其他各种制剂的给药，这些制剂包括片剂，胶囊，可注射的溶液，脂质体中的胶囊，微粒，微胶囊，等等。引入的方法包括但是不局限于皮肤的，皮内，肌内，腹膜内的，静脉内的，皮下的，鼻腔内的，肺的，硬膜外的，眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药，例如通过注入或快速浓注，通过上皮的或粘膜线路(例如，口腔粘膜，直肠和肠粘膜，等等)吸收或通过负载药物的支架以及可以于其他生物活性剂一起给药。可以全身或局部给药。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
本发明实施例中所用的试验材料均为本领域常规的试验材料，均可通过商业渠道购买得到。
本发明中通式(1)的化合物的制备方法如下所示，各取代基如发明内容部分所定义。
化合物A01-A08的合成路线a：
a试剂与条件：(a)正丙胺，三乙胺(TEA)，室温1.5h；(b)四(三苯基膦)钯(Pd[P(C6H5)3]4)，2mol/L碳酸钾(K2CO3)，N2，1，4-二氧六环，105℃，回流3h；(c)溴乙烷，二甲基甲酰胺，100℃，2h；(d)氰基硼氢化钠(NaBH3CN)，甲醇(MeOH)，室温2h；(e)双(2-氧-3-噁唑烷基)次磷酰氯(Bop-Cl)，TEA，二氯甲烷(DCM)，室温6h。
化合物A09-A24的合成路线a：
a试剂与条件：(a)正丙胺，TEA，室温1.5h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)NaBH3CN，MeOH，室温2h；(d)Bop-Cl，TEA，DCM，室温6h。
化合物A25-A31的合成路线a：
a试剂与条件：(a)正丙胺，TEA，室温1.5h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)NaBH3CN，MeOH，室温2h；(d)Bop-Cl，TEA，DCM，室温6h。
化合物A32-A37的合成路线a：
a试剂与条件：(a)正丙胺，TEA，室温1.5h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)NaBH3CN，MeOH，室温2h；(d)Bop-Cl，TEA，DCM，室温6h。
化合物A38-A47的合成路线a：
a试剂与条件：(a)正丙胺，TEA，室温1.5h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)NaBH3CN，MeOH，室温2h；(d)Bop-Cl，TEA，DCM，室温6h。
化合物A48-A49的合成路线a：
a试剂与条件：(a)正丙胺，TEA，室温1.5h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)NaBH3CN，MeOH，室温2h；(d)Bop-Cl，TEA，DCM，室温6h。
化合物A50的合成路线a：
a试剂与条件：(a)氨水，THF，室温6h；(b)Pd[P(C6H5)3]4，2mol/L K2CO3，N2，1，4-二氧六环，105℃，回流3h；(c)N,N'-羰基二咪唑，1,8-二氮杂二环[5.4.0]十一碳-7-烯，N2，THF，室温4h；(d)盐酸EA或三氟乙酸，DCM，室温2h；(e)NaBH3CN，MeOH，室温2h；(f)Bop-Cl，TEA，DCM，室温6h。
具体实施例：
下面通过具体的实施例对本发明进行详细说明，但这些例举性实施例的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
中间体5-氯-2-丙氧基苯甲醛(2)的制备：
将5-氯-2-羟基苯甲醛(500mg，3.2mmol)置于50mL茄形瓶中，加入10mL二甲基甲酰胺(DMF)溶解后，再加入K2CO3(1.1g，8mmol)，搅拌10min，加入溴乙烷(558mg，5.12mmol)，100℃反应2h。薄层色谱法检测反应完全。向反应液中加入10mL乙酸乙酯，反复用水洗涤3-5次，向有机相中加入饱和氯化钠(NaCl，5mL)洗涤3次，然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥，15-20min后浓缩得到粗品中间体2，无需柱色谱分离即可投下一步(淡黄色固体，550mg，收率86.7％)。1H-NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.64(dd,J＝9.0,2.5Hz,1H),7.57(d,J＝2.5Hz,1H),7.24(d,J＝9.1Hz,1H),4.10–4.03(m,2H),1.81–1.70(m,2H),0.99–0.94(m,3H)。
目标化合物的制备：
实施例1：N-(5-氯-2-丙氧基苄基)-N-(2-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)苯并呋喃-2-甲酰胺(A01)的合成：
a.5-溴-N-丙基噻吩-2-磺酰胺(4)的合成：
将正丙胺(27mg，0.38mmol)置于25mL茄形瓶中，加入2mL二氯甲烷(DCM)溶解，冰浴降温后加入三乙胺(TEA，80μL，0.57mmol)，搅拌10min后加入5-溴噻吩-2-磺酰氯(100mg，0.38mmol)，室温反应过夜。薄层色谱法检测反应完全。依次向反应液中加饱和碳酸氢钠(NaHCO3，5mL)、1mol/L盐酸(HCl，5mL)、饱和氯化钠(NaCl，5mL)各洗1次，然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩得到粗品中间体4，无需柱色谱分离即可投下一步。(白色固体，96mg，收率88.9％)。1H-NMR(400MHz,DMSO-d6)δ7.90(t,J＝5.8Hz,1H),7.38(d,J＝4.0Hz,1H),7.30(d,J＝4.0Hz,1H),2.81–2.72(m,2H),1.44–1.30(m,2H),0.78(t,J＝7.4Hz,3H)。
b.5-(2-氨甲基)苯基-N-丙基噻吩-2-磺酰胺(5)的合成：
依次将中间体4(500mg，1.75mmol)、(2-(氨甲基)苯基)硼酸(344mg，2.275mmol)、四(三苯基膦)钯(202mg，0.175mmol)置于50mL三颈烧瓶中，加入1，4-二氧六环(10mL)溶解，再向反应液中加入2mol/L碳酸钾水溶液(K2CO3，3mL)，氮气保护，105℃回流3h。薄层色谱法检测反应完全。将反应液中有机溶剂蒸干。加入乙酸乙酯溶解，再依次用饱和碳酸氢钠(NaHCO3，8mL)、1mol/L盐酸(HCl，8mL)、饱和氯化钠(NaCl，8mL)各洗1次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体5。(淡黄色油状物，400mg，收率73.8％，PE/EA＝10/1)。1H-NMR(400MHz,DMSO-d6)δ8.92(s,2H),7.99(s,1H),7.77(d,J＝7.7Hz,1H),7.63(d,J＝3.5Hz,1H),7.60–7.52(m,1H),7.49(s,2H),7.33(d,J＝3.5Hz,1H),4.07(s,2H),2.86(t,J＝7.2Hz,2H),1.51–1.38(m,2H),0.84(t,J＝7.4,1.9Hz,3H)。
c.5-(2-((5-氯-2-丙氧基苄基氨基)甲基)苯基)-N-丙基噻吩-2-磺酰胺(6)的合成：
将中间体5(570mg，1.84mmol)和中间体2(364mg，1.84mmol)置于50mL茄形瓶中，加入甲醇(MeOH，15mL)溶解。室温反应2h。再将反应液冰浴降温后加入甲基橙、氰基硼氢化钠(NaBH3CN，2g，11.04mmol)，滴入盐酸甲醇溶液(1:1)调PH至3-5。室温反应1-2h。薄层色谱法检测反应完全。将反应液蒸干后加入饱和NaHCO3(10mL)调PH至8-9，再加入EA萃取(8mL×3)。然后将有机相用饱和NaCl洗1次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体6。(淡黄色固体，800mg，收率88.4％，PE/EA＝7：1)。1H-NMR(400MHz,DMSO-d6)δ7.81(t,J＝5.8Hz,1H),7.56–7.51(m,1H),7.48(d,J＝3.8Hz,1H),7.42–7.36(m,2H),7.35–7.29(m,2H),7.27(d,J＝3.8Hz,1H),7.17(dd,J＝8.7,2.7Hz,1H),6.90(d,J＝8.8Hz,1H),3.86(t,J＝6.3Hz,2H),3.65(d,J＝18.0Hz,4H),2.82–2.74(m,2H),1.69–1.58(m,2H),1.44–1.33(m,2H),0.88(t,J＝7.4Hz,3H),0.78(t,J＝7.4Hz,3H)。
d.N-(5-氯-2-丙氧基苄基)-N-(2-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)苯并呋喃-2-甲酰胺(A01)的合成：
将苯并呋喃-2-羧酸(724mg，0.15mmol)置于25mL茄形瓶中，加入DCM(2mL)溶解，冰浴降温后加入三乙胺(26μL，0.18mmol)、双(2-氧-3-噁唑烷基)次磷酰氯(Bop-Cl,76mg，0.3mmol)，反应30min后加入中间体4(60mg,0.12mmol)，室温反应过夜。薄层色谱法检测反应完全。向反应液中依次加入饱和碳酸氢钠(NaHCO3，8mL)、1mol/L盐酸(HCl，8mL)、饱和氯化钠(NaCl，8mL)，各洗1次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到目标化合物A01。(白色固体，50mg，收率52.6％)。1H NMR(400MHz,DMSO-d6)δ7.83(t,J＝5.9Hz,1H),7.75–7.62(m,1H),7.51–7.23(m,9H),7.11(s,3H),6.86(s,1H),5.01(s,1H),4.81–4.47(m,3H),3.78(s,2H),2.80–2.65(m,2H),1.52–1.32(m,4H),0.85–0.70(m,6H).13C NMR(126MHz,DMSO-d6)δ155.80,154.44,148.52,131.74,128.24,127.18,127.01,124.15,123.01,113.65,112.11,69.92,60.19,44.95,22.70,11.56,10.69。
实施例2：2-溴-N-(5-氯-2-丙氧基苄基)-N-(2-(5-(N-丙基氨基磺酰基)噻吩-2-苯基)乙酰胺(A02)
合成方法参考实施例1，总收率39.0％。1H-NMR(400MHz,DMSO-d6)δ7.89–7.79(m,1H),7.53–7.34(m,3H),7.34–7.13(m,4H),7.09–6.99(m,1H),6.94–6.85(m,1H),4.72–4.59(m,1H),4.52–4.29(m,4H),4.14(s,1H),3.82(t,J＝6.4Hz,1H),3.76(t,J＝6.4Hz,1H),2.79–2.72(m,2H),1.64–1.44(m,2H),1.44–1.33(m,2H),0.87–0.76(m,6H)。13C NMR(126MHz,DMSO-d6)δ173.02,155.76,146.64,141.92,135.79,131.77,130.94,129.98,129.54,128.92,128.35,128.16,127.60,127.41,126.39,124.30,113.67,69.99,60.69,55.37,48.04,46.26,44.98,22.72,22.31,11.58,10.77。
实施例3：N-(5-氯-2-丙氧基苄基)-N-(2-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)环丙烷甲酰胺(A03)
合成方法参考实施例1，总收率44.0％。1H-NMR(400MHz,DMSO-d6)δ7.91–7.77(m,1H),7.53–7.45(m,1H),7.40–7.27(m,3H),7.25–7.04(m,3H),6.97–6.80(m,2H),4.82(s,1H),4.57(s,2H),4.35(s,1H),3.84(t,J＝6.3Hz,1H),3.75(t,J＝6.5Hz,1H),2.76(dd,J＝12.0,6.2Hz,2H),1.99–1.79(m,1H),1.62–1.34(m,4H),0.90–0.70(m,10H)。13C NMR(126MHz,DMSO-d6)δ174.05,155.69,146.68,141.88,136.40,131.87,131.63,131.01,129.87,128.81,128.60,128.45,127.91,127.56,127.47,126.72,124.33,113.68,69.84,49.42,47.00,44.99,44.97,22.70,11.57,11.25,10.81,8.18。
实施例4：N-(5-氯-2-丙氧基苄基)-N-(3-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)苯并呋喃-2-甲酰胺(A04)
合成方法参考实施例1，总收率42.9％。1H-NMR(400MHz,DMSO-d6)δ7.85(t,J＝5.7Hz,1H),7.70(d,J＝7.9Hz,1H),7.62–7.54(m,2H),7.54–7.49(m,2H),7.47(d,J＝3.9Hz,1H),7.44–7.32(m,3H),7.31–7.14(m,4H),6.97–6.81(m,1H),4.99–4.81(m,2H),4.71–4.55(m,2H),3.86–3.70(m,2H),2.82–2.74(m,2H),1.60–1.33(m,4H),0.78(t,J＝7.4Hz,6H)。13C-NMR(126MHz,DMSO-d6)δ161.27,155.84,154.46,138.95,132.75,131.99,131.49,128.73,127.20,127.06,124.42,124.19,123.03,113.74,112.14,111.71,69.99,45.05,22.73,22.27,11.60,10.66。
实施例5：2-溴-N-(5-氯-2-丙氧基苄基)-N-(3-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)乙酰胺(A05)
合成方法参考实施例1，总收率46.0％。1H-NMR(400MHz,DMSO-d6)δ7.85(t,J＝5.8Hz,1H),7.65–7.47(m,3H),7.47–7.28(m,2H),7.26–7.17(m,1H),7.16–7.07(m,1H),6.91(d,J＝8.7Hz,1H),4.65(d,J＝9.7Hz,1H),4.59–4.45(m,2H),4.38(d,J＝5.9Hz,1H),4.30(d,J＝5.2Hz,1H),3.85–3.76(m,2H),2.82–2.73(m,2H),1.66–1.49(m,2H),1.47–1.34(m,2H),0.86–0.74(m,6H)。13C-NMR(126MHz,DMSO-d6)δ172.87,155.83,149.10,140.67,139.37,132.65,130.13,129.67,128.87,128.33,127.77,126.88,125.61,125.34,124.83,124.43,113.72,70.06,60.68,49.81,48.50,45.05,22.74,22.34,11.61,10.71。
实施例6：N-(5-氯-2-丙氧基苄基)-N-(3-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)环丙烷甲酰胺(A06)
合成方法参考实施例1，总收率47.0％。1H-NMR(400MHz,DMSO-d6)δ7.89–7.83(m,1H),7.62–7.51(m,2H),7.49–7.37(m,3H),7.34(t,J＝7.7Hz,1H),7.25–7.13(m,2H),7.03(dd,J＝6.9,2.7Hz,1H),6.91(dd,J＝11.8,8.8Hz,1H),4.81(s,1H),4.64(s,1H),4.53(s,1H),4.44(s,1H),3.87–3.76(m,2H),2.83–2.76(m,2H),2.05–1.84(m,1H),1.67–1.52(m,2H),1.45–1.35(m,2H),0.86–0.69(m,10H)。13C-NMR(126MHz,DMSO-d6)δ173.87,155.72,149.12,140.66,139.81,132.92,132.76,130.09,128.56,128.25,127.88,127.58,125.69,125.16,124.61,124.49,124.31,113.76,70.03,50.98,45.05,44.23,22.74,22.38,11.60,11.40,10.78,10.75,8.12。
实施例7：N-(5-氯-2-丙氧基苄基)-N-(4-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)苯并呋喃-2-甲酰胺(A07)
合成方法参考实施例1，总收率54.0％。1H-NMR(400MHz,DMSO-d6)δ7.90–7.82(m,1H),7.80–7.61(m,4H),7.60–7.49(m,3H),7.48–7.37(m,2H),7.37–7.20(m,4H),7.18–6.89(m,1H),4.93(s,1H),4.86(s,1H),4.64(s,1H),4.57(s,1H),3.87(s,1H),3.81(s,1H),2.79(d,J＝6.5Hz,2H),1.60(s,1H),1.51(s,1H),1.44–1.33(m,2H),0.83–0.68(m,6H)。13C-NMR(126MHz,DMSO-d6)δ161.15,155.80,154.45,140.40,138.62,132.80,128.95,127.21,127.12,127.03,124.41,124.32,124.18,123.02,113.84,112.14,111.73,70.03,45.05,30.27,29.46,22.74,14.39,11.60,10.74。
实施例8：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4-(5-(N-丙基氨基磺酰基)噻吩-2-基)苄基)乙酰胺(A08)
合成方法参考实施例1，总收率58.0％。1H-NMR(400MHz,DMSO-d6)δ7.83(t,J＝5.8Hz,1H),7.70(d,J＝7.8Hz,2H),7.65(d,J＝11.9Hz,2H),7.58–7.50(m,4H),7.42–7.38(m,2H),7.32(d,J＝8.1Hz,3H),7.30–7.22(m,2H),4.93(s,1H),4.86(s,1H),4.64(s,1H),4.58(s,1H),3.84(s,2H),2.84–2.75(m,2H),1.65–1.48(m,3H),1.45–1.36(m,3H),0.79(t,J＝7.4Hz,6H)。13C-NMR(126MHz,DMSO-d6)δ172.72,155.77,149.03,140.44,139.01,132.78,131.45,128.87,128.27,128.03,126.90,126.27,124.39,124.23,113.69,69.96,60.66,48.27,45.05,43.88,22.75,22.33,11.61。
实施例9：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)甲基)苯并呋喃-2-甲酰胺(A09)
合成方法参考实施例1，总收率59.0％。1H-NMR(400MHz,DMSO-d6)δ7.71(dd,J＝11.9,7.6Hz,3H),7.57(d,J＝6.5Hz,2H),7.48–7.36(m,5H),7.36–7.29(m,3H),7.27(d,J＝7.6Hz,1H),7.21(d,J＝6.9Hz,1H),7.14(s,1H),6.92–6.69(m,1H),4.85(s,1H),4.63(s,1H),4.53(s,1H),4.46(s,1H),3.79(s,1H),3.73(s,1H),2.68–2.52(m,2H),1.57–1.31(m,4H),0.81–0.64(m,6H)。13C-NMR(126MHz,DMSO-d6)δ155.79,154.42,148.57,129.99,128.84,127.12,127.03,126.82,124.13,122.98,113.59,112.14,69.90,49.04,44.70,22.83,11.56,10.69。
实施例10：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基甲基)乙酰胺(A10)
合成方法参考实施例1，总收率42.0％。1H-NMR(400MHz,DMSO-d6)δ7.73(dd,J＝13.7,7.9Hz,2H),7.66–7.55(m,1H),7.47–7.26(m,4H),7.25–7.10(m,3H),6.95–6.68(m,2H),5.52(s,3H),4.41–4.31(m,2H),4.30–4.13(m,3H),4.10–4.00(m,1H),3.83–3.71(m,2H),2.70–2.58(m,2H),1.64–1.42(m,2H),1.42–1.28(m,2H),0.87–0.70(m,6H)。13C-NMR(126MHz,DMSO-d6)δ172.87,155.74,144.28,139.99,134.58,130.49,130.04,128.85,128.58,128.25,127.90,127.47,127.27,126.73,126.23,124.16,113.57,69.96,60.65,47.88,45.76,44.74,22.88,22.30,11.58,10.77。
实施例11：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-甲基)环丙烷甲酰胺(A11)
合成方法参考实施例1，总收率45.3％。1H-NMR(400MHz,DMSO-d6)δ7.76(d,J＝8.3Hz,1H),7.71(d,J＝8.1Hz,1H),7.67–7.55(m,1H),7.48(d,J＝8.1Hz,1H),7.45–7.31(m,3H),7.23(t,J＝6.0Hz,1H),7.20–7.10(m,2H),6.92–6.72(m,2H),4.67(d,J＝11.1Hz,1H),4.43(d,J＝14.8Hz,2H),4.30(d,J＝11.1Hz,1H),3.86–3.70(m,2H),2.73–2.59(m,2H),1.86(d,J＝10.3Hz,1H),1.67–1.55(m,1H),1.54–1.41(m,1H),1.42–1.33(m,2H),0.89–0.69(m,10H)。13C-NMR(126MHz,DMSO-d6)δ173.91,155.62,144.36,140.07,139.65,135.27,130.39,130.06,128.91,128.64,128.20,127.77,127.50,126.87,126.63,124.20,113.46,69.89,49.04,46.48,44.77,44.52,22.83,11.58,11.29,10.85,8.17。
实施例12：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯基]-3-基)甲基)苯并呋喃-2-甲酰胺(A12)
合成方法参考实施例1，总收率50％。1H-NMR(400MHz,DMSO-d6)δ7.87–7.67(m,5H),7.65–7.48(m,4H),7.41(d,J＝10.0Hz,3H),7.34–7.12(m,4H),6.98–6.80(m,1H),4.97(s,1H),4.88(s,1H),4.70(s,1H),4.62(s,1H),3.81(s,1H),3.73(s,1H),2.74–2.61(m,2H),1.62–1.40(m,2H),1.40–1.28(m,2H),0.84–0.58(m,6H)。13C-NMR(126MHz,DMSO-d6)δ161.26,155.84,154.45,148.72,139.94,138.56,128.68,127.78,127.55,127.17,127.08,124.38,124.18,123.02,113.77,112.14,111.64,69.98,49.04,44.83,22.86,11.59,10.65。
实施例13：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)甲基)乙酰胺(A13)
合成方法参考实施例1，总收率44.9％。1H-NMR(400MHz,DMSO-d6)δ7.80(d,J＝6.6Hz,2H),7.78–7.68(m,2H),7.62–7.49(m,1H),7.48–7.40(m,1H),7.39–7.30(m,1H),7.19(dd,J＝8.7,2.7Hz,1H),7.15(t,J＝2.2Hz,1H),7.10(dd,J＝16.4,2.8Hz,1H),6.86(d,J＝8.9Hz,1H),4.67(s,1H),4.49(d,J＝10.2Hz,2H),4.39(s,1H),4.25(d,J＝4.2Hz,2H),3.79–3.71(m,2H),2.66(t,J＝7.1Hz,2H),1.60–1.46(m,2H),1.38–1.28(m,2H),0.79–0.71(m,6H)。13C-NMR(126MHz,DMSO-d6)δ172.88,155.93,144.17,139.99,139.32,138.97,138.40,129.87,129.45,129.09,128.85,128.42,128.28,127.84,127.54,126.94,126.69,126.45,126.08,124.43,113.68,70.09,60.82,49.04,44.84,29.02,22.87,22.30,11.60,10.70。
实施例14：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)甲基)环丙烷甲酰胺(A14)
合成方法参考实施例1，总收率46.7％。1H-NMR(400MHz,DMSO-d6)δ7.82(dd,J＝8.2,4.0Hz,2H),7.76(t,J＝7.4Hz,2H),7.65–7.52(m,2H),7.51–7.35(m,2H),7.30–7.15(m,2H),7.05(d,J＝12.4Hz,1H),6.96–6.87(m,1H),4.84(s,1H),4.65(s,1H),4.57(s,1H),4.47(s,1H),3.90–3.73(m,2H),2.74–2.62(m,2H),2.07–1.83(m,1H),1.66–1.51(m,2H),1.42–1.28(m,2H),0.87–0.64(m,11H)。13C-NMR(126MHz,DMSO-d6)δ173.85,155.53,144.02,140.01,139.31,139.04,129.85,128.49,128.33,128.23,128.14,127.96,127.75,127.56,127.04,126.35,126.18,125.92,124.35,113.68,69.93,51.24,46.02,44.84,22.87,22.35,11.59,10.73,8.23。
实施例15：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-4-基)甲基)苯并呋喃-2-甲酰胺(A15)
合成方法参考实施例1，总收率67.2％。1H-NMR(400MHz,DMSO-d6)δ7.97–7.81(m,4H),7.80–7.68(m,3H),7.68–7.56(m,2H),7.50–7.36(m,4H),7.30(dd,J＝16.4,8.6Hz,2H),7.06–6.91(m,1H),5.00(s,1H),4.91(s,1H),4.71(s,1H),4.63(s,1H),3.88(d,J＝16.9Hz,2H),2.82–2.66(m,2H),1.72–1.51(m,2H),1.49–1.34(m,2H),0.94–0.72(m,6H)。13C-NMR(126MHz,DMSO-d6)δ161.17,155.81,154.47,139.85,137.96,128.88,128.63,128.37,127.69,127.58,127.21,127.18,127.05,124.43,124.19,123.03,113.85,112.15,111.72,70.04,49.04,44.84,22.89,22.27,11.59,10.74。
实施例16：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-4-基甲基)乙酰胺(A16)
合成方法参考实施例1，总收率62.3％。1H-NMR(400MHz,DMSO-d6)δ7.88–7.77(m,4H),7.70(d,J＝8.0Hz,1H),7.61(t,J＝7.3Hz,2H),7.31–7.19(m,3H),7.13–7.00(m,1H),6.94(d,J＝8.8Hz,1H),4.55(s,1H),4.50(s,1H),4.44(s,1H),4.38(s,1H),3.90–3.81(m,2H),2.73–2.64(m,2H),1.68–1.55(m,2H),1.42–1.30(m,2H),0.90–0.79(m,3H),0.77(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ172.86,155.79,143.93,139.88,138.33,137.85,128.71,128.28,127.98,127.82,127.74,127.68,127.56,127.40,126.95,124.49,113.86,70.09,60.72,49.59,44.97,43.95,22.89,22.35,11.60,10.79。
实施例17：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)苯并呋喃-2-甲酰胺(A17)
合成方法参考实施例1，总收率52.3％。1H-NMR(400MHz,DMSO-d6)δ7.71(d,J＝8.1Hz,2H),7.65(d,J＝5.6Hz,1H),7.56(d,J＝7.8Hz,1H),7.47(d,J＝7.7Hz,3H),7.36(s,3H),7.34–7.28(m,2H),7.28–7.18(m,2H),7.11(d,J＝7.9Hz,1H),6.87(d,J＝8.8Hz,1H),6.44(s,1H),5.01(d,J＝14.8Hz,1H),4.14(d,J＝14.8Hz,1H),3.80–3.61(m,2H),2.75–2.63(m,2H),1.50–1.43(m,2H),1.34(d,J＝7.1Hz,2H),0.83–0.76(m,6H)。13C-NMR(126MHz,DMSO-d6)δ159.85,155.77,154.18,148.25,142.41,140.28,139.70,137.93,131.52,129.90,129.77,129.45,129.34,128.97,127.52,127.15,126.93,126.66,124.16,124.10,123.21,113.75,112.53,111.92,69.85,47.54,44.80,26.79,22.83,22.24,11.60,10.77。
实施例18：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)环丙烷甲酰胺(A18)
合成方法参考实施例1，总收率49.6％。1H-NMR(400MHz,DMSO-d6)δ7.80(d,J＝8.4Hz,2H),7.65(t,J＝5.8Hz,1H),7.50–7.43(m,4H),7.42–7.37(m,1H),7.18(dd,J＝8.7,2.7Hz,1H),7.11–7.07(m,1H),7.02(d,J＝2.7Hz,1H),6.82(d,J＝8.9Hz,1H),4.78(d,J＝14.9Hz,1H),3.85(d,J＝14.9Hz,1H),3.74–3.66(m,1H),3.65–3.55(m,1H),2.74–2.65(m,2H),1.45–1.31(m,5H),0.84–0.70(m,10H)。13C-NMR(126MHz,DMSO-d6)δ173.31,155.63,142.75,140.23,139.90,138.64,131.57,130.42,129.86,129.62,129.60,129.04,128.63,127.45,127.09,126.83,124.04,113.64,69.72,46.32,44.83,22.84,22.26,12.92,11.58,10.75,9.00,8.86。
实施例19：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)乙酰胺(A19)
合成方法参考实施例1，总收率54.9％。1H-NMR(400MHz,DMSO-d6)δ7.82(d,J＝7.9Hz,2H),7.72–7.66(m,1H),7.52–7.46(m,3H),7.44–7.24(m,2H),7.22–7.13(m,3H),6.83(d,J＝8.7Hz,1H),4.73(d,J＝15.1Hz,1H),4.07(d,J＝12.1Hz,1H),3.93(d,J＝12.0Hz,1H),3.75(d,J＝15.1Hz,1H),3.73–3.57(m,2H),2.74–2.66(m,2H),1.48–1.29(m,4H),0.78–0.72(m,6H)。13C-NMR(126MHz,DMSO-d6)δ166.68,155.53,142.31,140.53,138.84,137.91,131.83,129.90,129.83,129.70,129.66,129.60,129.38,129.24,128.81,127.24,126.87,126.57,124.14,113.64,69.90,69.76,50.32,46.74,44.83,29.20,22.83,22.22,11.62,11.58,10.76,10.73。
实施例20：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-2-(噻吩-3-基)乙酰胺(A20)
合成方法参考实施例1，总收率47.8％。1H-NMR(400MHz,DMSO-d6)δ7.82–7.77(m,2H),7.69–7.58(m,1H),7.49–7.45(m,2H),7.45–7.35(m,4H),7.34–7.25(m,1H),7.21–7.14(m,1H),7.11–7.08(m,1H),7.08–7.04(m,1H),6.85–6.79(m,2H),4.76(d,J＝15.2Hz,1H),3.73(d,J＝15.2Hz,1H),3.70–3.54(m,3H),3.47(d,J＝15.7Hz,1H),2.74–2.66(m,2H),1.46–1.28(m,4H),0.80–0.69(m,6H)。13C-NMR(126MHz,DMSO-d6)δ170.59,155.53,142.66,140.37,139.69,137.91,135.34,131.71,130.45,129.72,129.54,129.32,129.28,129.25,129.09,128.60,127.25,127.21,126.18,124.12,123.12,113.61,69.73,46.24,44.82,35.75,22.84,22.21,11.58,10.72。
实施例21：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯基]-3-基)苯并呋喃-2-甲酰胺(A21)
合成方法参考实施例1，总收率55.3％。1H-NMR(400MHz,DMSO-d6)δ8.09–7.53(m,9H),7.53–7.06(m,7H),7.06–6.40(m,1H),5.12(s,2H),3.76(s,2H),2.69(s,2H),1.68–1.27(m,4H),0.81(s,6H)。13C-NMR(126MHz,DMSO-d6)δ159.66,155.89,154.13,148.44,143.03,142.98,140.24,140.00,130.33,129.90,128.89,128.34,127.78,127.56,127.25,127.17,126.93,126.79,126.74,124.22,124.00,123.08,113.80,112.28,111.91,69.96,48.28,44.82,22.86,22.28,11.58,10.76。
实施例22：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)环丙烷甲酰胺(A22)
合成方法参考实施例1，总收率46.8％。1H-NMR(400MHz,DMSO-d6)δ7.87–7.77(m,4H),7.68–7.58(m,3H),7.47(t,J＝7.8Hz,1H),7.26–7.13(m,3H),6.88(d,J＝9.0Hz,1H),4.89(s,2H),3.76–3.66(m,2H),2.73–2.63(m,2H),1.46–1.29(m,5H),0.86–0.71(m,10H)。13C-NMR(126MHz,DMSO-d6)δ172.83,155.74,143.40,143.17,140.27,140.21,130.54,129.58,128.56,128.47,128.04,127.87,127.61,127.01,126.46,124.13,113.73,69.86,44.83,22.87,22.27,12.96,11.58,10.75,8.70。
实施例23：2-溴-N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)乙酰胺(A23)
合成方法参考实施例1，总收率46％。1H-NMR(400MHz,DMSO-d6)δ7.83(s,4H),7.70(d,J＝8.7Hz,2H),7.63(t,J＝5.9Hz,1H),7.48(t,J＝7.7Hz,1H),7.30(dd,J＝14.0,5.1Hz,2H),7.21(dd,J＝8.7,2.7Hz,1H),6.89(d,J＝8.9Hz,1H),4.85(s,2H),3.92(s,1H),3.70(t,J＝6.3Hz,2H),2.71–2.64(m,2H),1.50–1.41(m,2H),1.38–1.31(m,2H),0.76(t,J＝7.4Hz,6H)。13C-NMR(126MHz,DMSO-d6)δ171.90,155.72,143.10,140.24,130.54,129.60,128.65,127.89,127.61,127.55,124.22,113.72,69.87,60.73,55.36,47.31,44.83,22.86,22.23,11.58。
实施例24：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A24)
合成方法参考实施例1，总收率60.5％。1H-NMR(400MHz,DMSO-d6)δ7.81(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,2H),7.69–7.58(m,2H),7.52(s,1H),7.45(t,J＝7.8Hz,1H),7.39(d,J＝4.2Hz,1H),7.27(s,1H),7.18(t,J＝7.9Hz,2H),7.02(s,1H),6.90–6.80(m,2H),4.86(s,2H),3.69(t,J＝6.6Hz,2H),3.50(s,2H),2.73–2.60(m,2H),1.46–1.30(m,4H),0.79–0.72(m,6H)。13C-NMR(126MHz,DMSO-d6)δ170.14,155.69,143.23,143.14,140.23,140.12,135.79,130.48,129.53,129.17,128.56,128.46,127.83,127.52,127.31,126.76,125.98,124.18,122.79,113.69,69.85,44.83,35.89,22.87,22.23,11.59,10.72。
实施例25：N-(5-氯-2-(2，2-二氟丙氧基)苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯基]-2-基)-2-(噻吩-3-基)乙酰胺(A25)
合成方法参考实施例1，总收率49.0％。1H-NMR(400MHz,DMSO-d6)δ7.79(d,J＝7.9Hz,2H),7.71–7.59(m,1H),7.49–7.25(m,6H),7.21(dd,J＝8.8,2.4Hz,1H),7.15(d,J＝7.8Hz,1H),7.06(t,J＝3.8Hz,2H),6.91(d,J＝8.8Hz,1H),6.85(d,J＝4.9Hz,1H),4.83(d,J＝15.5Hz,1H),4.17–3.88(m,2H),3.75(d,J＝15.4Hz,1H),3.66(d,J＝15.8Hz,1H),3.51(d,J＝15.8Hz,1H),2.74–2.66(m,2H),1.55–1.42(m,3H),1.40–1.31(m,2H),0.76(t,J＝7.3Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.68,154.37,142.58,140.39,139.46,138.00,135.26,131.83,130.42,129.86,129.52,129.40,129.28,129.09,128.63,127.37,127.20,126.19,125.39,123.19,122.38,114.30,69.60,46.26,44.80,35.77,22.86,20.77,11.57。
实施例26：(S)2-(2-氨基丁氧基)-5-氯苄基-N-(4-丙基氨基磺酰基)-2-噻吩-3-乙酰胺盐酸盐(A26)
合成方法参考实施例1，总收率46.0％。1H-NMR(400MHz,DMSO-d6)δ8.15(s,3H),7.83(t,J＝8.2Hz,2H),7.77–7.71(m,1H),7.55–7.50(m,4H),7.47–7.42(m,2H),7.29–7.23(m,1H),7.10–7.00(m,2H),6.98–6.89(m,2H),6.85–6.78(m,1H),5.23–4.92(m,1H),4.22–4.09(m,1H),4.04–3.80(m,2H),3.63–3.56(m,1H),3.41(s,1H),3.34(s,2H),3.20–3.06(m,1H),2.78–2.71(m,2H),1.65–1.46(m,2H),1.44–1.35(m,2H),0.95–0.86(m,3H),0.81(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.84,170.69,154.77,142.49,140.37,139.87,138.39,135.16,131.84,129.99,129.82,129.76,129.51,129.22,129.15,128.77,127.45,127.20,126.30,124.97,123.26,113.85,67.47,51.73,47.65,44.84,35.84,22.90,22.59,11.62,10.14。
实施例27：2-氨基丙氧基-5-氯苄基-4-丙基氨基磺酰基-1，1-联苯-2-基)-2-噻吩-3-乙酰胺(A27)
合成方法参考实施例1，总收率51.5％。1H-NMR(400MHz,DMSO-d6)δ7.79(dd,J＝8.3,3.5Hz,2H),7.46(d,J＝4.3Hz,2H),7.44–7.34(m,4H),7.16(dd,J＝8.7,2.7Hz,1H),7.09–7.03(m,2H),6.99(dd,J＝11.2,2.7Hz,1H),6.86–6.81(m,1H),4.93–4.78(m,1H),3.87–3.70(m,1H),3.65–3.52(m,2H),3.52–3.40(m,3H),2.88–2.79(m,1H),2.71(t,J＝7.1Hz,2H),1.40–1.30(m,2H),0.86(d,J＝6.5Hz,3H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.79,154.78,142.51,140.37,139.74,138.33,135.15,131.83,130.04,129.98,129.78,129.52,129.43,129.27,129.17,128.83,128.71,127.35,127.14,126.29,124.93,123.27,113.66,69.45,49.03,46.40,44.84,35.88,22.89,15.52,11.62。
实施例28：N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-2-噻吩-3-基-N-(4-三氟甲基)苄基乙酰胺(A28)
合成方法参考实施例1，总收率43.0％。1H-NMR(400MHz,DMSO-d6)δ7.84–7.79(m,2H),7.67(t,J＝5.9Hz,1H),7.58(d,J＝8.1Hz,2H),7.52–7.45(m,4H),7.40–7.35(m,2H),7.28(d,J＝8.1Hz,2H),7.06–7.00(m,2H),6.78(dd,J＝4.9,1.3Hz,1H),5.12(d,J＝15.1Hz,1H),3.78(d,J＝15.1Hz,1H),3.63–3.52(m,1H),3.45–3.37(m,1H),2.79–2.67(m,2H),1.44–1.30(m,2H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.53,142.61,142.33,140.40,139.60,138.16,135.18,131.96,130.32,129.93,129.75,129.48,129.25,128.35,128.10,127.21,126.17,126.11,125.74,125.61,125.58,125.55,123.27,123.17,51.96,44.84,35.70,35.62,22.85,11.60。
实施例29：N-(4-氟苄基)-N-(4'-(正丙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A29)
合成方法参考实施例1，总收率59.0％。1H-NMR(400MHz,DMSO-d6)δ7.84–7.74(m,4H),7.69–7.60(m,2H),7.46(dd,J＝15.7,7.9Hz,2H),7.39(d,J＝4.1Hz,1H),7.22(dd,J＝8.3,5.5Hz,2H),7.15–7.00(m,4H),6.86(d,J＝4.8Hz,1H),4.90(s,2H),3.51(s,2H),2.71–2.64(m,2H),1.41–1.30(m,2H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.16,162.75,160.81,143.07,142.98,140.27,140.23,135.81,134.17,134.15,130.59,129.22,128.66,127.92,127.53,127.38,126.88,125.99,122.83,115.63,115.46,51.79,44.84,35.85,22.88,11.59。
实施例30：N-(4-氰基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A30)
合成方法参考实施例1，总收率61.0％。1H-NMR(400MHz,DMSO-d6)δ7.84–7.77(m,4H),7.77–7.71(m,2H),7.70–7.61(m,2H),7.58(t,J＝2.0Hz,1H),7.50–7.36(m,4H),7.27–7.18(m,1H),7.05(s,1H),6.87(d,J＝5.2Hz,1H),5.00(s,2H),3.55(s,2H),2.71–2.63(m,2H),1.41–1.29(m,2H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.50,143.86,143.04,140.29,135.66,132.77,130.69,129.25,128.48,127.97,127.52,127.23,126.96,126.02,122.93,119.20,110.37,44.83,35.75,22.87,11.60。
实施例31：N-(4-硝基苄基)-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A31)
合成方法参考实施例1，总收率41.0％。1H-NMR(400MHz,DMSO-d6)δ8.15–8.11(m,2H),7.83–7.77(m,4H),7.70–7.65(m,1H),7.65–7.59(m,2H),7.51(d,J＝8.7Hz,2H),7.46(d,J＝7.8Hz,1H),7.39(dd,J＝4.9,3.0Hz,1H),7.25–7.22(m,1H),7.06(s,1H),6.87(d,J＝4.7Hz,1H),5.06(s,2H),3.56(s,2H),2.71–2.63(m,2H),1.41–1.28(m,2H),0.81–0.72(m,3H)。13C-NMR(126MHz,DMSO-d6)δ170.54,147.11,146.01,143.03,140.39,140.29,135.63,130.72,129.49,129.25,128.47,127.99,127.52,127.20,127.01,126.04,123.98,122.96,52.27,44.83,35.75,22.87,11.59。
实施例32：N-(4'-(N-甲基氨基磺酰基)-[1，1'-联苯]-3-基)-2-噻吩-3-基-N-(4-三氟甲基)苄基乙酰胺(A32)
合成方法参考实施例1，总收率45.0％。1H-NMR(400MHz,DMSO-d6)δ7.78(d,J＝1.8Hz,4H),7.65(dd,J＝15.7,7.8Hz,3H),7.55–7.37(m,6H),7.22(d,J＝7.9Hz,1H),7.05(s,1H),6.87(d,J＝5.0Hz,1H),5.01(s,2H),3.55(s,2H),2.40(d,J＝5.0Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.41,143.22,143.04,142.89,140.30,138.91,135.69,130.69,129.41,129.24,129.17,128.57,128.33,128.08,127.99,127.71,127.29,126.98,126.16,126.03,125.71,125.68,123.26,122.92,52.28,35.78,35.72,29.10,22.53。
实施例33：N-(4'-(N-乙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-噻吩-3-基-N-(4-三氟甲基)苄基)乙酰胺(A33)
合成方法参考实施例1，总收率43.9％。1H-NMR(400MHz,DMSO-d6)δ7.83–7.73(m,4H),7.69–7.59(m,4H),7.53(t,J＝1.9Hz,1H),7.45(dd,J＝10.3,8.0Hz,3H),7.39(dd,J＝4.9,3.0Hz,1H),7.21(dd,J＝7.7,1.9Hz,1H),7.08–7.01(m,1H),6.87(d,J＝4.9Hz,1H),5.01(s,2H),3.54(s,2H),2.80–2.72(m,2H),1.31–1.16(m,2H),0.95(t,J＝7.2Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.41,143.09,143.03,142.89,140.31,140.22,135.69,130.69,129.24,129.18,128.54,128.34,128.09,127.95,127.53,127.29,126.97,126.02,125.79,125.71,125.68,125.65,123.63,122.92,38.00,35.78,15.19。
实施例34：4-氟-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-3-基)-N-(4-三氟甲基苄基)苯甲酰胺(A34)
合成方法参考实施例1，总收率47.9％。1H-NMR(400MHz,DMSO-d6)δ7.78(d,J＝8.0Hz,2H),7.72–7.59(m,5H),7.55(d,J＝6.2Hz,3H),7.48–7.39(m,3H),7.26(t,J＝7.8Hz,1H),7.11–7.00(m,3H),5.25(s,2H),2.70–2.62(m,2H),1.39–1.29(m,2H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ169.48,163.88,161.91,143.73,143.02,142.71,140.24,139.79,132.80,132.77,131.56,131.49,130.19,129.08,128.09,127.83,127.49,126.64,125.78,125.75,125.72,125.69,115.42,115.25,52.75,44.81,22.86,11.57。
实施例35：N-(4'-(N-己基氨基磺酰基)-[1，1'-联苯]-3-基)-2-噻吩-3-基-N-(4-三氟甲基)苄基)乙酰胺(A35)
合成方法参考实施例1，总收率46.0％。1H-NMR(400MHz,DMSO-d6)δ7.85–7.71(m,4H),7.70–7.57(m,4H),7.53–7.36(m,5H),7.22(d,J＝7.9Hz,1H),7.05(s,1H),6.87(d,J＝5.0Hz,1H),5.01(s,2H),3.55(s,2H),2.76–2.65(m,2H),1.37–1.25(m,2H),1.20–1.09(m,6H),0.75(t,J＝6.8Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.40,143.03,140.30,135.69,130.70,129.23,128.34,127.92,127.50,127.28,126.95,126.02,125.70,125.63,122.90,52.28,42.97,35.78,31.17,29.34,26.10,22.38,14.26。
实施例36：2-溴-N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-N-(4-三氟甲基)苄基)乙酰胺(A36)
合成方法参考实施例1，总收率51.0％。1H-NMR(400MHz,DMSO-d6)δ7.83(d,J＝7.9Hz,2H),7.69(t,J＝5.8Hz,1H),7.64–7.52(m,4H),7.52–7.45(m,2H),7.44–7.37(m,1H),7.31(dd,J＝8.2,2.6Hz,2H),7.22–7.08(m,1H),5.08(dd,J＝15.2,4.5Hz,1H),4.33–4.12(m,2H),4.09–3.92(m,1H),3.88–3.67(m,1H),2.76–2.67(m,2H),1.41–1.28(m,2H),0.76(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ172.27,166.62,142.54,142.09,141.63,140.53,138.22,138.09,131.98,130.31,130.14,129.90,129.82,129.70,129.62,129.34,129.31,127.22,125.63,125.58,61.07,51.79,44.84,22.86,11.58。
实施例37：N-(4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-N-(4-(三氟甲基)苄基)环丙烷甲酰胺(A37)
合成方法参考实施例1，总收率49.0％。1H-NMR(400MHz,DMSO-d6)δ7.81(d,J＝8.1Hz,2H),7.65(t,J＝5.9Hz,1H),7.59(d,J＝8.1Hz,2H),7.53(d,J＝8.2Hz,2H),7.50–7.44(m,2H),7.44–7.37(m,1H),7.27(d,J＝8.0Hz,2H),7.09(d,J＝7.8Hz,1H),5.14–5.05(m,1H),3.94–3.86(m,1H),2.75–2.67(m,2H),1.41–1.29(m,3H),0.76(t,J＝7.4Hz,4H),0.70–0.48(m,3H)。13C-NMR(126MHz,DMSO-d6)δ170.16,155.71,143.32,143.27,140.12,138.87,135.81,130.50,129.53,129.18,128.57,128.50,127.90,127.82,127.75,127.33,126.80,125.99,124.20,122.80,113.69,69.86,47.30,35.89,29.12,22.24,10.72。
实施例38：N-(4'-(10H-吩噻嗪-10-基)磺酰基)-[1，1'-联苯]-2-基甲基)-N-(5-氯-2-丙氧基苄基)环丙烷甲酰胺(A38)
合成方法参考实施例1，总收率49.8％。1H-NMR(400MHz,DMSO-d6)δ7.66(t,J＝7.1Hz,2H),7.51–7.40(m,3H),7.40–7.29(m,5H),7.29–7.17(m,3H),7.14–7.06(m,4H),7.00–6.87(m,2H),4.64(s,1H),4.54(s,1H),4.43(d,J＝5.9Hz,2H),3.88(t,J＝6.4Hz,1H),3.83(t,J＝6.3Hz,1H),1.96–1.76(m,1H),1.68–1.50(m,2H),0.87–0.78(m,5H),0.76–0.66(m,2H)。13C-NMR(126MHz,DMSO-d6)δ174.01,155.68,146.14,139.26,137.01,135.34,135.12,132.84,130.22,130.17,129.99,129.13,128.87,128.67,128.32,128.05,127.99,127.96,127.73,127.59,127.52,127.38,127.33,127.18,126.21,124.37,113.80,70.01,49.27,46.92,44.88,22.28,11.33,10.71,8.12。
实施例39：N-(5-氯-2-丙氧基苄基)-N-(4，4-二氢异喹啉-2(1H)-磺酰基)-[1，1'-联苯]-3-基)甲基)-2-噻吩-3-基乙酰胺(A39)
合成方法参考实施例1，总收率44.0％。1H-NMR(400MHz,DMSO-d6)δ7.84(d,J＝7.9Hz,2H),7.48–7.34(m,6H),7.17–7.01(m,9H),6.82(d,J＝5.0Hz,1H),6.78(d,J＝8.8Hz,1H),4.73(d,J＝15.1Hz,1H),4.20(d,J＝7.1Hz,2H),3.75–3.41(m,5H),3.29(d,J＝6.2Hz,3H),2.83(t,J＝6.0Hz,2H),1.39–1.28(m,2H),0.68(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.58,155.48,143.52,139.73,137.58,135.56,135.31,133.36,131.95,131.69,130.48,129.86,129.74,129.38,129.28,129.13,128.56,128.18,127.23,127.14,126.87,126.59,126.12,124.08,123.15,113.54,69.68,47.76,46.32,44.10,35.78,28.31,22.38,10.78。
实施例40：N-(5-氯-2-丙氧基苄基)-N-(3，4-二氢异喹啉-2(1H)-磺酰基)-[1，1'-联苯]-2-基)苯并呋喃-2-甲酰胺(A40)
合成方法参考实施例1，总收率55.0％。1H-NMR(400MHz,DMSO-d6)δ7.87–7.78(m,2H),7.75(t,J＝5.2Hz,2H),7.64(d,J＝7.9Hz,1H),7.60(s,1H),7.50(d,J＝7.8Hz,1H),7.43–7.25(m,4H),7.24–7.11(m,3H),7.10–6.97(m,4H),6.89(dd,J＝8.8,3.0Hz,1H),6.54(s,1H),5.06(s,2H),4.15(s,2H),3.25(t,J＝5.7Hz,2H),2.79(t,J＝5.9Hz,2H),2.64(s,1H),2.29(s,1H),1.50–1.36(m,2H),0.76–0.66(m,3H)。13C-NMR(126MHz,DMSO-d6)δ159.65,155.88,154.14,148.43,143.87,143.03,139.78,135.50,133.42,132.00,130.39,129.88,129.10,128.90,128.55,127.98,127.26,127.16,127.08,126.92,126.88,126.86,126.81,126.55,124.23,124.00,123.08,113.79,112.31,111.92,69.95,55.35,47.65,43.98,28.43,22.27,10.76。
实施例41：N-(5-氯-2-丙氧基苄基)-N-(3，4-二氢异喹啉-2(1H)-磺酰基)-[1，1'-联苯]-2-基)环丙烷甲酰胺(A41)
合成方法参考实施例1，总收率54.9％。1H-NMR(400MHz,DMSO-d6)δ7.90–7.80(m,4H),7.64(d,J＝7.9Hz,1H),7.60(d,J＝1.9Hz,1H),7.47(t,J＝7.9Hz,1H),7.25–7.16(m,3H),7.13–7.04(m,4H),6.89–6.83(m,1H),4.88(s,2H),4.20(s,2H),3.70(t,J＝6.4Hz,2H),3.29(d,J＝5.9Hz,2H),2.82(t,J＝6.0Hz,2H),1.49–1.29(m,3H),0.85–0.79(m,2H),0.75(t,J＝7.4Hz,3H),0.68–0.58(m,2H)。13C-NMR(126MHz,DMSO-d6)δ172.81,155.73,143.99,143.43,139.96,135.57,133.44,132.02,130.59,129.56,129.12,128.59,128.56,128.05,128.02,127.10,127.06,126.87,126.57,124.12,113.73,69.85,49.04,47.67,44.01,28.42,22.26,12.96,10.75,8.69,8.12。
实施例42：N-(5-氯-2-丙氧基苄基)-N-(3，4-二氢异喹啉-2(1H)-磺酰基)-[1，1'-联苯]-2-基)-2-噻吩-3-乙酰胺(A42)
合成方法参考实施例1，总收率62.3％。1H-NMR(400MHz,DMSO-d6)δ7.86(d,J＝8.5Hz,2H),7.79(d,J＝8.5Hz,2H),7.65(d,J＝7.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.45(t,J＝7.9Hz,1H),7.38(dd,J＝4.9,3.0Hz,1H),7.26(d,J＝2.7Hz,1H),7.18(dd,J＝8.7,2.6Hz,2H),7.14–7.04(m,4H),7.02–6.97(m,1H),6.85(dd,J＝12.3,6.8Hz,2H),4.85(s,2H),4.20(s,2H),3.68(t,J＝6.4Hz,2H),3.49(s,2H),3.29(d,J＝5.9Hz,2H),2.83(t,J＝6.0Hz,2H),1.49–1.32(m,2H),0.72(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.15,155.69,143.98,143.29,135.78,135.54,133.43,132.01,130.53,129.53,129.15,129.12,128.57,128.51,128.04,127.79,127.36,127.10,126.86,126.58,125.99,124.20,122.79,113.68,69.84,47.66,47.29,44.00,35.89,28.42,22.23,10.71。
实施例43：5-氯-2-丙氧基苄基-N-甲基氨基磺酰基-1，1-联苯-3-基)-2-噻吩-3-乙酰胺(A43)
合成方法参考实施例1，总收率46.0％。1H-NMR(400MHz,DMSO-d6)δ7.79(q,J＝8.3Hz,4H),7.66(d,J＝7.7Hz,1H),7.56–7.42(m,3H),7.39(s,1H),7.27(s,1H),7.18(d,J＝8.2Hz,2H),7.02(s,1H),6.87(d,J＝9.5Hz,2H),4.86(s,2H),3.70(d,J＝6.9Hz,2H),3.51(s,2H),2.41(d,J＝4.6Hz,3H),1.50–1.36(m,2H),0.76(d,J＝7.9Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.16,155.71,143.32,143.27,140.12,138.87,135.81,130.50,129.53,129.18,128.57,128.50,127.90,127.82,127.75,127.33,126.80,125.99,124.20,122.80,113.69,69.86,47.30,35.89,29.12,22.24,10.72。
实施例44：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-乙基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A44)
合成方法参考实施例1，总收率40.0％。1H-NMR(400MHz,DMSO-d6)δ7.82(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.66(d,J＝7.9Hz,1H),7.61(t,J＝5.7Hz,1H),7.52(s,1H),7.45(t,J＝7.9Hz,1H),7.41–7.36(m,1H),7.27(s,1H),7.18(dd,J＝6.2,2.8Hz,2H),7.02(s,1H),6.86(t,J＝7.3Hz,2H),4.86(s,2H),3.74–3.64(m,2H),3.50(s,2H),2.82–2.72(m,2H),1.49–1.35(m,2H),0.95(t,J＝7.2Hz,3H),0.74(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.16,155.71,143.25,143.20,140.17,135.81,130.49,129.54,129.17,128.57,128.48,127.86,127.82,127.57,127.33,126.79,125.99,124.20,122.80,113.69,69.86,55.35,38.01,35.89,22.24,15.20,10.72。
实施例45：N-(5-氯-2-丙氧基苄基)-N-(4'-(N-己基氨基磺酰基)-[1，1'-联苯]-3-基)-2-(噻吩-3-基)乙酰胺(A45)
合成方法参考实施例1，总收率45.0％。1H-NMR(400MHz,DMSO-d6)δ7.86–7.72(m,4H),7.70–7.56(m,2H),7.52(s,1H),7.49–7.36(m,2H),7.27(s,1H),7.22–7.13(m,2H),7.06–6.91(m,1H),6.86(t,J＝7.6Hz,2H),4.86(s,2H),3.75–3.58(m,2H),3.50(s,2H),2.76–2.66(m,2H),1.49–1.36(m,2H),1.36–1.25(m,2H),1.23–1.09(m,6H),0.76(t,J＝6.5Hz,6H)。13C-NMR(126MHz,DMSO-d6)δ170.15,155.71,143.26,140.27,135.80,130.49,129.53,129.13,128.57,127.82,127.55,127.30,126.77,125.98,124.20,122.79,113.69,69.85,47.29,42.98,35.89,31.17,29.34,26.11,22.38,14.27,10.71。
实施例46：N-(5-氯-2-丙氧基苄基)-N-(3'-氟-4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-2-(噻吩-3-基)乙酰胺(A46)
合成方法参考实施例1，总收率57.8％。1H-NMR(400MHz,DMSO-d6)δ7.96(t,J＝5.8Hz,1H),7.76(t,J＝7.9Hz,1H),7.50–7.46(m,2H),7.43–7.39(m,2H),7.18–7.14(m,2H),7.13–7.12(m,1H),7.10(dd,J＝5.1,1.5Hz,1H),7.08(d,J＝2.7Hz,1H),7.04–7.01(m,1H),6.82(dd,J＝4.9,1.3Hz,1H),6.79(d,J＝8.8Hz,1H),4.75(d,J＝15.1Hz,1H),3.85(d,J＝15.1Hz,1H),3.73–3.55(m,3H),3.52–3.46(m,1H),2.85–2.77(m,2H),1.45–1.30(m,4H),0.77–0.71(m,6H)。13C-NMR(126MHz,DMSO-d6)δ170.63,157.32,155.54,145.42,139.63,136.76,135.23,131.66,130.56,130.23,129.38,129.32,129.18,129.02,128.64,128.46,128.34,128.23,127.08,126.51,126.24,125.19,124.14,123.15,117.53,113.54,69.84,69.70,46.38,44.72,44.69,35.81,22.93,22.21,11.48,10.68。
实施例47：N-(5-氯-2-丙氧基苄基)-N-(2'-氟-4'-(N-丙基氨基磺酰基)-[1，1'-联苯]-2-基)-2-(噻吩-3-基)乙酰胺(A47)
合成方法参考实施例1，总收率48.0％。1H-NMR(400MHz,DMSO-d6)δ7.78(t,J＝5.8Hz,1H),7.68(dd,J＝4.1,1.6Hz,1H),7.67–7.64(m,1H),7.50–7.46(m,2H),7.45(d,J＝2.4Hz,1H),7.44–7.40(m,2H),7.15(dd,J＝8.7,2.7Hz,1H),7.09(dd,J＝2.5,1.3Hz,1H),7.04(d,J＝2.7Hz,1H),6.87(dd,J＝4.9,1.2Hz,1H),6.82(d,J＝8.8Hz,1H),4.75(d,J＝15.3Hz,1H),3.74–3.70(m,1H),3.68(t,J＝3.3Hz,1H),3.64(s,1H),3.37(d,J＝15.6Hz,1H),2.78–2.71(m,2H),1.47–1.38(m,2H),1.39–1.30(m,2H),0.78–0.76(m,3H),0.76–0.72(m,3H)。13C-NMR(126MHz,DMSO-d6)δ170.70,160.06,158.08,155.41,143.13,140.70,135.62,132.86,132.50,132.34,130.43,130.35,129.29,129.02,128.96,128.50,127.23,126.07,124.13,123.06,114.50,113.53,69.74,46.07,44.86,35.56,22.86,22.19,11.55,10.68。
实施例48：3-(5-氯-2-丙氧基苄基)-2-噻吩-3-基乙酰氨基)-N-丙基-1，1'-联苯-4-甲酰胺(A48)
a.中间体4-溴正丙基苯甲酰胺(21)的合成：
将4-溴苯甲酸(3g，14.92mmol)置于100mL茄形瓶中，加入20mL DCM溶解，冰浴降温后加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU，5.7g，17.91mmol)、三乙胺(3.1mL，22.38mmol)，反应30min后加入正丙胺(1.47mL，17.91mmol)，室温反应过夜。薄层色谱法检测反应完全。依次用饱和碳酸氢钠(NaHCO3，8mL)、1mol/L盐酸(HCl，8mL)、饱和氯化钠(NaCl，8mL)各洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥，15-20min后浓缩，经柱色谱分离得到中间体21，用于下一步合成(白色固体，2.8g，收率78.0％)。1H-NMR(400MHz,DMSO-d6)δ8.51(t,J＝5.7Hz,1H),7.77–7.72(m,2H),7.63(d,J＝8.6Hz,2H),3.20–3.13(m,2H),1.53–1.43(m,2H),0.84(t,J＝7.4Hz,3H)。
b.中间体2'-氨基-N-丙基-[1，1'-联苯]-4-甲酰胺(22)的合成：
依次将中间体21(840mg，3.49mmol)、(2-氨基苯基)硼酸(618mg，4.53mmol)、四(三苯基膦)钯(403mg，0.349mmol)置于100mL三颈烧瓶中，加入1，4-二氧六环(15mL)溶解，再向反应液中加入2mol/L碳酸钾水溶液(K2CO3，3mL)，氮气保护，105℃回流4h。薄层色谱法检测反应完全。将反应液中有机溶剂蒸干。加入乙酸乙酯溶解，再依次用饱和碳酸氢钠(NaHCO3，10mL)、1mol/L盐酸(HCl，10mL)、饱和氯化钠(NaCl，10mL)各洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体22(淡黄色油状物，600mg，收率67.6％，PE/EA＝7/1)。1H-NMR(400MHz,DMSO-d6)δ8.46(t,J＝5.7Hz,1H),7.92–7.86(m,2H),7.49–7.45(m,2H),7.06–7.00(m,1H),6.97(dd,J＝7.6,1.6Hz,1H),6.74(d,J＝8.0Hz,1H),6.61(t,J＝7.2Hz,1H),4.83(s,2H),3.24–3.17(m,2H),1.58–1.45(m,2H),0.86(t,J＝7.4Hz,3H)。
c.中间体2-(5-氯-2-丙氧基苄基)氨基-N-丙基-1，1-联苯-4-甲酰胺(23)的合成：
将中间体22(345mg，1.36mmol)和5-氯-2-丙氧基苯甲醛(323mg，1.63mmol)置于50mL茄形瓶中，加入甲醇(MeOH，5mL)溶解。室温反应2h。再将反应液冰浴降温后加入甲基橙、氰基硼氢化钠(NaBH3CN，513mg，8.16mmol)，滴入盐酸甲醇溶液(1:1)调PH至3-5。室温反应1-2h。薄层色谱法检测反应完全。将反应液蒸干后加入饱和NaHCO3(5mL)调PH至8-9，再加入EA萃取(5mL×3)。然后将有机相用饱和NaCl(5mL)洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥，15-20min后浓缩，经柱色谱分离得到中间体23(淡黄色固体，400mg，收率67.5％，PE/EA＝10：1)。1H-NMR(400MHz,DMSO-d6)δ8.47(t,J＝5.7Hz,1H),7.95–7.89(m,2H),7.47–7.42(m,2H),7.22–7.15(m,2H),7.08(ddd,J＝8.5,7.4,1.6Hz,1H),6.99–6.93(m,2H),6.64(td,J＝7.4,1.0Hz,1H),6.53(dd,J＝8.3,1.1Hz,1H),4.19(dd,J＝13.1,6.3Hz,2H),3.87(t,J＝6.5Hz,2H),3.24–3.18(m,2H),1.63–1.45(m,4H),0.87(td,J＝7.4,4.2Hz,6H)。
d.目标化合物3-(5-氯-2-丙氧基苄基)-2-噻吩-3-基乙酰氨基)-N-丙基-1，1'-联苯-4-甲酰胺(A48)的合成：
将23(100mg，0.23mmol)置于25mL茄形瓶中，加入DCM(2mL)溶解，再加入三乙胺(48μL，0.344mmol)、N2保护，-5℃降温后加入噻吩乙酸(30μL，0.344mmol)，反应2h。薄层色谱法检测反应完全。将反应液用饱和NaCl(5mL)洗1次，然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到目标化合物A48(白色固体，80mg，收率62.5％，PE/EA＝6/1)。1H-NMR(400MHz,DMSO-d6)δ8.53(t,J＝5.7Hz,1H),7.95–7.89(m,2H),7.71–7.61(m,3H),7.52–7.40(m,3H),7.33–7.27(m,1H),7.25–7.16(m,2H),7.06(s,1H),6.90(t,J＝7.2Hz,2H),4.90(s,2H),3.72(t,J＝6.7Hz,2H),3.54(s,2H),3.27–3.20(m,2H),1.60–1.51(m,2H),1.51–1.40(m,2H),0.90(t,J＝7.4Hz,3H),0.79(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ170.16,166.06,155.71,143.19,141.90,140.80,135.84,134.29,130.40,129.50,129.17,128.54,128.24,127.99,127.86,127.07,126.90,126.60,125.98,124.21,122.77,113.69,69.86,41.46,35.87,22.86,22.24,11.93,10.73。
实施例49：2-(2-溴-N-(5-氯-2-丙氧基苄基)乙酰氨基)-N-丙基-1，1-联苯-4-甲酰胺(A49)。
具体合成方法参考实施例48，总收率53.0％。1H-NMR(400MHz,DMSO-d6)δ8.59–8.41(m,1H),8.00–7.77(m,2H),7.53–7.26(m,5H),7.23–7.08(m,3H),6.90–6.77(m,1H),4.83–4.69(m,1H),4.16–3.87(m,2H),3.86–3.54(m,3H),3.27–3.13(m,2H),1.63–1.37(m,4H),0.94–0.84(m,4H),0.82–0.68(m,3H)。13C-NMR(126MHz,DMSO-d6)δ172.29,166.01,155.53,141.37,138.50,138.10,134.29,131.67,130.23,129.45,129.32,128.59,128.55,127.93,127.26,124.13,113.60,69.71,61.06,46.14,41.46,22.84,22.22,11.91,10.68。
实施例50：N-(3'-(N-(5-氯-2-丙氧基苄基)-2-(噻吩-3-基)乙酰氨基)-[1，1'-联苯]-4-基)磺酰基丙酰胺(A50)
a.中间体4-溴苯磺酰胺(24)的合成：
将4-溴苯磺酰氯(2g，7.83mmol)置于100mL茄形瓶中，加入四氢呋喃(20mL)溶解。冰浴降温后加入氨水(3.6mL，93.96mmol)，室温反应1-1.5h。薄层色谱法检测反应完全。将反应液旋干后加入DCM和水，抽滤，取滤饼真空干燥，无需纯化得到中间体24，直接投下一步(白色固体，1.5g，收率81.5％)。1H-NMR(400MHz,DMSO-d6)δ7.75(d,J＝12.7Hz,1H),7.45(s,1H)。
b.中间体(4'-氨基磺酰基-[1，1'-联苯]-3-基)氨基甲酸叔丁酯(25)的合成：
将中间体24(900mg，3.83mmol)、(3-((叔丁氧羰基)氨基)苯基)硼酸(1.36g，5.75mmol)和四(三苯基膦)钯(442mg，0.383mmol)置于三颈烧瓶中，加入1，4-二氧六环溶解(15mL)，再加入2mol/L K2CO3水溶液(3mL)，氮气保护，105℃回流4h。薄层色谱法检测反应完全。将反应液中有机溶剂蒸干。加入乙酸乙酯溶解，再依次用饱和碳酸氢钠(NaHCO3，8mL)、1mol/L盐酸(HCl，8mL)、饱和氯化钠(NaCl，8mL)各洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体25(黄色固体，900mg，收率69.2％，PE/EA＝15/1)。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.90–7.85(m,2H),7.83(t,J＝1.9Hz,1H),7.76–7.71(m,2H),7.44(dd,J＝2.6,1.3Hz,1H),7.37(d,J＝5.4Hz,2H),7.33(d,J＝7.9Hz,1H),7.29–7.25(m,1H),1.45(s,9H)。
c.中间体4'-(N-丙酰基氨基磺酰基)-[1，1'-联苯]-3-基)氨基甲酸叔丁酯(26)的合成：
将正丙酸(139μL，1.867mmol)溶于四氢呋喃(15mL)，加入N,N-羰基二咪唑(CDI，303mg，1.867mmol)，氮气保护，70℃回流1h。然后将反应液降至室温，向反应液中加入中间体25(500mg，1.436mmol)和1，8-二氮杂二环十一碳-7-烯(DBU，536μL，3.59mmol)，室温反应4h。薄层色谱法检测反应完全。将四氢呋喃旋干，加入DCM溶解，再依次用水(5mL)、饱和氯化钠(NaCl，8mL)各洗1次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体26(白色固体，500mg，收率66.0％，PE/EA＝5/1)。1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),9.49(s,1H),7.96(ddd,J＝8.5,4.3,2.4Hz,4H),7.88–7.52(m,7H),7.45(d,J＝7.9Hz,2H),7.40–7.32(m,2H),7.29(tt,J＝6.2,2.4Hz,2H),2.21(dd,J＝9.0,5.8Hz,4H),1.46(dd,J＝4.4,2.7Hz,18H),0.95–0.79(m,6H)。
d.中间体N-(3'-氨基-[1，1'-联苯]-4-磺酰基)丙酰胺(27)的合成
将中间体26(400mg)置于50mL茄形瓶中，加入3mL DCM溶解，再滴入1mL盐酸乙酸乙酯，室温反应2h。薄层色谱法检测反应完全。向反应液中加入饱和碳酸氢钠调PH至8-9，加入DCM(5mL)萃取1次，再将有机相用饱和氯化钠(5mL)洗1次然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体27(淡黄色固体，250mg，收率83.3％)。1H-NMR(400MHz,DMSO-d6)δ7.91–7.86(m,2H),7.73–7.67(m,2H),7.09(t,J＝7.8Hz,1H),6.84(t,J＝1.9Hz,1H),6.80–6.77(m,1H),6.61–6.57(m,1H),2.21–2.12(m,2H),0.85(t,J＝7.5Hz,3H)。
e.中间体N-(3'-((5-氯-2-丙氧基苄基)氨基)-[1，1'-联苯]-4-基)磺酰基)丙酰胺(28)的合成
将中间体27(300mg，0.99mmol)和5-氯-2-丙氧基苯甲醛(196mg，0.99mmol)置于50mL茄形瓶中，加入甲醇(MeOH，10mL)溶解。室温反应2h。再将反应液冰浴降温后加入甲基橙、氰基硼氢化钠(NaBH3CN，186mg，2.96mmol)，滴入盐酸甲醇溶液(1:1)调PH至3-5。室温反应1-2h。薄层色谱法检测反应完全。将反应液蒸干后加入饱和NaHCO3(10mL)调PH至8-9，再加入EA萃取(8mL×3)。然后将有机相用饱和NaCl洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到中间体28(淡黄色固体，400mg，收率83.6％，PE/EA＝8：1)。1H-NMR(400MHz,DMSO-d6)δ12.02(s,1H),7.93–7.88(m,2H),7.75–7.69(m,2H),7.26–7.12(m,3H),6.98(d,J＝8.8Hz,1H),6.86–6.81(m,2H),6.60–6.54(m,1H),6.34(t,J＝6.2Hz,1H),4.26(d,J＝6.0Hz,2H),3.96(t,J＝6.4Hz,2H),2.24–2.15(m,2H),1.79–1.66(m,2H),0.95(t,J＝7.4Hz,3H),0.86(t,J＝7.4Hz,3H)。f.目标化合物N-(3'-(N-(5-氯-2-丙氧基苄基)-2-(噻吩-3-基)乙酰氨基)-[1，1'-联苯]-4-基)磺酰基丙酰胺(A50)的合成
将2-(噻吩-3-基)乙酸(78mg，0.617mmol)置于25mL茄形瓶中，加入DCM(5mL)溶解，冰浴降温后加入三乙胺(86μL，0.617mmol)、双(2-氧代-3-噁唑烷基)次磷酰氯(Bop-Cl，157mg，0.617mmol)，反应30min后加入中间体28(100mg,0.21mmol)，室温反应过夜。薄层色谱法检测反应完全。向反应液中依次加入饱和碳酸氢钠(NaHCO3，8mL)、1mol/L盐酸(HCl，8mL)、饱和氯化钠(NaCl，8mL)，各洗3次。然后向有机相中加入适量无水硫酸钠(Na2SO4)干燥15-20min后浓缩，经柱色谱分离得到终产物A50(白色固体，80mg，收率62.5％)。1H-NMR(400MHz,DMSO-d6)δ12.07(s,1H),7.93(d,J＝8.3Hz,2H),7.82–7.76(m,2H),7.66(d,J＝7.8Hz,1H),7.53(s,1H),7.46(t,J＝7.8Hz,1H),7.39(d,J＝3.6Hz,1H),7.26(s,1H),7.19(s,2H),7.02(s,1H),6.88(d,J＝8.8Hz,1H),6.84(s,1H),4.86(s,2H),3.70(t,J＝6.5Hz,2H),3.50(s,2H),2.26–2.16(m,2H),0.86(t,J＝7.4Hz,3H),0.74(t,J＝7.4Hz,3H)。13C-NMR(126MHz,DMSO-d6)δ172.77,170.15,155.71,144.45,143.29,139.94,138.96,135.79,130.52,129.55,129.18,128.71,128.58,127.79,127.45,126.90,125.98,124.20,122.82,113.68,69.85,47.32,35.90,29.15,22.24,10.71,8.68。
实施例51：目标化合物抑制LPS/ATP诱导小鼠巨噬细胞J774A.1释放IL-1β的活性研究将J774A.1细胞铺到96孔板上，每孔1×105个细胞。12h后，加入细菌脂多糖(LPS)(1μg/mL)，37℃下孵育4.5h；加入不同浓度的目标化合物37℃孵育0.5h，随后加入腺嘌呤核苷三磷酸(ATP)。0.5h后，收集细胞上清液，采用IL-1βElisa试剂盒测定IL-1β含量，计算出目标化合物对NLRP3炎症小体的抑制活性。实验结果见下表：
表1目标化合物抑制LPS/ATP诱导小鼠巨噬细胞J774A.1释放IL-1β的活性(IC50：μM)a
a表中IC50数值：++++为≤0.5μM；+++为≤1μM；++为≤10μM；+为≤30μM。表中数据为三次独立实验数据。
所设计的化合物均具有显著的抑制LPS/ATP诱导的小鼠巨噬细胞J774A .1产生IL-1β的活性。在这些活性中大部分化合物的抑制IC50都小于1μM，优于已报道的同类化合物格列本脲和JC-124。此外，代表性化合物A18、A20、A23、A28、A49的抑制活性突出，IC50达到低于0.5μM。
实施例52：目标化合物A20和A28对LPS诱导的小鼠腹膜炎的抑制实验
实验方法：
(1)将4-8周雄性C57BL/6小鼠随机分成5组，每组5只，具体分组处理如下：
第1组：空白5只；第2组：腹腔注射空白媒介物，1h后腹腔注射LPS(35mg/kg)，5只；第3-5组：腹腔注射目标化合物A20(10mg/kg)、A28(10mg/kg)和阳性药MCC950(10mg/kg)，1h后腹腔注射LPS(35mg/kg)，各5只。
(2)LPS腹腔注射2.5h后，眼球取血，将所取血液静置1h，然后3500r/min离心20min。
(3)将步骤(2)所得血液上清用ELISA的方法进行IL-1β、TNF-α含量测定。
实验结果(如图1和2所示)：在体内抗炎实验中，代表性化合物A20和A28能显著的抑制LPS诱导的小鼠急性腹膜炎中的IL-1β的释放(图1)，而不影响另一炎症因子TNF-α的释放(图2)，表明上述化合物能特异性的抑制NLRP3炎症小体，具有一定的选择性。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明的保护范围，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种如通式(I)所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物：
其中，选自/>n＝0-1；R1取代基选自/>其中A选自C1-C8的脂肪族烷烃、C2～C8的脂肪族炔烃、C2～C8的脂肪族烯烃、C3～C12的环烷烃、五元芳杂环或苯环或六元芳杂环；
R2和R3取代的基团在苯环或芳杂环骨架上的位置不定，其中R2选自H、 其中，X1选自O、S，n＝0-1，R4取代基选自H、卤素、羟基、甲氧基；
R3选自H、其中，R5选自H、OH、/> 卤素、C1～C6烷基，其中n＝0-6；R6选自H、卤素；R7选自H、CF3、CN、NO2、OH、卤素。
2.如权利要求1通式(I)所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物，其特征在于，选自/>n＝0；R1选自/>R2和R3在联苯母核的邻位或间位，其中R2选自/>R3选自
3.如权利要求1所述化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物，其特征在于，式(I)所示的化合物选自：
4.如权利要求1-3中任一项所述的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物的制备方法，其特征在于包括以下步骤：
(1)当R1为时，其步骤如下：
以化合物1为起始原料，与氨基化合物反应得到中间体2；中间体2在四(三苯基膦)钯的催化下与取代或非取代的硼酸芳环或芳杂环类似物发生铃木反应得到中间体3；进一步中间体3与取代醛基化合物发生还原胺化反应生成中间体4；最后中间体4与取代羧酸发生缩合反应得到目标化合物5；
(2)当R1为时，其步骤如下：
以化合物6为起始原料，与氨基化合物发生缩合反应得到中间体7；中间体7在四(三苯基膦)钯的催化下与取代或非取代的硼酸芳环或芳杂环类似物发生铃木反应得到中间体8；进一步中间体8与取代醛基化合物发生还原胺化反应生成中间体9；最后中间体9与取代羧酸发生缩合反应得到目标化合物10。
5.一种药物组合物，其特征在于包含如权利要求1-3中任一项所述的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物以及药学上可接受的稀释剂或载体。
6.如权利要5所述的药物组合物，其特征在于所述的化合物或其光学异构体、或其药学上可接受的盐、氘代物的含量为0.1-99.9wt％。
7.如权利要求1-3中任一项所述的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物在制备NLRP3炎症小体抑制剂中的用途。
8.如权利要求1-3中任一项所述的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、氘代物在制备治疗与NLRP3炎症小体活性异常活化相关疾病的药物中的用途。
9.如权利要求8所述的用途，其特征在于所述与NLRP3炎症小体异常活化相关疾病包括阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤、亨廷顿病、炎症性肠病、急性肺炎、非典型肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急慢性胃炎、急慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染性休克、痛风、非酒精性脂肪肝、II型糖尿病、心力衰竭、动脉粥样硬化、急性心肌梗塞、冠状动脉疾病、肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷吡啉相关周期性综合症或***性红斑狼疮。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410088664.1A CN118084884A (zh) | 2024-01-22 | 2024-01-22 | 含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410088664.1A CN118084884A (zh) | 2024-01-22 | 2024-01-22 | 含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118084884A true CN118084884A (zh) | 2024-05-28 |
Family
ID=91158104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410088664.1A Pending CN118084884A (zh) | 2024-01-22 | 2024-01-22 | 含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118084884A (zh) |
-
2024
- 2024-01-22 CN CN202410088664.1A patent/CN118084884A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2016328150B2 (en) | Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof | |
| WO2017049470A1 (en) | Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof | |
| CN106279047A (zh) | 一种前列环素受体激动剂的制备方法 | |
| Tang et al. | Synthesis of novel β-amino ketones containing ap-aminobenzoic acid moiety and evaluation of their antidiabetic activities | |
| CN118084884A (zh) | 含联苯或苯基取代芳杂环母核的nlrp3炎症小体抑制剂及其制备方法和应用 | |
| JP2011511053A (ja) | ボリノスタットの新規な製造方法 | |
| CN110483417B (zh) | 一种DACOs类NNRTIs氨基酸酯衍生物、其制备方法、药物组合物及应用 | |
| CN116041230B (zh) | 一种nlrp3炎症小体抑制剂及其制备方法和应用 | |
| CN110759901A (zh) | 四氢异喹啉类衍生物及其制备方法和用途 | |
| KR100780934B1 (ko) | 카테콜 ｎ-메틸히드라자이드 카바믹에스테르 유도체 및 그제조방법 | |
| CN115010642B (zh) | β-榄香烯酰亚胺类衍生物及其应用 | |
| CN115043782B (zh) | 4h-3,1-苯并噁嗪-4-酮衍生物及其制备方法和应用 | |
| AU2024202645A1 (en) | Deuterated nucleoside compounds and use thereof | |
| KR100866286B1 (ko) | 신규한 카테콜 히드라지드 유도체 및 그의 제조방법 | |
| KR100866285B1 (ko) | 신규한 카테콜 히드라지드 유도체 및 그의 제조방법 | |
| KR100736838B1 (ko) | 신규한 카테콜 ｎ-메틸히드라지드 유도체 및 그의 제조방법 | |
| TW202229235A (zh) | 環胺衍生物及其製備方法和應用 | |
| JP2023540636A (ja) | ベンゾ酸素含有複素環化合物及びその医薬用途 | |
| KR20040065438A (ko) | 불소가 치환된 신규한 캐테콜 엔-메틸히드라자이드 유도체 | |
| KR20030055769A (ko) | 신규한 카테콜 벤즈아미드 유도체 및 그의 제조방법 | |
| JPH09227559A (ja) | スピロ置換三環性複素環式化合物 | |
| JPH05294917A (ja) | ニトロ化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |