CN116023247A - 2-propylene-1 ketone compound and preparation method and application thereof - Google Patents
2-propylene-1 ketone compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN116023247A CN116023247A CN202111257510.3A CN202111257510A CN116023247A CN 116023247 A CN116023247 A CN 116023247A CN 202111257510 A CN202111257510 A CN 202111257510A CN 116023247 A CN116023247 A CN 116023247A
- Authority
- CN
- China
- Prior art keywords
- dimethylphenyl
- methyl
- dihydroxy
- groups
- methylphenyl
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- -1 ketone compound Chemical class 0.000 title claims description 122
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 68
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 25
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims abstract description 22
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000003112 inhibitor Substances 0.000 claims abstract description 7
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 54
- 125000001931 aliphatic group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- RJWLXGOSIRVRAR-UHFFFAOYSA-N 2,4-dimethylbenzene-1,3-diol Chemical compound CC1=CC=C(O)C(C)=C1O RJWLXGOSIRVRAR-UHFFFAOYSA-N 0.000 claims description 17
- 125000002252 acyl group Chemical group 0.000 claims description 16
- 239000000543 intermediate Substances 0.000 claims description 13
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- FNYDIAAMUCQQDE-UHFFFAOYSA-N 4-methylbenzene-1,3-diol Chemical compound CC1=CC=C(O)C=C1O FNYDIAAMUCQQDE-UHFFFAOYSA-N 0.000 claims description 9
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- AOPMHYFEQDBXPZ-UHFFFAOYSA-N 2,4-dihydroxy-3-methylbenzaldehyde Chemical compound CC1=C(O)C=CC(C=O)=C1O AOPMHYFEQDBXPZ-UHFFFAOYSA-N 0.000 claims description 7
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 claims description 7
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical class C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 7
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- FUASSFFRJZEPLA-CMDGGOBGSA-N (e)-1-(2-hydroxy-4-methoxy-5-methylphenyl)-3-phenylprop-2-en-1-one Chemical compound C1=C(C)C(OC)=CC(O)=C1C(=O)\C=C\C1=CC=CC=C1 FUASSFFRJZEPLA-CMDGGOBGSA-N 0.000 claims description 5
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000002662 enteric coated tablet Substances 0.000 claims description 2
- 239000007941 film coated tablet Substances 0.000 claims description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000007940 sugar coated tablet Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 229940119568 Inducible nitric oxide synthase inhibitor Drugs 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 7
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 3
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 abstract description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N Resorcinol Natural products OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 abstract description 2
- 150000004677 hydrates Chemical class 0.000 abstract description 2
- 229940002612 prodrug Drugs 0.000 abstract description 2
- 239000000651 prodrug Substances 0.000 abstract description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 24
- 239000002158 endotoxin Substances 0.000 description 22
- 229920006008 lipopolysaccharide Polymers 0.000 description 22
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 210000002540 macrophage Anatomy 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000006180 TBST buffer Substances 0.000 description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 4
- 229940109262 curcumin Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- RJUIDDKTATZJFE-NSCUHMNNSA-N (e)-but-2-enoyl chloride Chemical group C\C=C\C(Cl)=O RJUIDDKTATZJFE-NSCUHMNNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 3
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 3
- RKKPUBAAIGFXOG-YTXTXJHMSA-N Sorbicillin Chemical compound C\C=C\C=C\C(=O)C1=CC(C)=C(O)C(C)=C1O RKKPUBAAIGFXOG-YTXTXJHMSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NFFPFTGFVSWSTH-SNAWJCMRSA-N (e)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl chloride Chemical compound COC1=CC(\C=C\C(Cl)=O)=CC(OC)=C1OC NFFPFTGFVSWSTH-SNAWJCMRSA-N 0.000 description 2
- GLBIKPKWQDIQCJ-ZZXKWVIFSA-N (e)-3-(4-fluorophenyl)prop-2-enoyl chloride Chemical compound FC1=CC=C(\C=C\C(Cl)=O)C=C1 GLBIKPKWQDIQCJ-ZZXKWVIFSA-N 0.000 description 2
- CGOJOQBYEAVATL-QPJJXVBHSA-N (e)-3-(4-methoxyphenyl)prop-2-enoyl chloride Chemical compound COC1=CC=C(\C=C\C(Cl)=O)C=C1 CGOJOQBYEAVATL-QPJJXVBHSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 2
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000004148 curcumin Substances 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical class C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 2
- ZFOVCSTVYYYRSU-ZZXKWVIFSA-N (e)-3-(4-chlorophenyl)prop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=C(Cl)C=C1 ZFOVCSTVYYYRSU-ZZXKWVIFSA-N 0.000 description 1
- ARGVABDJPRRAQI-VOTSOKGWSA-N (e)-3-(4-methylphenyl)prop-2-enoyl chloride Chemical compound CC1=CC=C(\C=C\C(Cl)=O)C=C1 ARGVABDJPRRAQI-VOTSOKGWSA-N 0.000 description 1
- LPAMMSFOMIQXDN-UHFFFAOYSA-N 1,3-dimethoxy-2,4-dimethylbenzene Chemical compound COC1=CC=C(C)C(OC)=C1C LPAMMSFOMIQXDN-UHFFFAOYSA-N 0.000 description 1
- OSNMRWURXNWCGA-UHFFFAOYSA-N 2,4-dimethoxy-1-methylbenzene Chemical compound COC1=CC=C(C)C(OC)=C1 OSNMRWURXNWCGA-UHFFFAOYSA-N 0.000 description 1
- VFQOFJQVKVEXIY-UHFFFAOYSA-N 3-(phenylmethoxycarbonylamino)-3-piperidin-3-ylpropanoic acid Chemical compound C1CCNCC1C(CC(=O)O)NC(=O)OCC1=CC=CC=C1 VFQOFJQVKVEXIY-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006595 Griess deamination reaction Methods 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 description 1
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 description 1
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 1
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 239000012468 concentrated sample Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- GRTWTVFDPBKQNU-UHFFFAOYSA-N hexa-2,4-dienoyl chloride Chemical group CC=CC=CC(Cl)=O GRTWTVFDPBKQNU-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Abstract
The invention discloses a 2-propylene-1-ketone compound, a preparation method and application thereof, and belongs to the technical field of medicines. The invention designs and synthesizes a series of 2-propylene-1-ketone compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof based on an Inducible Nitric Oxide Synthase (iNOS) mediated Nitric Oxide (NO) generation model by taking methyl substituted resorcinol as a starting material. The present invention is directed to processes for their preparation and their use in the preparation of therapeutic agents for inflammation, in particular in the preparation of inhibitors of Nitric Oxide (NO) production, with potential application as anti-inflammatory agents.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a preparation method and medical application of a novel 2-propylene-1-ketone compound, and in particular relates to a novel 2-propylene-1-ketone compound, a preparation method thereof and an effect of inhibiting Nitric Oxide (NO), and has potential application in the aspect of serving as an anti-inflammatory medicine.
Background
Nitric Oxide (NO) plays an important role in normal physiological and pathological processes, and abnormalities in NO production are closely related to almost all pathological processes of inflammatory diseases [ Hesslinger et al, biochem soc Trans,2009, 37:886-891]. Under normal physiological conditions, NO is produced catalytically by nitric oxide synthase type i (nNOS, also known as neuronal nitric oxide synthase), inducible Nitric Oxide Synthase (iNOS) and nitric oxide synthase type iii (eNOS, also known as vascular endothelial cell nitric oxide synthase). Nitric oxide synthase catalyzes the production of NO and L-citrulline from L-arginine. Among them, iNOS is upregulated by various pro-inflammatory factors and signaling molecules, and is associated with a variety of inflammatory diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and rheumatoid arthritis [ Santolini, J InorgBiochem,2011, 105:127-141]. Thus, compounds capable of inhibiting iNOS-mediated NO release can be new therapeutic agents for inflammation.
2-propen-1-one is an important pharmacophore, and king et al report a preparation method of the derivatives of this type and therapeutic agents for diseases caused by PPARα and PPARδ and their application in metabolic syndrome, cardiovascular and cerebrovascular diseases, inflammation and neurodegenerative diseases [ king et al, invention patent application 2019,CN109265380A 20190125]. Raphael et al report the use of a class of 1, 3-diphenyl-2-propen-1-one derivatives in liver protection and treatment of liver fibrosis, fatty liver and the like [ U.S.Pat.App.Publ.,2015,US20150051145A1 20150219]. Karine et al report on the use of a class of 1, 3-diphenyl-2-propen-1-one derivatives as PPAR agonists in the biomedical and cosmetic fields [ PCT Int. Appl. (2005), WO 2005073184 A1 20050811]. At present, 2-propylene-1-ketone compounds are rarely reported in studies for inhibiting iNOS-mediated NO release.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention aims to provide a 2-propylene-1-ketone compound.
Another object of the present invention is to provide a process for producing the above 2-propen-1-one compound.
It is still another object of the present invention to provide the use of the above 2-propen-1-one compounds.
The invention designs and synthesizes a novel 2-propylene-1-ketone compound and carries out drug creation research on treatment of inflammation-related diseases.
The aim of the invention is achieved by the following technical scheme:
the invention relates to novel 2-propen-1-one compounds with a general formula (I) or pharmaceutically acceptable salts thereof, and optical active bodies and diastereoisomers thereof.
wherein ,
r1 is any one of the following groups: (1) an H atom, (2) a methyl group, and (3) an aliphatic hydrocarbon group having 2 or more carbon atoms;
r2 is any one of the following groups: (1) H atoms, (2) methyl groups, (3) aliphatic hydrocarbon groups containing 2 or more carbon atoms, (4) acyl groups of aliphatic hydrocarbons of any length, and (5) acyl groups containing aromatic rings;
r3 is any one of the following groups: (1) H atoms, (2) methyl groups, (3) aliphatic hydrocarbon groups containing 2 or more carbon atoms, (4) acyl groups of aliphatic hydrocarbons of any length, and (5) acyl groups containing aromatic rings;
r4 is any one of the following groups: (1) methyl, (2) aliphatic hydrocarbon groups having 2 or more carbon atoms, and (3) substituted or unsubstituted aromatic rings having alkyl groups, hydroxyl groups, alkoxy groups, alkylenedioxy groups, halogens, and the like;
further:
r1 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms;
r2 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms, (4) acyl of aliphatic hydrocarbon group containing 2-5 carbon atoms, and (5) acyl containing aromatic ring;
r3 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms, (4) acyl of aliphatic hydrocarbon group containing 2-5 carbon atoms, and (5) acyl containing aromatic ring;
r4 is (1) methyl, (2) aliphatic hydrocarbon group having 2 to 5 carbon atoms, or (3) substituted or unsubstituted aromatic ring having alkyl group, hydroxyl group, alkoxy group, alkylenedioxy group, halogen or the like;
further:
r1 is (1) H atom, (2) methyl;
r2 is (1) H atom, (2) methyl;
r3 is (1) H, (2) methyl, (3) 2-butene-1-acyl, 2, 4-hexadiene-1-acyl, (4) 4-fluorobenzoyl, 4-chlorobenzoyl;
r4 is (1) methyl, (2) propenyl, (3) benzene ring containing methyl, hydroxyl, methoxy, methylenedioxy, halogen substituted or unsubstituted such as fluorine, chlorine, etc.
Preferred compounds of the invention are:
p1: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3-phenylprop-2-en-1-one;
p2: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methylphenyl) prop-2-en-1-one;
p3: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one;
p4: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p5: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4-methylenedioxyphenyl) -2-propen-1-one;
p6: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p7: (E) -4- [ (E) -3- (4-fluorophenyl) -acryl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-fluorophenyl) acrylate;
p8: (E) -4- [ (E) -3- (4-chlorophenyl) -acryloyl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-chlorophenyl) acrylate;
p9: (2 e,4 e) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) hex-2, 4-dien-1-one;
p10: (2 e,4 e) -4- [ (2 e,4 e) -hexa-2, 4-dienoyl) -3-hydroxy-2, 6-dimethylphenyl) hexa-2, 4-dienoic acid ester;
p11: (E) -4- [ (E) -but-2-enoyl) -3-hydroxy-2, 6-dimethylphenyl) but-2-enoate;
p12: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p13: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p14: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p15: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p16: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p17: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p18: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one;
p19: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p20: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p21: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) but-2-en-1-one;
p22: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) but-2-en-1-one;
p23: (E) -1- (2, 4-dimethoxy-5-methylphenyl) but-2-en-1-one;
p24: (E) -1- (2, 4-dihydroxy-5-methylphenyl) but-2-en-1-one;
for the preparation of the 2-propen-1-ones of the general formula (I) according to the invention, and their optically active forms, the compounds are synthesized by the following route:
firstly, using 2, 4-dihydroxyl-3-methylbenzaldehyde (1 a) as a starting material, firstly, making lithium aluminum hydride (LiAlH) 4 ) Reduction to give 2, 4-dimethylresorcinol (2 a) intermediate, intermediate 2a in aluminum trichloride (AlCl) 3 ) The reaction with freshly prepared acid chloride under catalysis of the catalyst gives the product (equation 1). Wherein the acid chloride is reacted with thionyl chloride (SOCl) via the corresponding carboxylic acid 2 ) Prepared (equation 2).
(II) starting from 2, 4-dihydroxy-3-methylbenzaldehyde (1 a) and 2, 4-dihydroxybenzaldehyde (1 b), first of all by lithium aluminum hydride (LiAlH) 4 ) Reduction gives intermediates of 2, 4-dimethylresorcinol (2 a) and 4-methylresorcinol (2 b), and reaction of intermediates 2a and 2b with methyl iodide (MeI) gives intermediates 3a and 3b. Intermediate 3a and 3b are prepared in aluminum trichloride (AlCl 3 ) Is subjected to Friedel-crafts acylation reaction with freshly prepared acyl chloride to obtain a product A (reaction formula 3), wherein the acyl chloride is prepared by reacting the corresponding carboxylic acid with thionyl chloride (SOCl) 2 ) Prepared (equation 2). Product A was purified by boron tribromide (BBr 3 ) Demethylation gives the products B and C.
The specific reaction formula is as follows:
reaction formula 1:
reaction formula 2:
reaction formula 3:
wherein ,
a pharmaceutical composition comprising the above 2-propen-1-one compound or a pharmaceutically acceptable salt thereof, an optically active substance, a diastereoisomer and a pharmaceutically acceptable carrier.
Application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing Nitric Oxide (NO) generation inhibitor medicines.
Application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition in preparing an inhibitor drug for inhibiting NO generation mediated by iNOS (inducible nitric oxide synthase).
Application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition in preparing an iNOS (inducible nitric oxide synthase) inhibitor.
The application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing anti-inflammatory drugs.
The medicine is in the form of injection, instillation liquid, powder injection, granule, tablet, granule, powder, oral liquid, sugar-coated tablet, film-coated tablet, enteric-coated tablet, buccal agent, granule, pill, paste, pellet, spray, dripping pill, disintegrating agent, orally disintegrating tablet or micropill.
Compared with the prior art, the invention has the following advantages and effects:
the invention designs and synthesizes a series of 2-propylene-1-ketone compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof based on an Inducible Nitric Oxide Synthase (iNOS) mediated Nitric Oxide (NO) generation model by taking methyl substituted resorcinol as a starting material. The present invention is directed to processes for their preparation and their use in the preparation of therapeutic agents for inflammation, in particular in the preparation of inhibitors of Nitric Oxide (NO) production.
Drawings
FIG. 1 is a standard curve for the NO concentration test of the standard.
FIG. 2 is the inhibition of LPS-induced Nitric Oxide (NO) release by the compounds P1-P24 in mouse mononuclear macrophage RAW264.7 cells; wherein "+" is model set; the concentration of NO is detected by using the nitric oxide detection kit, the experiment is repeated for three times, the experimental result is mean value + -S.E.M, and compared with the DMSO group ### p<0.001, compared with LPS group (model group, +) and * p<0.05、 ** p<0.01、 *** p<0.001。
FIG. 3 is the effect of compounds P1-P11 on LPS-induced expression levels of the iNOS protein in mouse mononuclear macrophage RAW264.7 cells; wherein "+" is model set; detection of protein expression Using immunoblotting, experimentsThe data were repeated three times and the experimental results were mean.+ -. S.E.M, compared to the DMSO group ### p<0.001, compared with LPS group (model group, +) and ** p<0.01、 *** p<0.001。
FIG. 4 is the effect of compounds P12-P24 on LPS-induced expression levels of the iNOS protein in mouse mononuclear macrophage RAW264.7 cells; wherein "+" is model set; the expression quantity of the protein is detected by using an immunoblotting method, experimental data are repeated three times, the experimental result is mean value + -S.E.M, and compared with a DMSO group ### p<0.001, compared with LPS group (model group, +) and *** p<0.001。
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The materials, reagents and the like used, unless otherwise specified, are those obtained commercially.
Example 1: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3-phenylprop-2-en-1-one (P1)
2.2g of aluminum trichloride (AlCl) 3 6.6mmol,1.0 eq) was dissolved in 55mL dry Tetrahydrofuran (THF) and 625.0mg lithium aluminum hydride (LiAlH) was slowly added 4 16.5mmol,2.5 eq) followed by an ice bath under argon atmosphere to 0 ℃. 1.0g of 2, 4-dihydroxy-3-methylbenzaldehyde (1 a,6.6 mmol) was dissolved in 5mL of THF, slowly added dropwise to the reaction system, and then reacted at 65℃under reflux for 3 hours. After cooling the reaction to 0deg.C, 1M HCl was added to terminate the reaction. Diluted with ethyl acetate (EtOAc) followed by 1M HCl, saturated sodium bicarbonate (NaHCO) 3 ) And water washing, then washing with anhydrous sodium sulfate (Na 2 SO 4 ) Drying, and concentrating under reduced pressure to dry. The residue was eluted with silica gel open column chromatography petroleum ether-ethyl acetate (10:1, vol. As described below) to give compound 2a (2, 4-dimethylresorcinol) as a white powder in 71% yield (650 mg). ESI-MS m/z=137.1.
100mg of 2, 4-dimethylresorcinol (2 a,0.7 mmol) was dissolvedThe solution was dissolved in anhydrous Dichloromethane (DCM) and ice-cooled to 0℃under argon. Slowly adding 120-150 mu L of cinnamoyl chloride (1.5 eq) and 120mg of aluminum trichloride (AlCl) 3 0.9mmol,1.3 eq) of cinnamic acid chloride with thionyl chloride (SOCl) 2 ) And (3) reacting to obtain the product. After stirring the reaction at room temperature for 1h, the reaction was quenched by addition of 1M HCl. Diluted with DCM and then sequentially diluted with 1M HCl, saturated NaHCO 3 The solution was washed with water, then dried over anhydrous sodium sulfate (Na 2 SO 4 ) Drying, and concentrating under reduced pressure to dry. The residue was purified by High Performance Liquid Chromatography (HPLC) (85% MeOH-H) 2 After O) compound P1 was obtained as a pale yellow solid in a yield of 13.5%. 1 H NMR(300MHz,DMSO-d 6 ):δ H 13.76(1H,s),8.00(1H,d,J＝15.5Hz),7.98(1H,s),7.92-7.89(2H,m),7.79(1H,dd,J＝15.5Hz),7.49-7.45(3H,m),2.20(3H,s),2.05(3H,s). 13 C NMR(75MHz,CDCl 3 )δ C 191.3,162.2,161.7,143.2,134.7,130.5,129.5,128.9(×4),121.4,116.3,112.1,110.5,16.1,8.2.ESI-MS m/z＝291.0[M+Na] + 。
Example 2: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methylphenyl) prop-2-en-1-one (P2)
The procedure for the preparation of the compound of example 2 is as in example 1, except that the acid chloride added in the reaction is 4-methylcinnamoyl chloride, and the reaction residue is prepared by HPLC (80% MeOH-H) 2 O) gives compound P2 as a pale yellow solid in a separation yield of 27.4%. 1 H NMR(300MHz,CDCl 3 )δ13.60(s,1H),7.75(d,J＝15.5Hz,1H),7.53–7.48(m,4H),7.17-7.15(overlapped,2H),2.32(s,3H),2.18(s,3H),2.08(s,3H). 13 C NMR(75MHz,CDCl 3 )δ192.1,162.3,160.3,143.9,141.1,132.2,129.7(×2),128.8,128.5(×2),119.7,115.8,113.2,111.1,21.5,16.0,7.7。ESI-MS m/z＝283.3[M+H] + 。
Example 3: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (P3)
The procedure for the preparation of the compound of example 3 is as in example 1, except that the acid chloride added in the reaction is 4-methoxycinnamoyl chloride, and the reaction residue is prepared by HPLC (80% MeOH-H) 2 O) gives the compound P3 as pale yellowThe color solid was isolated in 19.6% yield. 1 H NMR(300MHz,CDCl 3 )δ7.85(d,J＝15.4Hz,1H),7.65–7.59(m,2H),7.55(s,1H),7.48(d,J＝15.4Hz,1H),6.98–6.91(m,2H),3.86(s,3H),2.25(s,3H),2.17(s,3H). 13 C NMR(75MHz,CDCl 3 )δ191.9,162.8,161.8,158.8,144.0,130.5(×2),129.0,127.8,118.3,114.6(×3),113.8,110.6,55.3,15.6,7.3。ESI-MS m/z＝299.2[M+H] + 。
Example 4: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (P4)
The procedure for the preparation of the compound of example 4 is as in example 1, except that the acid chloride added in the reaction is 3,4, 5-trimethoxycinnamoyl chloride, and the reaction residue is prepared by HPLC (80% MeOH-H) 2 O) gives compound P4 as a pale yellow solid in 18.1% isolated yield. 1 H NMR(400MHz,DMSO-d 6 )δ13.82(s,1H),7.94(s,1H),7.91(d,J＝15.3Hz,1H),7.76(d,J＝15.3Hz,1H),7.23(s,2H),3.87(s,6H),3.72(s,3H),2.21(s,3H),2.05(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ191.6,162.2(×2),161.1,153.1(×2),144.0,139.9,130.2,129.5,120.4,116.1,112.3,110.6,106.8,60.2,56.2(×2),16.3,8.2。ESI-MS m/z＝359.4[M+H] + 。
Example 5: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4-methylenedioxyphenyl) -2-propen-1-one (P5)
The procedure for the preparation of the compound of example 5 is as in example 1, except that the acid chloride added in the reaction is 3, 4-methylenedioxy cinnamoyl chloride, and the reaction residue is prepared by HPLC (80% MeOH-H) 2 O) gives compound P5 as a pale yellow solid in a separation yield of 16.0%. 1 H NMR(400MHz,DMSO-d 6 )δ13.83(s,1H),7.98(s,1H),7.85(d,J＝15.3Hz,1H),7.72(d,J＝15.3Hz,1H),7.70(s,1H),7.32(d,J＝8.0Hz,1H),6.99(dd,J＝8.0,2.0Hz,1H),6.11(s,2H),2.19(s,3H),2.04(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ191.5,162.2,161.0,149.6,148.2,143.5,129.5,129.3,126.2,119.2,116.1,112.3,110.5,108.5,107.0,101.7,16.1,8.2。ESI-MS m/z＝313.1[M+H] + 。
Example 6: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one (P6)
The procedure for the preparation of the compound of example 6 is as in example 1, except that the acid chloride added in the reaction is 4-fluorocinnamoyl chloride, and the reaction residue is prepared by HPLC (90% MeOH-H) 2 O) gives compound P6 as a pale yellow solid in a separation yield of 9.1%. 1 H NMR(400MHz,CDCl 3 )δ13.53(s,1H),7.84(d,J＝15.5Hz,1H),7.67-7.64(m,2H),7.54(s,1H),7.53(d,J＝15.5Hz,1H),7.14–7.10(m,2H),2.26(s,3H),2.17(s,3H). 13 C NMR(101MHz,CDCl 3 )δ191.8,164.2(d,J＝250Hz),162.9,159.1,142.9,130.6(d,J＝9.0Hz)(×2),128.9,120.5,116.3(d,J＝21.0Hz)(×2),114.8,113.7,110.7,100.2,15.8,7.7。ESI-MS m/z＝287.4[M+H] + 。
Example 7: (E) -4- [ (E) -3- (4-fluorophenyl) -propenoyl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-fluorophenyl) acrylate (P7)
The procedure for the preparation of the compound of example 7 is as in example 6, and the reaction residue is prepared by HPLC (90% MeOH-H) 2 O) gave P7 as a pale yellow solid at the same time, isolated in 18.9%. 1 H NMR(300MHz,CDCl 3 )δ13.20(s,1H),7.92(d,J＝5.1Hz,1H),7.87(d,J＝4.5Hz,1H),7.70–7.53(m,6H),7.17-7.11(m,4H),6.62(d,J＝16.0Hz,1H),2.20(s,3H),2.13(s,3H). 13 CNMR(75MHz,CDCl 3 )δ193.1,166.1,165.0(×2),164.0,161.8,154.2,146.2,144.0,131.1,130.8(d,J＝11.0Hz)(×2),130.5(d,J＝10.0Hz)(×2),,128.4,121.1,120.3,120.2,117.6,116.5(d,J＝5.0Hz)(×2),116.2(d,J＝5.0Hz)(×2),116.0,16.4,9.2。ESI-MS m/z＝435.4[M+H] + 。
Example 8: (E) -4- [ (E) -3- (4-chlorophenyl) -acryloyl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-chlorophenyl) acrylic acid ester (P8)
The procedure for the preparation of the compound of example 8 is as in example 1, except that the acid chloride added in the reaction is 4-chlorocinnamoyl chloride, and the reaction residue is prepared by HPLC (90% MeOH-H) 2 O) gives compound P8 as a pale yellow solid in a isolation yield of 7.5%. 1 H NMR(300MHz,CDCl 3 )δ13.16(s,1H),7.90(d,J＝7.2Hz,1H),7.85(d,J＝6.6Hz,1H),7.64–7.54(m,6H),7.43-7.40(m,4H),6.67(d,J＝16.0Hz,1H),2.20(s,3H),2.12(s,3H). 13 C NMR(75MHz,CDCl 3 )δ193.0,163.9,161.9,154.2,146.1,143.8,137.1,136.9,133.3,132.5,129.9(×2),129.7(×2),129.5(×4),128.4,121.1,121.0,120.4,117.6,116.9,16.4,9.2。ESI-MS m/z＝465.1[M-H] - 。
Example 9: (2E, 4E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) hex-2, 4-dien-1-one (P9)
The compound of example 9 was prepared in the same manner as in example 1 except that the acid chloride reagent was replaced with 2, 4-hexadienoyl chloride. The concentrated residue of the reaction filtrate was purified by High Performance Liquid Chromatography (HPLC) (90% MeOH-H) 2 O) gives compound P9 as a pale yellow solid in 19.6% yield. 1 H NMR(300MHz,CDCl 3 ):δ H 13.59(1H,s),7.44(1H,s),7.45(1H,dd,J＝14.8,10.2Hz),6.94(1H,d,J＝14.8Hz),6.40-6.21(2H,m),2.21(3H,s),2.14(3H,s),1.90(3H,d,J＝6.0Hz). 13 C NMR(75MHz,CDCl 3 )δ C 192.7,162.7,158.9,144.7,141.3,130.7,128.9,122.0,114.6,113.6,110.6,19.1,15.8,7.7.ESI-MS m/z＝233.0[M+H] + 。
Example 10: (2E, 4E) -4- [ (2E, 4E) -hexa-2, 4-dienoyl) -3-hydroxy-2, 6-dimethylphenyl) hexa-2, 4-dienoic acid ester (P10)
The procedure for the preparation of the compound of example 10 is as in example 9, and the concentrated residue of the reaction filtrate is prepared by High Performance Liquid Chromatography (HPLC) (90% MeOH-H) 2 O) gives another compound P10 as a pale yellow solid in a yield of 8.5%. 1 H NMR(400MHz,CDCl 3 ):δ H 13.24(1H,s),7.53(1H,s),7.53-7.46(2H,m),6.96(1H,d,J＝15.2Hz),6.40-6.22(4H,m),6.01(1H,d,J＝15.2Hz),2.13(3H,s),2.07(3H,s),1.92(3H,d,J＝5.2Hz),1.91(3H,d,J＝5.2Hz). 13 C NMR(101MHz,CDCl 3 )δ C 193.7,164.4,161.7,154.1,147.7,145.7,142.1,141.4,130.7,129.8,128.3,121.9,120.9,120.1,117.5,117.2,19.1,18.9,16.3,9.1.ESI-MS m/z＝349.1[M+Na] + 。
Example 11: (E) -4- [ (E) -but-2-enoyl) -3-hydroxy-2, 6-dimethylphenyl) but-2-enoate (P11)
Example 11The procedure for the preparation of the compound was as in example 1, except that the acid chloride reagent was replaced with 2-butenoyl chloride. The concentrated residue of the reaction filtrate was purified by High Performance Liquid Chromatography (HPLC) (85% MeOH-H) 2 O) compound P11 was obtained as a pale yellow solid in 18.2% yield. 1 H NMR(300MHz,CDCl 3 ):δ H 13.12(1H,s),7.55(1H,s),7.33-7.15(2H,m),7.03(1H,dd,J＝14.8,2.0Hz),6.12(1H,dd,J＝14.8,2.0Hz),2.14(3H,s),2.08(3H,s),2.05(3H,dd,J＝6.0,2.0Hz),2.02(3H,dd,J＝6.0,2.0Hz). 13 C NMR(75MHz,CDCl 3 )δ C 193.5,163.5,161.7,154.0,147.9,145.6,128.6,125.8,121.3,120.9,120.1,117.0,18.8,18.4,16.2,9.0.ESI-MS m/z＝275.0[M+H] + 。
Example 12: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one (P12)
1.05g (7.88 mmol) AlCl was weighed out 3 20mL of anhydrous THF was added and cooled to 0deg.C. Slowly add 0.3g (7.9 mmol) LiAlH 4 After removing air N 2 And (5) protecting. 3.29mmol of 2, 4-dihydroxy-benzaldehyde (1 b) was dissolved in 2mL of THF and slowly injected into the reaction system by syringe. Refluxing in water bath at 65 ℃ for 3 hours. After the reaction was completed, 1MHCl was slowly added under ice bath to quench the reaction, extracted with EtOAc, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/8:1) to give compound 2b (4-methylresorcinol).
0.89mmol of 4-methylresorcinol (2 b) and 240mg (1.74 mmol) of K were weighed out 2 CO 3 Dissolved in DMF. 0.3mL (6.96 mmol) of methyl iodide (MeI) was added thereto, and the mixture was reacted at room temperature for 30 hours. After the reaction, water and DCM were added, and the combined organic phases were washed twice with saturated aqueous NaCl solution and with anhydrous Na 2 SO 4 And (5) drying. After filtration, the compound 3b (4-methyl-1, 3-dimethoxybenzene) was obtained by eluting with silica gel open column chromatography (petroleum ether-ethyl acetate/80:1).
1.44mmol of 4-fluorocinnamic acid was weighed out in 2mL of SOCl 2 1 drop of DMF was added thereto, and the mixture was refluxed at 60℃for 60 minutes. After the reaction, concentrating under reduced pressure to remove excessive SOCl 2 1.5mL of DCM was added to dilute the solution (4-fluorocinnamoyl chloride DCM). 0.6mmol of intermediate 3b was takenDissolved in 3mL DCM, 96mg (0.72 mmol) AlCl was slowly added at 0deg.C 3 ，N 2 And (5) protecting. The freshly prepared acid chloride DCM solution was slowly added with a syringe and reacted for 3h. After the reaction was completed, it was quenched with 1M HCl and extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate and filtered, eluting with silica gel open column chromatography (petroleum ether-ethyl acetate/12:1) to give compound P12 as a pale yellow solid in a total yield of 15.2%. 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝15.8Hz,1H),7.60–7.54(m,3H),7.48(d,J＝15.8Hz,1H),7.08–7.04(m,2H),6.42(s,1H),3.92(d,J＝1.4Hz,3H),3.89(d,J＝2.0Hz,3H),2.16(s,3H). 13 C NMR(101MHz,CDCl 3 )δ190.2(s),163.8(d,J＝250.0Hz),162.3,159.3(s),140.4(s),133.0(s),131.9(d,J＝4.0Hz),130.2(d,J＝8.0Hz)(×2),127.2(d,J＝2.3Hz),120.8(s),119.3(s),116.0(d,J＝20.0Hz)(×2),94.8(s),56.2(s),55.6(s),15.3(s).HRMS(ESI)m/zcalcd.forC 18 H 18 FO 3 [M+H] + 301.1287；found,301.1288。
Example 13: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one (P13)
Example 13 the procedure for the preparation of the compound was as in example 12, and 0.31mmol of Compound P12 was weighed and dissolved in 3mL of DCM, N 2 Stirring at-20deg.C for 10min under protection, slowly dripping 1.86mmol 1MBBr 3 The reaction was continued for 1h and then shifted to room temperature overnight. After the reaction was completed, DCM was added to dilute the mixture, and the organic phase was washed twice with water and dried over anhydrous Na 2 SO 4 And (5) drying. The filtrate after filtration was concentrated under reduced pressure and eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/30:1) to give compound P13 as a pale yellow solid in a total yield of 6.8%. 1 H NMR(400MHz,CDCl 3 )δ13.39(s,1H),7.79(d,J＝15.5Hz,1H),7.64–7.60(m,2H),7.57(s,1H),7.47(d,J＝15.5Hz,1H),7.09(t,J＝8.6Hz,2H),6.40(s,1H),3.84(s,3H),2.16(s,3H). 13 C NMR(101MHz,CDCl 3 )δ191.5(s),165.5,164.1(d,J＝250Hz),164.7(s),142.8(s),131.2(d,J＝3.3Hz),130.6(s),130.5(d,J＝10.0Hz)(×2),120.2(d,J＝2.3Hz),118.16(s),116.2(d,J＝20.0Hz)(×2),113.2(s),99.2(s),55.8(s),15.8(s).HRMS(ESI)m/zcalcd.forC 17 H 16 FO 3 [M+H] + 287.1072；found,287.1085。
Example 14: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one (P14)
The procedure for the preparation of the compound of example 14 is as in example 13, and the concentrated sample is eluted with silica gel open column chromatography (petrol ether-ethyl acetate/10:1) to give compound P14 as a pale yellow solid in 8.1% yield. 1 HNMR(400MHz,DMSO-d 6 )δ13.30(s,1H),10.77(s,1H),8.06(s,1H),7.99–7.96(m,2H),7.94(d,J＝15.5Hz,1H),7.77(d,J＝15.5Hz,1H),7.30(d,J＝8.8Hz,1H),7.28(d,J＝8.8Hz,1H),6.35(s,1H),2.12(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ191.2(s),164.2(s),163.7(s),163.4(d,J＝249.0Hz),142.2(s),132.6(s),131.4,131.3(d,J＝10.0Hz)(×2),121.3,116.7(s),115.9(d,J＝20.0Hz)(×2),112.6(s),102.0(s),15.1(s).HRMS(ESI)m/zcalcd.forC 16 H 14 FO 3 [M+H] + 273.0916；found,273.0928。
Example 15: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one (P15)
Example 15 the compound was prepared in the same manner as in example 12 except that the acid chloride reagent added was cinnamoyl chloride. After the reaction, the filtrate concentrate was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/12:1) to give compound P15 as a pale yellow solid in a yield of 12.9%. 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝15.8Hz,1H),7.61-7.59(m,3H),7.55(d,J＝15.8Hz,1H),7.42–7.36(m,3H),6.44(s,1H),3.93(s,3H),3.91(s,3H),2.17(s,3H). 13 C NMR(101MHz,CDCl 3 )δ190.7,162.3,159.3,141.8,135.8,133.0,130.0,128.9(×2),128.4(×2),127.5,121.0,119.3,94.9,56.3,55.7,15.4.HRMS(ESI)m/zcalcd.forC 18 H 19 O 3 [M+H] + 283.1393；found,283.1370。
Example 16: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one (P16)
The procedure for the preparation of the compound of example 16 is as in example 15, with 1M BBr being the compound P15 obtained 3 Demethylation of DCM solution, reaction junctionThe postbundle filtrate concentrate was eluted by silica gel open column chromatography (petroleum ether-ethyl acetate/50:1) to give compound P16 as a pale yellow solid in 5.8% yield. 1 H NMR(400MHz,CDCl 3 )δ13.42(s,1H),7.87(d,J＝15.5Hz,1H),7.67–7.65(m,2H),7.61(s,1H),7.58(d,J＝15.5Hz,1H),7.43-7.41(m,3H),6.43(s,1H),3.86(s,3H),2.18(s,3H). 13 C NMR(101MHz,CDCl 3 )δ191.8,165.5,164.7,144.1,135.0,130.8,130.7,129.1(×2),128.6(×2),120.6,118.2,113.3,99.2,55.8,15.8.HRMS(ESI)m/zcalcd.forC 17 H 17 O 3 [M+H] + 269.1178；found,269.1180。
Example 17: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3-phenylpropan-2-en-1-one (P17)
The procedure for the preparation of the compound of example 17 is as in example 16, and the filtrate concentrate is eluted with silica gel open column chromatography (petrol ether-ethyl acetate/10:1) to give compound P17 as a pale yellow solid in 6.8% yield. 1 H NMR(400MHz,DMSO-d 6 )δ13.31(s,1H),10.77(s,1H),8.09(s,1H),8.00(d,J＝15.5Hz,1H),7.92-7.89(m,2H),7.78(d,J＝15.5Hz,1H),7.47-7.45(m,3H),6.36(s,1H),2.13(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ191.3,164.2,163.7,143.4,134.7,132.6,130.6,129.0(×2),128.9(×2),121.4,116.7,112.6,102.0,15.1.HRMS(ESI)m/zcalcd.for C 16 H 15 O 3 [M+H] + 255.1021；found,255.1026。
Example 18: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (P18)
The procedure for the preparation of the compound of example 18 was as in example 12, except that 4-methoxycinnamoyl chloride was used as the acid chloride reagent, and the filtrate concentrate after the completion of the reaction was eluted by silica gel open column chromatography (petroleum ether-ethyl acetate/10:1) to give compound P18 as a pale yellow solid in a total yield of 12.6%. 1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝15.7Hz,1H),7.57–7.54(m,3H),7.43(d,J＝15.7Hz,1H),6.91(d,J＝8.6Hz,2H),6.43(s,1H),3.91(s,3H),3.89(s,3H),3.83(s,3H),2.16(s,3H). 13 CNMR(101MHz,CDCl 3 )δ190.7,162.0,161.3,159.0,141.8,132.9,130.0(×2),128.4,125.3,121.2,119.1,114.4(×2),94.9,56.2,55.6,55.5,15.3.HRMS(ESI)m/zcalcd.for C 19 H 21 O 4 [M+H] + 313.1499；found,313.1483。
Example 19: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (P19)
The compound of example 19 was prepared in the same manner as in example 12 except that the methylated starting material was changed to 2, 4-dimethylresorcinol (2 a) and reacted with MeI to give 2, 4-dimethyl-1, 3-dimethoxybenzene (3 a), the acid chloride reagent added was 3,4, 5-trimethoxy substituted cinnamoyl chloride. After the reaction, the filtrate concentrate was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/6:1) to give compound P19 as a pale yellow solid in a yield of 12.9%. 1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝15.7Hz,1H),7.28(d,J＝15.7Hz,1H),7.26(s,1H),6.78(s,2H),3.84–3.81(overlapped,9H),3.69(m,3H),3.63(m,3H),2.20(s,6H). 13 C NMR(101MHz,CDCl 3 )δ192.4,160.5,156.9,153.4(×2),143.7,140.2,130.4,129.4,129.1,126.9,125.7,125.0,105.6(×2),62.3,60.8,59.7,56.1(×2),15.7,9.3.HRMS(ESI)m/zcalcd.forC 22 H 27 O 6 [M+H] + 387.1808；found,387.1825。
Example 20: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (P20)
The compound of example 20 was prepared in the same manner as in example 12 except that the acid chloride reagent added was 3,4, 5-trimethoxycinnamoyl chloride. After the reaction, the filtrate concentrate was subjected to silica gel open column chromatography (petroleum ether-ethyl acetate/10:1) to give compound P20 as a pale yellow solid in a yield of 12.6%. 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝15.7Hz,1H),7.56(s,1H),7.41(d,J＝15.7Hz,1H),6.82(s,2H),6.44(s,1H),3.92(s,3H),3.90(s,3H),3.89(s,6H),3.88(s,3H),2.16(s,3H). 13 C NMR(101MHz,CDCl 3 )δ190.6,162.1,159.1,153.5(×2),142.1,140.0,132.9,131.2,126.9,121.0,119.3,105.6(×2),94.9,61.1,56.3(×3),55.7,15.3.HRMS(ESI)m/zcalcd.forC 21 H 25 O 6 [M+H] + 373.1710；found,373.1703。
Example 21: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) but-2-en-1-one (P21)
The procedure for the preparation of the compound of example 21 was as in example 19, except that 2-butenoyl chloride was used as the acid chloride reagent, and the filtrate concentrate after the completion of the reaction was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/50:1) to give compound P21 as a pale yellow solid in 17.5% yield. 1 H NMR(400MHz,CDCl 3 )δ7.18(s,1H),6.95–6.85(m,1H),6.73(dd,J＝15.4,1.2Hz,1H),3.72(s,3H),3.66(s,3H),2.24(s,3H),2.22(s,3H),1.94(dd,J＝6.8,1.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ193.4,160.4,156.8,144.7,131.8,129.3,129.1,126.8,125.1,62.4,59.9,18.5,15.9,9.5.HRMS(ESI)m/zcalcd.forC 14 H 19 O 3 [M+H] + 235.1334；found,235.1341。
Example 22: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) but-2-en-1-one (P22)
The procedure for the preparation of the compound of example 22 is as in example 21, with 1M BBr of the compound P21 obtained 3 Demethylation. After the reaction, the filtrate concentrate was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/15:1) to give compound P22 as a pale yellow solid in a yield of 12.5%. 1 H NMR(300MHz,MeOH-d 4 )δ7.51(s,1H),7.12(d,J＝15.0Hz,1H),7.10–7.01(m,1H),2.16(s,3H),2.06(s,3H),1.98(d,J＝5.1Hz,3H). 13 C NMR(75MHz,MeOH-d 4 )δ193.7,163.7,162.2,144.8,130.3,127.0,117.1,113.3,112.0,18.6,16.4,8.0.HRMS(ESI)m/zcalcd.forC 12 H 15 O 3 [M+H] + 207.1021；found,207.1023。
Example 23: (E) -1- (2, 4-dimethoxy-5-methylphenyl) but-2-en-1-one (P23)
The compound of example 23 was prepared in the same manner as in example 12 except that the acid chloride reagent added was 2-butenoyl chloride. After the reaction, the filtrate concentrate was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/15:1) to give compound P23 as a pale yellow solid in 17.2% yield. 1 H NMR(400MHz,CDCl 3 )δ7.47(s,1H),6.97–6.83(m,2H),6.40(s,1H),3.88(s,6H),2.14(s,3H),1.93(dd,J＝6.4,0.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ191.1,161.9,158.9,142.1,132.8,132.2,120.8,119.0,94.9,56.1,55.6,18.5,15.3.HRMS(ESI)m/zcalcd.forC 13 H 17 O 3 [M+H] + 221.1178；found,221.1180。
Example 24: (E) -1- (2, 4-dihydroxy-5-methylphenyl) but-2-en-1-one (P24)
Example 24 the compound P23 was isolated by the same procedure as in example 23, and passed through 1M BBr 3 Is demethylated in DCM solution. After the reaction, the filtrate concentrate was eluted with silica gel open column chromatography (petroleum ether-ethyl acetate/15:1) to give compound P24 as a pale yellow solid in a yield of 12.1%. 1 H NMR(400MHz,CDCl 3 )δ13.12(s,1H),7.55(s,1H),7.19–7.09(m,1H),6.98(dd,J＝15.1,1.2Hz,1H),6.36(s,1H),2.20(s,3H),2.02(dd,J＝6.8,1.5Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ192.4,164.8,161.2,144.7,132.3,125.8,115.9,113.8,103.3,18.8,15.3.HRMS(ESI)m/zcalcd.forC 11 H 13 O 3 [M+H] + 193.0865；found,193.0864。
EXAMPLE 25 pharmacological investigation of 2-propen-1-ones according to the invention
Experimental methods
(1) Effect on Lipopolysaccharide (LPS) -induced mouse mononuclear macrophage RAW264.7 Nitric Oxide (NO) release
Determination of NO Release by Griess method, NO readily oxidized in vivo or in aqueous solution to give NO 2 - Under acidic conditions, NO promotes Griess reactions to form diazonium compounds. Concentration of diazonium compound generated by the reaction and NO 2 - The concentration of the compound is linear, and the compound can be quantitatively measured at 540-560 nm. The experimental method comprises taking mouse mononuclear macrophage RAW264.7 (conventional commercially available) cells in logarithmic growth phase at 2×10 5 Density of wells/density of wells was seeded in 96-well plates at 37℃in 5% CO 2 Culturing overnight in an incubator. After 0.5 mug/mL Lipopolysaccharide (LPS) treatment, 10 mu M sample is added for treatment, and the blank control group isDMSO, model (+) was LPS plus an equal volume of DMSO, positive controls were hydrocortisone (Hyd) and curcumin (Cur) at a concentration of 20 μm, treatment time was 24 hours. Standards (NaNO) were grown in DMEM whole medium 2 Standard solution) was diluted to 40.0, 20.0, 10.0, 5.0, 2.5, 1.25, 0 μm (light-shielding) for standard curve preparation. Cell supernatants of standard and test samples were added to 96-well plates at 50. Mu.L per well, and Griess reagent was added to 96-well plates at room temperature at 50. Mu.L per well. The mixture was gently mixed and absorbance was measured at 540 nm. 3 replicates were set for each treatment.
(2) Effect on Lipopolysaccharide (LPS) -induced mouse mononuclear macrophage RAW264.7 Inducible Nitric Oxide Synthase (iNOS) levels
The influence of 2-propylene-1-ketone compounds on the expression level of mouse mononuclear macrophage iNOS induced by LPS is detected by adopting a Western blot method. RAW264.7 cells at 2X 10 per well 6 Inoculating to six-hole plate, culturing in incubator at 37deg.C overnight, and loading. DMSO was a blank control group, model group was LPS plus equal volume of DMSO, drug treatment group was 10 μm sample plus LPS, positive control group was 20 μm hydrocortisone (Hyr) plus LPS. After 24 hours of treatment, the cells were collected into an EP tube, a prepared cell lysate (protein lysate to PMSF+Aprotin was prepared at a volume ratio of 100:1) was added, the cells were disrupted 3 times, 10 s/time using an ultrasonic disrupter, and then placed into a high-speed centrifuge at 4℃for centrifugation at 12000g for 10 minutes, and the supernatant was taken into a fresh EP tube. Protein concentration quantification was performed using BCA assay kit. Adding Loading Buffer (final concentration 1×) into the calculated protein solution, mixing, and boiling in water bath for denaturation for 5min. After cooling, SDS-PAGE gel electrophoresis experiments were performed on the samples. Adding denatured sample protein into the hole according to the calculated volume, then performing SDS-PAGE, pressing for 60V and 20min, setting 20-25 mA current for each gel, and running the gel for 1-2 hours. And after the completion, pressing the sample glue on a PVDF film activated by methanol for film transfer, wherein the film transfer voltage is set to be 100V, and the film transfer time is set to be 1.25h. After the transfer of the membrane, the PVDF membrane is sheared into strips according to the molecular weight of the target protein, the molecular weight and the marked protein name are noted, and the strips are put into 5 percent of skim milk powderThe whole is sealed by shaking at room temperature for 1h, skim milk powder is recovered, and the strips are washed 3 times with TBST buffer solution for 5min each time. The protein bands were then incubated overnight in a 4℃shaker (diluted 1:1000 in TBST buffer) with the corresponding iNOS antibody (Cell Signaling Technology, # 13120S), and the bands were washed 8 min. Times.5 times with TBST buffer the next day. The washed strips were then placed in secondary antibodies (horseradish peroxidase conjugated) to the corresponding seed sources, and incubated on a shaker at room temperature for 1 hour, followed by washing the strips 5 times with TBST for 8 minutes each. And finally, imaging by a gel imaging system, and processing and analyzing the result by Image J software.
(II) results of experiments
(1) Effect of Compounds P1-P24 on LPS-induced mouse mononuclear macrophage RAW264.7 NO Release
Standard NO concentration test standard curve is shown in fig. 1. From the experimental results of fig. 2, other compounds except for the compounds P5, P7 and P8 showed a remarkable effect of inhibiting LPS-induced release of NO by mouse mononuclear macrophages, wherein most of the compounds showed better activity than the positive control drug curcumin (Cur).
(2) Effect of Compounds P1-P24 on Lipopolysaccharide (LPS) -induced mouse mononuclear macrophage RAW 264.7-Inducible Nitric Oxide Synthase (iNOS) protein levels
From the experimental results shown in fig. 3 and 4, the compounds P2-P8 and P10-P24 obviously inhibit the expression level of the LPS-induced mouse mononuclear macrophage iNOS protein, which indicates that the compounds have good anti-inflammatory activity.
The experimental results show that the synthesized compounds have obvious anti-inflammatory effect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1.2-propylene-1-one compounds, characterized in that: the compound has a structure shown in a general formula (I):
wherein ,
r1 is any one of the following groups: (1) an H atom, (2) a methyl group, and (3) an aliphatic hydrocarbon group having 2 or more carbon atoms;
r2 is any one of the following groups: (1) H atoms, (2) methyl groups, (3) aliphatic hydrocarbon groups containing 2 or more carbon atoms, (4) acyl groups of aliphatic hydrocarbons of any length, and (5) acyl groups containing aromatic rings;
r3 is any one of the following groups: (1) H atoms, (2) methyl groups, (3) aliphatic hydrocarbon groups containing 2 or more carbon atoms, (4) acyl groups of aliphatic hydrocarbons of any length, and (5) acyl groups containing aromatic rings;
r4 is any one of the following groups: (1) methyl, (2) aliphatic hydrocarbon groups having 2 or more carbon atoms, and (3) aromatic rings having alkyl groups, hydroxyl groups, alkoxy groups, alkylenedioxy groups, halogen substitutions or unsubstituted.
2. 2-propen-1-one compound according to claim 1, characterized in that:
r1 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms;
r2 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms, (4) acyl of aliphatic hydrocarbon group containing 2-5 carbon atoms, and (5) acyl containing aromatic ring;
r3 is (1) H, (2) methyl, (3) aliphatic hydrocarbon group containing 2-5 carbon atoms, (4) acyl of aliphatic hydrocarbon group containing 2-5 carbon atoms, and (5) acyl containing aromatic ring;
r4 is (1) methyl, (2) aliphatic hydrocarbon group containing 2-5 carbon atoms, and (3) aromatic ring containing alkyl, hydroxy, alkoxy, alkylenedioxy, halogen substituted or unsubstituted.
3. 2-propen-1-one compounds according to claim 2, characterized in that:
r1 is (1) H atom, (2) methyl;
r2 is (1) H atom, (2) methyl;
r3 is (1) H, (2) methyl, (3) 2-butene-1-acyl, 2, 4-hexadiene-1-acyl, (4) 4-fluorobenzoyl, 4-chlorobenzoyl;
r4 is (1) methyl, (2) propenyl, (3) phenyl ring containing methyl, hydroxyl, methoxy, methylenedioxy and fluoro, chloro substituted or unsubstituted.
4. A 2-propen-1-one compound according to claim 3, characterized in that:
p1: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3-phenylprop-2-en-1-one;
p2: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methylphenyl) prop-2-en-1-one;
p3: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one;
p4: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p5: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (3, 4-methylenedioxyphenyl) -2-propen-1-one;
p6: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p7: (E) -4- [ (E) -3- (4-fluorophenyl) -acryl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-fluorophenyl) acrylate;
p8: (E) -4- [ (E) -3- (4-chlorophenyl) -acryloyl-3-hydroxy-2, 6-dimethylphenyl ] -3- (4-chlorophenyl) acrylate;
p9: (2 e,4 e) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) hex-2, 4-dien-1-one;
p10: (2 e,4 e) -4- [ (2 e,4 e) -hexa-2, 4-dienoyl) -3-hydroxy-2, 6-dimethylphenyl) hexa-2, 4-dienoic acid ester;
p11: (E) -4- [ (E) -but-2-enoyl) -3-hydroxy-2, 6-dimethylphenyl) but-2-enoate;
p12: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p13: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p14: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3- (4-fluorophenyl) prop-2-en-1-one;
p15: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p16: (E) -1- (2-hydroxy-4-methoxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p17: (E) -1- (2, 4-dihydroxy-5-methylphenyl) -3-phenylpropan-2-en-1-one;
p18: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one;
p19: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p20: (E) -1- (2, 4-dimethoxy-5-methylphenyl) -3- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one;
p21: (E) -1- (2, 4-dimethoxy-3, 5-dimethylphenyl) but-2-en-1-one;
p22: (E) -1- (2, 4-dihydroxy-3, 5-dimethylphenyl) but-2-en-1-one;
p23: (E) -1- (2, 4-dimethoxy-5-methylphenyl) but-2-en-1-one;
p24: (E) -1- (2, 4-dihydroxy-5-methylphenyl) but-2-en-1-one;
5. the process for producing 2-propen-1-one compounds as claimed in claim 3 or 4, wherein: the method comprises the following steps:
firstly, reducing 2, 4-dihydroxyl-3-methylbenzaldehyde 1a serving as a starting raw material by lithium aluminum hydride to obtain a 2, 4-dimethylresorcinol 2a intermediate, and carrying out a Friedel-crafts acylation reaction on the intermediate 2a and freshly prepared acyl chloride under the catalysis of aluminum trichloride to obtain a product, wherein the reaction formula 1;
wherein, acyl chloride is prepared by corresponding carboxylic acid and thionyl chloride, and the reaction formula is 2;
(II) or, taking 2, 4-dihydroxyl-3-methylbenzaldehyde 1a and 2, 4-dihydroxybenzaldehyde 1b as starting materials, firstly reducing by lithium aluminum hydride to obtain intermediates of 2, 4-dimethylresorcinol 2a and 4-methylresorcinol 2b, and reacting the intermediates 2a and 2b with methyl iodide to obtain intermediates 3a and 3b; the intermediates 3a and 3b undergo Friedel-crafts acylation reaction with freshly prepared acyl chloride under the catalysis of aluminum trichloride to obtain a product A, a reaction formula 3; the product A is demethylated by boron tribromide to obtain products B and C;
wherein, acyl chloride is prepared by corresponding carboxylic acid and thionyl chloride, and the reaction formula is 2;
the specific reaction formula is as follows:
reaction formula 1:
reaction formula 2:
reaction formula 3:
wherein ,
6. a pharmaceutical composition characterized by: comprising the 2-propen-1-one compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, an optically active substance, a diastereomer and a pharmaceutically acceptable carrier.
7. Use of a 2-propen-1-one compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 for the preparation of a nitric oxide generation inhibitor medicament.
8. The use according to claim 7, characterized in that:
the application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing a medicament for inhibiting an inducible nitric oxide synthase-mediated NO generation inhibitor;
or the application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing an inducible nitric oxide synthase inhibitor.
9. The use according to claim 7, characterized in that:
the application of the 2-propylene-1-ketone compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing anti-inflammatory drugs.
10. Use according to any one of claims 7 to 9, characterized in that:
the medicine is in the form of injection, instillation liquid, powder injection, granule, tablet, granule, powder, oral liquid, sugar-coated tablet, film-coated tablet, enteric-coated tablet, buccal agent, granule, pill, paste, pellet, spray, dripping pill, disintegrating agent, orally disintegrating tablet or micropill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111257510.3A CN116023247A (en) | 2021-10-27 | 2021-10-27 | 2-propylene-1 ketone compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111257510.3A CN116023247A (en) | 2021-10-27 | 2021-10-27 | 2-propylene-1 ketone compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116023247A true CN116023247A (en) | 2023-04-28 |
Family
ID=86078286
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111257510.3A Pending CN116023247A (en) | 2021-10-27 | 2021-10-27 | 2-propylene-1 ketone compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116023247A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688566A (en) * | 2002-10-01 | 2005-10-26 | 宝生物工程株式会社 | Remedies |
| CN102397269A (en) * | 2011-09-20 | 2012-04-04 | 温州医学院 | Application of chalcone compounds in preparations of inflammation resisting medicines |
| KR20170024291A (en) * | 2015-08-25 | 2017-03-07 | 한림대학교 산학협력단 | Synthetic methods for prenylated chalcones and pyranochalcones |
-
2021
- 2021-10-27 CN CN202111257510.3A patent/CN116023247A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688566A (en) * | 2002-10-01 | 2005-10-26 | 宝生物工程株式会社 | Remedies |
| CN102397269A (en) * | 2011-09-20 | 2012-04-04 | 温州医学院 | Application of chalcone compounds in preparations of inflammation resisting medicines |
| KR20170024291A (en) * | 2015-08-25 | 2017-03-07 | 한림대학교 산학협력단 | Synthetic methods for prenylated chalcones and pyranochalcones |
Non-Patent Citations (8)
| Title |
|---|
| AHMED AL FAHAD等: "Oxidative dearomatisation: the key step of sorbicillinoid biosynthesis", 《CHEMICAL SCIENCE》, no. 5, 20 November 2013 (2013-11-20), pages 524 * |
| ANNA SIB等: "Stereoselective Total Synthesis of Bisorbicillinoid Natural Products by Enzymatic Oxidative Dearomatization/Dimerization", 《ANGEW.CHEM》, vol. 56, 8 September 2017 (2017-09-08), pages 12888 - 3 * |
| CHAO QI等: "Total Synthesis and Stereochemical Assignment of (±)-Sorbiterrin A", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 136, no. 9, 24 February 2014 (2014-02-24), pages 3374 * |
| LIU, X. L.等: "Functionalized chalcones with basic functionalities have antibacterial activity against drug sensitive Staphylococcus aureus", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 43, no. 8, 11 October 2007 (2007-10-11), pages 9 - 152 * |
| RACHEL H. CARTER等: "The Synthesis of Indan-I -ones and lsocoumarins", 《JOURNAL OF THE CHEMICAL SOCIETY》, no. 2, 1 January 1981 (1981-01-01), pages 472 * |
| WEN-JIAN LAN等: "Novel Sorbicillin Analogues from the Marine Fungus Trichoderma sp.Associated with the Seastar Acanthaster planci", 《NATURAL PRODUCT COMMUNICATION》, vol. 7, no. 10, 28 November 2012 (2012-11-28), pages 1337 * |
| 张爽等: "查耳酮衍生物的结构修饰及生物活性研究进展", 《药学进展》, vol. 36, no. 6, 25 June 2012 (2012-06-25), pages 244 - 245 * |
| 张金玉: "《有机合成反应及路线设计研究》", 31 May 2021, 中国原子能出版传媒有限公司, pages: 91 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Harrak et al. | Synthesis and biological activity of new anti-inflammatory compounds containing the 1, 4-benzodioxine and/or pyrrole system | |
| CN101711231B (en) | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and uses thereof | |
| Boisvert et al. | Regiospecific addition of monooxygenated dienes to halo quinones | |
| Shiraishi et al. | Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation | |
| WO1995003044A1 (en) | Benzimidazolinones substituted with phenoxyphenylacetic acid derivatives | |
| JPH09503994A (en) | Balanoid | |
| JP2561354B2 (en) | Benzocycloalkenyldihydroxyalkanoic acid compound, method for producing the same and pharmaceutical composition containing the same | |
| CN102164905B (en) | Compounds as hypoxia mimetics, and compositions, and uses thereof | |
| Li et al. | Improving metabolic stability with deuterium: The discovery of GPU-028, a potent free fatty acid receptor 4 agonists | |
| JPH03501859A (en) | N-imidazolyl and N-imidazolylmethyl derivatives of substituted bicyclic compounds | |
| EP1742903B1 (en) | Pentenoic acid derivatives, processes for the preparation thereof, pharmaceutical compositions comprising them, and therapeutic applications thereof | |
| WO1994024119A1 (en) | Coumarin derivative and use thereof | |
| CN116023247A (en) | 2-propylene-1 ketone compound and preparation method and application thereof | |
| JPS6229582A (en) | Intermediate for synthesizing carboxylic acid | |
| JPH01305078A (en) | Novel heteroarotinoide derivative | |
| CN114292233A (en) | Syringopicroside aglycone derivative with bacteriostatic activity and synthesis method thereof | |
| JPH0347165A (en) | Pyrrole carboxylic acid derivative | |
| CN108586426B (en) | Alkoxy biphenyl/chalcone hybrid compound, and preparation method and medical application thereof | |
| US5705525A (en) | Thiophene compounds | |
| Lu et al. | Design, synthesis and biological evaluation of novel bergapten derivatives as potent lipid lowering agents | |
| US4013692A (en) | Certain 3-phenyl-benzofuran lower alkanoic acids and esters thereof | |
| CN115197236B (en) | Linear type glabra A analogue and preparation and application thereof | |
| JP2559814B2 (en) | Catechol derivative and pharmaceutical preparation containing the same | |
| JPS6144853A (en) | Gamma-linoleic acid derivative and thrombocyte coagulation suppressing agent containing same | |
| JP2002371033A (en) | ω-ARYL-alpha-SUBSTITUTED FATTY ACID DERIVATIVE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |