CN109912490A - A kind of indole compound Plancyindole E and preparation method thereof - Google Patents
A kind of indole compound Plancyindole E and preparation method thereof Download PDFInfo
- Publication number
- CN109912490A CN109912490A CN201811454305.4A CN201811454305A CN109912490A CN 109912490 A CN109912490 A CN 109912490A CN 201811454305 A CN201811454305 A CN 201811454305A CN 109912490 A CN109912490 A CN 109912490A
- Authority
- CN
- China
- Prior art keywords
- plancyindole
- indole compound
- compound
- water
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 21
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims 11
- -1 indole compound Chemical class 0.000 title claims 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims 11
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 3
- 239000002024 ethyl acetate extract Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 claims 1
- 229940125721 immunosuppressive agent Drugs 0.000 claims 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 abstract description 14
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 9
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 abstract description 8
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 238000011156 evaluation Methods 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000758 substrate Substances 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 4
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- PKYCWFICOKSIHZ-UHFFFAOYSA-N 1-(3,7-dihydroxyphenoxazin-10-yl)ethanone Chemical compound OC1=CC=C2N(C(=O)C)C3=CC=C(O)C=C3OC2=C1 PKYCWFICOKSIHZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000010355 oscillation Effects 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000005482 chemotactic factor Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- 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 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 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
- 241000908115 Bolivar Species 0.000 description 1
- 241001427554 Corydiidae Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 229940123241 Janus kinase 3 inhibitor Drugs 0.000 description 1
- SGUKUZOVHSFKPH-UHFFFAOYSA-N PGG2 Natural products C1C2OOC1C(C=CC(OO)CCCCC)C2CC=CCCCC(O)=O SGUKUZOVHSFKPH-UHFFFAOYSA-N 0.000 description 1
- 241000864228 Polyphaga plancyi Species 0.000 description 1
- 208000022329 Protein metabolism disease Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229940068840 d-biotin Drugs 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 229940089536 indocin Drugs 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- SGUKUZOVHSFKPH-YNNPMVKQSA-N prostaglandin G2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](OO)CCCCC)[C@H]2C\C=C/CCCC(O)=O SGUKUZOVHSFKPH-YNNPMVKQSA-N 0.000 description 1
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention is suitable for chemical medicine field, provides a kind of Benzazole compounds Plancyindole E with COX-2 and JAK3 inhibitory activity, and provide the preparation method of the compound.Pharmacological evaluation shows that compound Plancyindole E has and significantly inhibits the activity of COX-2, JAK3, diseases associated with inflammation and as in terms of there is practicability.
Description
Technical field
The invention belongs to chemical medicine field more particularly to a kind of Benzazole compounds Plancyindole E and its preparations
Method.
Background technique
Inflammatory reaction is constantly struggled against by the participation of a variety of media, inflammatory factor and body until reaching the complexity of a balance
Process.Common anti inflammatory medicine is divided into Steroidal anti-inflammatory drug (SAIDs) and non-steroidal anti-inflammatory drug (NSAIDs).SAIDs is sugar
Corticoid inhibitor such as hydrocortisone, dexamethasone, though there is fabulous anti-inflammatory curative effect, long-time service can cause water salt
Metabolism and sugar, fatty, protein metabolism disorder.NSAIDs be clinically mainly used for rheumatism, chronic inflammatory arthritis,
Respiratory tract infection, sports type damage etc. are a kind of by inhibiting Cycloxygenase (COX) to reach the drug of anti-inflammatory effect.
COX-1 is present in the physiological state in each organ cell, wherein prostaglandin E2 synthesized by the COX-1 of stomach lining
(PGE2) have and maintain gastric tissue normal blood flow amount, increase the effect of stomach lining mucus.COX-2 is expressed in normal tissue cell
Amount is few, COX-2 ability great expression after cell is inflamed by various stimulations.Arachidonic acid is under the action of COX-2
It is first converted into PGG2, is then further converted into PGH2, and dehydration or isomerization etc. occur under the action of enzyme
Different prostaglandins (PG) is formed, wherein PGE2 can induce inflammatory cell release chemotactic factor (CF), raise inflammatory cell movement, greatly
Amount expression inflammatory cytokine IL-1, IL-6, IL-23 etc., play pro-inflammatory effect.It is increasing with NSAIDs demand, with
Caused by digestive tract side effects become increasingly conspicuous.Traditional non-selective NSAIDs such as aspirin, indocin etc. is used for a long time,
It can inhibit COX-1 activity, reduce physiological PGs synthesis, it is difficult to maintain the normal physiological function of gastrointestinal tract, as a result cause stomach glutinous
The adverse reactions such as membrane damage, ulcer, perforation and bleeding.Therefore it is directed to COX-2 target drug, FDA releases first COX-2 within 1998
Inhibitor Celebrex reduces while playing anti-inflammatory and analgesic effect and eliminates gastrointestinal tract caused by inhibition COX-1
Adverse reaction, therefore be used widely.In recent years, COX-2 has become an important drug target, whether merely
Cox 2 inhibitor, or combine lipoxidase (LOX) double inhibitor, or using nitric oxide (NO) protect stomach and intestine
For the function in road, following is the important directions of NSAIDs research always using COX-2 as the anti-inflammatory inhibitor of target spot.
JAK3 is studied more, is the important channel for finding neotype immunosuppressant drug using it as target.Due to
JAK3 is initially expressed in hematopoietic cell, therefore the JAK3 inhibitor for being considered a kind of high degree of specificity can generate immunocyte
Accurately effect, so that the effect of drugs of discovery is also superior at present with other immunosuppressive drugs for target.
Ground bettle (Polyphaga plancyi Bolivar) is that the female adult of Corydiidae insect ground bettle is dry all, is begun
It is loaded in Shennong's Herbal, is had the function of by the stasis of blood, broken product, dredging collateral, reason wound etc., is traditional insects Chinese medicine simply.The present invention by
Shenzhen's Kechuang committee project (JCYJ20170412110504956) etc. supports that the compound being related to comes from ground bettle, belongs to indoles
Class noval chemical compound has no it in relation to relevant report anti-inflammatory and as disease of immune system prevention and treatment.
Summary of the invention
Benzazole compounds Plancyindole E provided by the invention has structure shown in the following figure,
The present invention also provides the pharmaceutical composition of the noval chemical compound, described pharmaceutical composition includes Plancyindole E
Or its pharmaceutically acceptable derivates and its esters.
Further, the pharmaceutical composition of the Benzazole compounds is pharmaceutical preparation, is by Plancyindole E
With Plancyindole C or its pharmaceutically acceptable derivates and its esters as active constituent and pharmaceutically acceptable
Excipient composition.
Wherein solid pharmaceutical preparation includes: tablet, capsule, pill, granule etc.；Semisolid preparation includes ointment, suppository
Deng；Liquid preparation includes: solution, injection, spray etc.；Eye-drops preparations includes: eye drops, gel for eye etc..
The present invention be also disclosed the Benzazole compounds Plancyindole E's the preparation method comprises the following steps:
70% ethyl alcohol heating and refluxing extraction (300L, 4h, 3h, 3h) of ground bettle dry polypide (50kg) is taken, is concentrated under reduced pressure,
It obtains total extract (6.32kg).After total extract adds suitable quantity of water to be suspended, is successively extracted 3 times with petroleum ether and ethyl acetate, obtain acetic acid second
Ester extraction part (127g).Ethyl acetate extract medicinal extract by MCI gel CHP 20P column chromatography draw section (methanol/water, 10%-
100%), TLC combining data detection identical component finally obtains 6 group sections, Fr.A-Fr.F.Fr.D (8.7g) is through Sephadex LH-
20 column chromatography for separation, methanol-water (80:20) elution, merging obtain 6 group sections, Fr.D1-D6.Fr.D6 (1.01g) warp
Sephadex LH-20 column chromatography for separation, methanol elution, merging obtain 4 group sections, Fr.D6.1-D6.4.Fr.D6.4(200mg)
The compound for purifying as shown in the figure through half preparation RP-18HPLC (acetonitrile-water, 21:79, flow velocity: 3mL/min)
Plancyindole E (1.0mg, tR=14.0min).
Further, the Benzazole compounds are obtained or are obtained by artificial synthesized by extracting from ground bettle
?.
Further, the application in terms of the Benzazole compounds are with inflammation inhibition and disease of immune system is intervened.
Compared with prior art, the present invention beneficial effect is:
1, present invention firstly discloses the sides that the separation noval chemical compound Plancyindole E is extracted from ground bettle
Method.
2, the noval chemical compound Plancyindole E in the present invention is the new chemical combination obtained for the first time from ground bettle separation identification
Object.
3, the noval chemical compound Plancyindole E in the present invention has the activity for inhibiting COX-2 and JAK3.
4., the noval chemical compound Plancyindole E in the present invention has and intervenes diseases associated with inflammation and disease of immune system
Purposes.
Specific embodiment
It, below will be to the embodiment of the present invention to enable the purpose of the present invention, feature, advantage more obvious and understandable
In technical solution be clearly and completely described, it is clear that described embodiments are only a part of the embodiments of the present invention,
And not all embodiments.Based on the embodiments of the present invention, those skilled in the art are without making creative work
Every other embodiment obtained, shall fall within the protection scope of the present invention.
The extraction separation of 1 Benzazole compounds Plancyindole E of embodiment and Structural Identification
70% ethyl alcohol heating and refluxing extraction (300L, 4h, 3h, 3h) of ground bettle dry polypide (50kg) is taken, is concentrated under reduced pressure,
It obtains total extract (6.32kg).After total extract adds suitable quantity of water to be suspended, is successively extracted 3 times with petroleum ether and ethyl acetate, obtain acetic acid second
Ester extraction part (127g).Ethyl acetate extract medicinal extract by MCI gel CHP 20P column chromatography draw section (methanol/water, 10%-
100%), TLC combining data detection identical component finally obtains 6 group sections, Fr.A-Fr.F.Fr.D (8.7g) is through Sephadex LH-
20 column chromatography for separation, methanol-water (80:20) elution, merging obtain 6 group sections, Fr.D1-D6.Fr.D6 (1.01g) warp
Sephadex LH-20 column chromatography for separation, methanol elution, merging obtain 4 group sections, Fr.D6.1-D6.4.Fr.D6.4(200mg)
The compound for purifying as shown in the figure through half preparation RP-18HPLC (acetonitrile-water, 21:79, flow velocity: 3mL/min)
Plancyindole E (1.0mg, tR=14.0min).
Compound structure identification is as follows:
Compound Plancyindole E (1), faint yellow solid, 371 (4.16) UV (MeOH) max (log ε), 272
(4.01), 206 (4.35) nm；HRESIMS m/z 282.0768[M–H]–(calcd for C16H12NO4,282.0772).1H
and 13C NMR data, is shown in Table 1.
1. compound 1 of table1H and13C NMR data
2 compound of embodiment inhibits COX-2 test method
The present embodiment is examined with Cayman ' s COX Fluorescent Inhibitor Screening Assay Kit
Survey the enzymatic activity of COX-2.Specific step is as follows:
1, compound gradient dilution: compound is first dissolved into 10mM storing liquid with DMSO, and dilute with DMSO 1:3 gradient
It is interpreted into 1000 × series of compounds concentration storing liquid of 10 concentration gradients, transfers to compound transferring apparatus adaptation
It is spare in 384PP plate.
2, every hole is added 10 μ l of enzyme dilution, blank control wells not 10 μ l 1xassay buffer of enzyme addition.
3, compound the compound that 1000 × gradient concentration of 20nl has diluted is transferred to be added in reaction solution, it is empty
DMSO is added in white control and DMSO control wells.It is incubated at room temperature 10-15min.
4, fluorogenic substrate ADHP is diluted with 1xassay buffer and d-Biotin eme, Heme extension rate is 100 times, ADHP
Extension rate is 40 times.4 μ l ADHP dilutions and 4 μ l Heme dilutions are added in every hole.
5, substrate arachidonic acid is prepared with water and potassium hydroxide working solution, extension rate are 40 times.2 μ l are added in every hole
Substrate, at once with fluorescence signal at microplate reader dynamic detection 531/595nm.
The results show that noval chemical compound, which has, inhibits COX-2 activity, IC50As shown in table 2.
The activity test method of 3 compound of embodiment inhibition protein kinase JAK3
Compound inhibits protein kinase activity detection to be detected with Z-lyte fluorescence resonance energy transfer method.Protein kinase and
Its corresponding substrate reagent box is purchased from Life technologies company.All reactions carry out on 384 microwell plates, and enzyme is anti-
Answering volume is 10 μ l.Reaction buffer ingredient is 50mM HEPES pH 7.5,10mM MgCl2,1mM EGTA, 0.01%
BRIJ-35.Specific reaction are as follows: the 5 suitable protein kinases of μ l substrate corresponding to 5 μ l is added in microwell plate first, and (reaction is dense eventually
Degree is 2 μM) mixed liquor, then use the Echo520 ultrasonic wave micro liquid transfer system (U.S.Labcyte company) be added it is a series of
The compound of gradient dilution is eventually adding the ATP of respective concentration, after oscillation mixes 5min, is placed in reaction in 29 degree of insulating boxs
1.5h；Then the detection liquid (Development Reagent) of 5 μ l respective concentrations is added, oscillation mixes 5min, is placed in 29 degree of perseverances
1h is reacted in incubator；5 μ l terminate liquids (Stop Reagent) are eventually adding, the Envision of PE company is used in oscillation after mixing
MultilabelReader multi-function microplate reader is detected, and a length of 400nm of excitation light wave, wavelength of transmitted light is respectively 445nm
And 520nm.Experiment is respectively set instrument connection (adding compound, enzyme, substrate and ATP), 0% phosphorylation hole (add DMSO, substrate and
ATP) 100% phosphorylation hole (only plus phosphorylated substrate), 0% inhibiting rate hole (adds DMSO, enzyme, substrate and ATP).According to fluorescence ratio
Value calculates compound to the inhibiting rate of enzyme reaction, carries out the IC that analysis meter calculates compound with GraphPad software50Value.
The results show that compound, which has, inhibits JAK3 activity, IC50As shown in table 2.
Inhibitory activity of 2. compound of table to COX-2, JAK3
Embodiment 4
Compound in embodiment 1, routinely method adds solvent for injection, and refined filtration can be made into injection after encapsulating sterilizing.
Embodiment 5
Compound in embodiment 1, is dissolved in sterile water for injection, is filtered with sterile funnel, packing, low temperature cold freeze-drying
It is sterile after dry to seal up to powder-injection.
Embodiment 6
Compound in embodiment 1, routinely method, which is equipped with various pharmaceutic adjuvants, can be made into tablet or capsule.Use embodiment
Compound is as active pharmaceutical ingredient in 1, uses several conventional excipients as preparing the auxiliary of composition of medicine tablet or capsule
Expect ingredient, the sample that every or every capsule contains drug ingedient 10-300mg is conventionally made.
In the above-described embodiments, it all emphasizes particularly on different fields to the description of each embodiment, there is no the portion being described in detail in some embodiment
Point, it may refer to the associated description of other embodiments.
The above are to a kind of Benzazole compounds Plancyindole E provided in an embodiment of the present invention and preparation method thereof
Description, for those skilled in the art, thought according to an embodiment of the present invention, in specific embodiments and applications
There will be changes, and to sum up, the contents of this specification are not to be construed as limiting the invention.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811454305.4A CN109912490B (en) | 2018-11-30 | 2018-11-30 | A kind of indole compound Plancyindole E and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811454305.4A CN109912490B (en) | 2018-11-30 | 2018-11-30 | A kind of indole compound Plancyindole E and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109912490A true CN109912490A (en) | 2019-06-21 |
| CN109912490B CN109912490B (en) | 2020-10-16 |
Family
ID=66959818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811454305.4A Active CN109912490B (en) | 2018-11-30 | 2018-11-30 | A kind of indole compound Plancyindole E and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109912490B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153911A (en) * | 2019-10-12 | 2020-05-15 | 深圳大学 | Lipid-lowering compound commiphorine A and its application in pharmacy |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124347A (en) * | 1991-07-31 | 1992-06-23 | Warner-Lambert Co. | 3-5-ditertiarybutylphenyl-4-hydroxymethylidene derivatives of 1,3-dihydro-2H-indole-2-ones as antiinflammatory agents |
| US5382593A (en) * | 1992-07-21 | 1995-01-17 | Adir Et Compagnie | New 3-(hydroxybenzylidenyl)-indolin-2-ones |
| CN1155838A (en) * | 1995-06-07 | 1997-07-30 | 苏根公司 | Indolinone compounds for the treatment of disease |
| CN101973925A (en) * | 2010-10-15 | 2011-02-16 | 中国药科大学 | 2-indolone compound with anti-inflammatory activity, preparation method and medicinal application thereof |
| CN102264699A (en) * | 2008-10-14 | 2011-11-30 | 新加坡国立大学 | Novel benzylidene-indolinones and their medical and diagnostic uses |
| US20130035364A1 (en) * | 2011-08-04 | 2013-02-07 | Mei Lin Go | Benzylidene-indolinone compounds and their medical use |
-
2018
- 2018-11-30 CN CN201811454305.4A patent/CN109912490B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124347A (en) * | 1991-07-31 | 1992-06-23 | Warner-Lambert Co. | 3-5-ditertiarybutylphenyl-4-hydroxymethylidene derivatives of 1,3-dihydro-2H-indole-2-ones as antiinflammatory agents |
| US5382593A (en) * | 1992-07-21 | 1995-01-17 | Adir Et Compagnie | New 3-(hydroxybenzylidenyl)-indolin-2-ones |
| CN1155838A (en) * | 1995-06-07 | 1997-07-30 | 苏根公司 | Indolinone compounds for the treatment of disease |
| CN102264699A (en) * | 2008-10-14 | 2011-11-30 | 新加坡国立大学 | Novel benzylidene-indolinones and their medical and diagnostic uses |
| CN101973925A (en) * | 2010-10-15 | 2011-02-16 | 中国药科大学 | 2-indolone compound with anti-inflammatory activity, preparation method and medicinal application thereof |
| US20130035364A1 (en) * | 2011-08-04 | 2013-02-07 | Mei Lin Go | Benzylidene-indolinone compounds and their medical use |
Non-Patent Citations (1)
| Title |
|---|
| MOUHSSIN OUFIR ET AL.: "Caco-2 Permeability Studies and In Vitro hERG Liability Assessment of Tryptanthrin and Indolinone", 《PLANTA MEDICA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153911A (en) * | 2019-10-12 | 2020-05-15 | 深圳大学 | Lipid-lowering compound commiphorine A and its application in pharmacy |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109912490B (en) | 2020-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103059043A (en) | Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof | |
| CN101434635B (en) | A class of water-soluble phenolic triterpenoids with antitumor activity and preparation method thereof | |
| CN114699419A (en) | Application of PLpro protein inhibitors in drugs for the treatment or prevention of novel coronavirus infection | |
| CN109912490A (en) | A kind of indole compound Plancyindole E and preparation method thereof | |
| CN109810049A (en) | A kind of compound containing pyridine and extraction method thereof | |
| CN107661322B (en) | New application of phloroglucinol compounds in Mianma Guanzhong | |
| CN110627760A (en) | Compound (+/-)-Lucidumone and its preparation method and application in pharmacy and food | |
| CN101342159B (en) | Application of bromine phenolic compound in preparing medicament for treating type 2 diabetes or adiposis | |
| CN106265681B (en) | Application of a kind of triterpene compound in the preparation of glycosidase inhibitor medicine | |
| CN110590779B (en) | 3,10-di-p-chlorophenyl 6,12-diazatetra-homocubic compound and its synthetic method, application and pharmaceutical composition | |
| CN113214350B (en) | Triterpenoid lactone of Dimmonium lucidum and its preparation method, pharmaceutical composition and use | |
| CN112851626B (en) | Levalacyclomorpholine, preparation method, pharmaceutical composition and application thereof | |
| CN109467529A (en) | A series of phenolic compounds with COX-2 inhibitory activity and preparation method thereof | |
| WO2004039797A1 (en) | A special kind of indole compounds, their preparation, and their use in treatment and prevention of those disease such as cancer | |
| CN109627229A (en) | A kind of phenoloid | |
| CN115124543B (en) | Tricyclic pyridone compounds with antiviral activity and application thereof | |
| CN101019861A (en) | New use of norsantharidin and its derivative in preventing and treating AIDS | |
| Li et al. | Therapeutic effect of iridoid and xanthone glycosides components extracted from Swertia Mussotti on calculous cholecystitis and its clinical complications by targeting COX2 | |
| CN104083347A (en) | Applications of compound ent-kaur-16-en-19-oic acid in preparation of glycosidase inhibitor medicines | |
| CN116942656B (en) | Application of naringenin derivative in preparation of anti-pancreatitis medicine | |
| CN107879958B (en) | 2-(4-Methoxyphenylmercapto)-5,8-dimethoxy-1,4-naphthoquinone, preparation method and medicine containing same | |
| CN103159720B (en) | 8-epi-isoandrographolidume-19-sulfate, preparation method and purposes of prepared medicine | |
| CN109438300B (en) | Phenolic compound and preparation method thereof | |
| CN118184659A (en) | Covalent conjugate for resisting novel coronavirus and preparation method thereof | |
| CN103910735B (en) | Pyrazolopyrimidinone compound and derivant, and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |