CN102504005B - 一类具有新型结构的化合物及其制备方法和用途 - Google Patents
一类具有新型结构的化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN102504005B CN102504005B CN201110312179.0A CN201110312179A CN102504005B CN 102504005 B CN102504005 B CN 102504005B CN 201110312179 A CN201110312179 A CN 201110312179A CN 102504005 B CN102504005 B CN 102504005B
- Authority
- CN
- China
- Prior art keywords
- compound
- thione
- acid
- phenoxy
- inflammation
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 206010061218 Inflammation Diseases 0.000 claims abstract description 29
- 230000004054 inflammatory process Effects 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 229940100243 oleanolic acid Drugs 0.000 claims description 35
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 claims description 28
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 claims description 27
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 claims description 27
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 claims description 27
- -1 3-[4-(3H-1,2-dithiol-3-thione-5-yl)-phenoxy]propyl oleanolic acid ester Chemical class 0.000 claims description 22
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 9
- FMIMFCRXYXVFTA-FUAOEXFOSA-N (4as,6ar,6as,6br,8ar,12ar,14bs)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-3,4,5,6,6a,7,8,8a,11,12,13,14b-dodecahydro-1h-picene-4a-carboxylic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C FMIMFCRXYXVFTA-FUAOEXFOSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 6
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 17
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 abstract description 13
- 238000002474 experimental method Methods 0.000 abstract description 13
- 229910000037 hydrogen sulfide Inorganic materials 0.000 abstract description 13
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 10
- 230000006378 damage Effects 0.000 abstract description 9
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 230000000144 pharmacologic effect Effects 0.000 abstract description 5
- 210000004204 blood vessel Anatomy 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- 230000000694 effects Effects 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 241000700159 Rattus Species 0.000 description 24
- 238000012360 testing method Methods 0.000 description 19
- 238000004896 high resolution mass spectrometry Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 16
- 230000002496 gastric effect Effects 0.000 description 16
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 206010042674 Swelling Diseases 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 230000008961 swelling Effects 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 238000001308 synthesis method Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 11
- IWBBKLMHAILHAR-UHFFFAOYSA-N chembl402341 Chemical compound C1=CC(O)=CC=C1C1=CC(=S)SS1 IWBBKLMHAILHAR-UHFFFAOYSA-N 0.000 description 11
- 206010014025 Ear swelling Diseases 0.000 description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960001259 diclofenac Drugs 0.000 description 9
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical group OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 9
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 229940117173 croton oil Drugs 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 208000007107 Stomach Ulcer Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 201000005917 gastric ulcer Diseases 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 208000011231 Crohn disease Diseases 0.000 description 5
- 208000007882 Gastritis Diseases 0.000 description 5
- 240000001307 Myosotis scorpioides Species 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010009900 Colitis ulcerative Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 201000011549 stomach cancer Diseases 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 239000004201 L-cysteine Substances 0.000 description 3
- 235000013878 L-cysteine Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102000020018 Cystathionine gamma-Lyase Human genes 0.000 description 2
- 108010045283 Cystathionine gamma-lyase Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 208000019926 Keshan disease Diseases 0.000 description 2
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 244000000231 Sesamum indicum Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000007321 biological mechanism Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000007211 cardiovascular event Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 210000000232 gallbladder Anatomy 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000009965 odorless effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007845 reactive nitrogen species Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- HWBYIPKEXQQINW-UHFFFAOYSA-N 5-[4-(2-bromoethoxy)phenyl]dithiole-3-thione Chemical compound C1=CC(OCCBr)=CC=C1C1=CC(=S)SS1 HWBYIPKEXQQINW-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 240000000031 Achyranthes bidentata Species 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- KYLIZBIRMBGUOP-UHFFFAOYSA-N Anetholtrithion Chemical compound C1=CC(OC)=CC=C1C1=CC(=S)SS1 KYLIZBIRMBGUOP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000023514 Barrett esophagus Diseases 0.000 description 1
- 208000023665 Barrett oesophagus Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000015163 Biliary Tract disease Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 208000018380 Chemical injury Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000035984 Colonic Polyps Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- 241000219104 Cucurbitaceae Species 0.000 description 1
- 244000304337 Cuminum cyminum Species 0.000 description 1
- 235000007129 Cuminum cyminum Nutrition 0.000 description 1
- 108010073644 Cystathionine beta-synthase Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 235000011511 Diospyros Nutrition 0.000 description 1
- 244000236655 Diospyros kaki Species 0.000 description 1
- 206010072268 Drug-induced liver injury Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000555682 Forsythia x intermedia Species 0.000 description 1
- 208000036495 Gastritis atrophic Diseases 0.000 description 1
- 206010017914 Gastroenteritis salmonella Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061172 Gastrointestinal injury Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018366 Glomerulonephritis acute Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000234318 Heliconiaceae Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010060708 Induration Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000005102 Kashin-Beck Disease Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000735234 Ligustrum Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 201000000090 Microsporidiosis Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000551546 Minerva Species 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 235000017879 Nasturtium officinale Nutrition 0.000 description 1
- 240000005407 Nasturtium officinale Species 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 102000012547 Olfactory receptors Human genes 0.000 description 1
- 108050002069 Olfactory receptors Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241000180649 Panax notoginseng Species 0.000 description 1
- 235000003143 Panax notoginseng Nutrition 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010061339 Perineal pain Diseases 0.000 description 1
- 241001425800 Pipa Species 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 244000179560 Prunella vulgaris Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 241000218201 Ranunculaceae Species 0.000 description 1
- 206010064993 Rectal fissure Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038372 Renal arteriosclerosis Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 241000220286 Sedum Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 206010040550 Shigella infections Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000303379 Styrax officinalis Species 0.000 description 1
- 235000001361 Styrax officinalis Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 244000223014 Syzygium aromaticum Species 0.000 description 1
- 235000016639 Syzygium aromaticum Nutrition 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 244000126002 Ziziphus vulgaris Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940011037 anethole Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229940105305 carbon monoxide Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004640 cellular pathway Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 201000008865 drug-induced hepatitis Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 208000037907 haemorrhagic injury Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000003990 molecular pathway Effects 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一类具有新型结构化合物的制备方法及其医药用途，所述化合物包含与硫化氢有关的部分，其通常与化合物共价结合或形成盐。其结构通式
或
。药理学实验结果显示，上述化合物具有显著的抗炎作用及抗肿瘤作用，而且未见显著的胃肠道损伤，上述化合物可能用于制备治疗各种疾病尤其是炎症、心血管、肿瘤相关疾病的药物。此外，本发明还提供了制备这些化合物的方法。
Description
技术领域
本发明涉及医药领域，具体涉及一类奇墩果酸衍生物及其药学上可接受的盐，其制备方法、含有这些衍生物的药用组合物以及它们的医药用途，特别是在制备抗炎、抗肿瘤和抗心血管疾病药物中的应用。
背景技术：
齐墩果酸(oleanolic acid,OA ) 是五环三萜类化合物, 是一种天然产物化学成分, 广泛分布于植物界, 据不完全统计，有126种植物含有OA。在常用的植物中，如丁香、大枣、川西獐牙菜、女贞子、牛膝、西洋参、苏合香、连翘、青叶胆、琵琶叶、柿叶、景天三七、人参、山芝麻、甘草、关木通、东北龙胆、雪胆、摁木、小茴香、夏枯草中都含有OA。OA在五加科、葫芦科、铁青树科、毛茛科等植物的根和根茎(如雪胆、摁木)中主要以游离或结合成苷的形式存在。
OA 为五环三萜类化合物, 化学名为(3β)-3-Hydroxyolean-12-en-28-oic acid, 分子式为C30H48O3,为白色簇状针晶, 无色、无味、无臭、不溶于水, 可溶于乙醇、氯仿、乙醚、丙酮等。熔点: 310℃, 比旋度:[α]12D+79.50 (氯仿中) ,Liebermann-Burchard 反应呈紫红色。
OA 是植物化学成分，毒性很低，具有多种生物活性：抗病毒、消炎、增强免疫和抑制免疫(免疫双向调解作用)、抑制血小板凝集、降血脂、降糖、保肝、护肾、抗艾滋病毒等。OA 对恶性肿瘤化疗造成的免疫功能下降的恢复和对抗结核药物的肝损害的保护意义重大， 恶性肿瘤是对人类生命威胁最严重的疾病， 而结核病近10 年来全球性漫延迅速，损害人类健康。降血脂、降糖、抗病毒，特别是抗艾滋病病毒活性的发现，说明OA有非常广阔的应用前景。但目前齐墩果酸制剂种类单一, 生物利用度不高, 和大部分中药有效成分一样, 具有多种药理作用, 但活性都不高。因此制备齐墩果酸衍生物，增强药理活性，提高生物利用度，是解决其临床应用的有效途径[张蜀艳，李政.齐墩果酸研究进展.食品与发酵科技，2010，46（4）:20-24.]。
在生物体及细胞内存在着复杂多样的信号途径，其中气体信号分子以其独有的可连续产生、迅速传播、快速弥散等特点引起科学界的广泛关注，气体信号分子的发现使生物医学研究进入了全新一页。最先发现的两个气体信号分子分别是一氧化氮( nitric oxide, NO)和一氧化碳( carbon monoxide, CO)。前者被发现具有舒张血管、抑制血小板聚集和抑制细胞增殖等广泛的生物学效应，后者也被证实可影响学习和记忆过程、脊索神经痛觉传递、嗅觉受体神经的发育和功能和具有舒张血管、抑制平滑肌细胞增殖等功能[Wang R, Wang ZZ, Wu L. Carbonmonoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol, 1997, 121(5):927-934.1]。
H2S是一种有臭鸡蛋样味道的气体。一直以来，人们都认为它仅仅是一种有毒并且对环境有害的气体。直到20世纪80年代末期，相继在大鼠、牛和人类等脑中发现了含量相当高的内源性H2S后，才逐渐认识到它可能具有生理和病理功能。目前，越来越多的研究证明，H2S是继NO和CO之后发现的一种新的气体信号分子，它们具有某些共同的特点：都是小分子质量的气体分子，能自由穿透细胞膜且不依赖受体产生信号转导，能按需要进行内源性合成，释放后能迅速降解，有特定的细胞和分子靶标，在很多水平上能彼此密切关联共同发挥作用。人们相继发现H2S在心血管、神经、炎症反应、呼吸、消化、血液、新陈代谢、炎症等多系统或疾病过程中具有重要的病理生理作用, 它可以舒张血管平滑肌；抑制低氧时肺动脉高压的形成,调节肺血管结构的重建；显著降低高血压大鼠的血压,并抑制平滑肌细胞增殖；明显减少心肌缺血再灌注损伤；减轻脂多糖诱导的大鼠水肿和血管通透性增高等炎症反应；H2S在炎症发生早期具有抗炎、抗氧化性损伤的作用，还能使非甾体类消炎药引起的胃黏膜损伤减轻60%～70%。
人体内源性H2S是以L-半胱氨酸(L-cysteine, L-Cys) 为底物，L-半胱氨酸是由食物中摄取的含硫氨基酸(L-半胱氨酸)通过转硫途径以同型半胱氨酸(Hcy)作为中间产物产生的，或由内源性蛋白质直接分解产生的。在吡多醛-5′-磷酸依赖性酶胱硫醚-β-合成酶(cystathionine-β-synthase, CBS)、胱硫醚-γ-裂解酶(cystathionine-γ-lyase,CSE)和半胱氨酸转移酶催化下产生的[S. Kubo, M. Kajiwara and A. Kawabata. Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats. Inflammopharmacol 2007;15: 288–292; Zhao P, Huang X, Wang ZY, Qiu ZX, Han YF, Lu HL, et al. Dual effect of exogenous hydrogen sulfide on the spontaneous contraction of gastric smooth muscle in guinea-pig. Eur. J. Pharmacol 2009;616:223–228; Tang, C.S, Li, X.H, Du, J.B, Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr. Vasc. Pharmacol. 2006; 4: 17–22]。
由于硫化氢上述奇特的生物学效应的发现，使得人们对许多生命现象有了新的理解和认识，同时人们也逐渐认识到硫化氢可以被用于疾病的治疗当中。很幸运的是，本发明人在经过大量的研究和试验后发现，某些化合物在被接入硫化氢释放基团后形成了具有较低副作用的衍生物，而且其活性与母体化合物相比有所增强或基本相当。例如，本发明的衍生物基本不产生或少产生胃肠和/或心血管副作用。
近年来，研究发现人类的恶性肿瘤与炎症密切相关[Lisa M, Zena W. Inflammation and cancer. Nature 2002,420: 860-867.], 比如肝癌与慢性肝炎, 胃癌与胃炎, 结肠癌与溃疡性结肠炎, 胰腺癌与胰腺炎, 黑色素瘤与皮肤炎症等, 据估计与炎症相关的恶性肿瘤占了人类癌症的15%左右。研究显示，炎症诱发肿瘤的分子生物学机制包含两个方面：首先，炎症细胞造成活性氧簇(ROS)和活性氮簇(RNS)的产生，导致细胞DNA损伤；其次，炎症细胞释放的细胞因子或炎症介质（如ROS、蛋白酶、基质金属蛋白酶(MMPs)、肿瘤坏死因子 (TNF-α)、白细胞介素(IL)、干扰素(IFN)、环氧合酶-2(COX-2)及核转录因子(NF-κB）增强了细胞增殖信号，促进了细胞增殖、细胞迁移和血管生成，直至肿瘤生长和转移[Chiara P, Paola Li, Monica R, Maria G, Paola A, Alberto M, Antonio S. Cellular and molecular pathways linking inflammation and cancer. Immunobiology 2009,214:761-777;Sgambato A, Cittadini A. Inflammation and cancer: a multifaceted link. Eur Rev Med Pharmacol Sci 2010,14:263-268; Mary P, Donald A, Hans S. Inflammation as a tumor promoter in cancer induction. Mut Res 2008,659:15-30.]。
由于恶性肿瘤与炎症有密切的联系,使得人们对抗炎药物用于预防/治疗恶性肿瘤的认识也日益深入[Kashfi K. Anti-inflammatory agents as cancer therapeutics. Adv Pharmacol 2009,57:31-89.]。近年流行病学、动物模型及临床应用的研究均表明NSAIDs能够通过诱导肿瘤细胞的凋亡、阻滞细胞周期、抑制肿瘤的侵袭和转移等而发挥抗肿瘤的作用。Harris等根据结果的一致性、关联性、不同剂量的效果及可能的生物学机制等流行病学的判断标准[Harris R, Beebe-Donk J, Doss H, Burr Doss D.Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non- selective COX-2 blockade. Oncol Rep 2005,13:559-583.]，总结了NSAIDs对10种人类恶性肿瘤的作用：结果显示，在7-10种恶性肿瘤中，每日服用NSAIDs可使结肠癌的患病风险降低63%，乳腺癌降低39%，肺癌降低36%，前列腺癌降低39%，食道癌降低73%，胃癌降低62%，卵巢癌降低47%，且用药时间越长效果越好。其中，NSAIDs对食道癌、胃癌及结肠癌的效果较好，对恶性黑色素瘤、霍奇金病及成人白血病也有保护作用。
但非甾体抗炎药长期应用存在疗效不满意和/或不良反应严重的问题[Arroyo M, Lanas A. NSAIDs-induced gastrointestinal damage. Minerva Gastroenterol Dietol 2006,52:249-259；Sostres C, Gargallo C, Arroyo M, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol 2010,24:121-132.]：经典的非甾体抗炎药长期或大量用药会对胃肠道产生副作用，给病人造成二次损害，给个人和社会带来继发性经济负担，甚至最终导致死亡的病例也不鲜见。新一代的非甾体抗炎药如昔布类药物虽然胃肠道副作用大大减轻，但是会引发心血管事件如血压升高、中风、心肌梗塞等，仍然难以满足临床要求[Scheiman J, Hindley C. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther 2010,32:667-677；Davies N, Reynolds J, Undeberg M, Gates B, Ohgami Y, Vega-Villa K. Minimizing risks of NSAIDs: cardiovascular, gastrointestinal and renal. Expert Rev Neurother 2006,6:1643-1655.]。因此，寻找更安全有效的具有抗肿瘤作用的非甾体抗炎药物仍然是一项长期而艰巨的任务。
发明内容
为了解决现有技术存在的问题，本发明人经过大量的实验，在齐墩果酸的结构上，引入硫化氢释放基团，合成了一系列新的化合物，有效地克服了现有技术的缺陷。
根据本发明，提供具有下列通式的化合物：
（式YLXYⅢ）
通式YLXYⅢ中，R代表氢、乙酰基、 、
；Y=氮、氧；Z= (CH2)n、CH2CO，其中n=2~4；S是能释放硫化氢的部分。
在一个优选的方案中，式YLXYⅢ的R代表氢、乙酰基、哌啶乙酰基、哌啶乙酰基；Y=氧；Z= (CH2)n，n=2，3或4；S代表。然而，应当理解的是，在本发明中可以使用任何无毒性、能释放硫化氢的有效部位。
优选的化合物如下所示：齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯 (R=H；Y= O；Z= (CH2)n，n=2；S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅢ-1)，齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (R=H；Y= O；Z= (CH2)n，n=3；S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅢ-2)，齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(R=H；Y= O；Z= (CH2)n，n=4；S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅢ-3)。
根据本发明，还提供具有下列通式的化合物，
（式YLXYⅣ）
通式YLXYⅣ中， R代表氢，羟基；X=氢，氧；Y=氮，氧；Z= (CH2)n、CH2CO，其中n=2~4；S是能释放硫化氢的部分。
在一个优选的方案中，式YLXYⅣ的R代表氢或羟基；X=氢；Y=氧；Z= (CH2)n, n=3或4；S代表。然而，应当理解的是，在本发明中可以使用任何无毒性、能释放硫化氢的有效部位。
优选的化合物如下所示：3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(R=H；Y=H2；Z= (CH2)n, n=3；Y= O；S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅣ-1)，3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(R=H；Y=H2；Z= (CH2)n, n=4；Y= O；S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅣ-2)，2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(R=OH；Y=H2；Z= (CH2)n, n=3；Y= O；S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚，即YLXYⅣ-3)。
本发明所述的化合物药理活性相当高，而且具有良好的安全性和耐受性，可以用于治疗和预防各种疾病，例如，各种氧化应激参与的疾病状态，呼吸系统疾病、心血管疾病、癌症、弥散性硬皮病、系统性硬结、溃疡性结肠炎、成胶质病变、Crohnn氏病(局部性回肠炎)、病毒性肝炎、药物性肝炎、肝硬、小动脉纤维性病变、动脉硬化、糖尿病、急、慢性肾小球肾炎、间质性肾炎、肾盂肾炎、肾动脉硬化、肾功能不全、急慢性胃炎、消化道溃疡、胃癌、大骨节病、克山病。同时，所述化合物可以用于各种跟炎症显著相关的疾病，例如，但不限于，癌症、哮喘、脑中风、心肌梗塞、心肌缺血、冠状动脉硬化、心绞痛、高血压、风湿性心脏病、心肌炎、克山病、心包炎、动脉粥样硬化。
更相关的是，本发明的化合物可以用于，但不限于，治疗炎症，或用于治疗与炎症有关的疾病，例如，用作解热镇痛抗炎药。例如，本发明的化合物可以用于治疗关节炎，包括但不限于，类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症。与皮肤有关的炎症，牛皮癣、湿疹、烧伤、皮炎。也可以用于治疗胃肠道病症，例如炎性肠病、克劳恩病、胃炎、过敏性肠综合症和溃疡性结肠炎。本发明的化合物可以用于治疗哮喘、支气管炎、滑囊炎、腱鞘炎。用于预防或治疗癌症，例如结肠直肠癌。该类化合物也可以用于治疗疼痛，包括但不限于，头痛、牙痛、颌面痛、颈项痛、肩、上肢痛、胸痛、腹痛、腰背痛、盆腔痛、下肢痛、肛门、会阴痛、手术痛、肌肉痛、癌性疼痛。也可以用于某些疾病中的炎症，这些疾病包括但不限于，血管疾病、偏头痛、结节性动脉炎、甲状腺炎、再生障碍性贫血、硬化病、风湿热、糖尿病、重症肌无力、牙龈炎、肾炎、过敏症、损伤后发生的肿胀、心肌缺血等；也可以用于肺部炎症，急性肺损伤、急性呼吸窘迫综合症、各种感染性（如细菌性、病毒性、支原体性、真菌性和寄生虫性）肺炎、理化性（如放谢性、吸入性的类脂性）肺炎以及变态反应性（如过敏性和风湿性）肺炎、慢性阻赛性肺病、内毒素休克症。与痔疮有关的炎症、痉挛性肛部痛和直肠裂；肝胆囊和/或胆道病症，例如，胆管炎、硬化性胆管炎、原发性胆汁性肝硬变和胆囊炎、肠痈。也可以用于治疗中枢神经系统疾病，如阿尔茨海默症（老年痴呆症）、帕金森病、动脉粥样硬化和由中风、缺血、创伤导致的中枢神经损害。除了用于人类疾病的治疗外，还可以用于其它哺乳动物，包括猪、牛、马、羊、猫、狗、鼠。
本发明的化合物可以用于预防或治疗各种疾病，特别是GI道的炎症，包括但不限于，口腔炎症例如粘膜炎、感染性疾病（例如，病毒、细菌、真菌疾病）和克劳恩病、食管的炎症例如食管炎、化学伤导致的疾病（例如，摄取碱液）、胃食管返流疾病、胆汁酸返流、巴雷特食管、食管狭窄、炎症例如胃炎（例如，幽门螺旋杆菌、酸、消化性疾病和萎缩性胃炎）、乳糜泻、消化性溃疡、胃的癌前期病变、非溃疡性消化不良和克劳恩病、胃部的炎症例如克劳恩病、溃疡性结肠炎、沙门氏菌肠炎、志贺氏杆菌感染、耶尔森菌病、隐孢子虫病、微孢子虫感染和病毒感染、辐射诱导的结肠炎、免疫妥协的宿主中的结肠炎（例如，盲肠炎）、结肠的癌前期病变（例如，发育异常、肠的炎症和结肠息肉）、直肠炎。
医生或患者可以根据各自的特殊情况或疾病状态，调整剂量来使用本发明的化合物，只要该剂量在有效和安全范围内。这是本领域技术人员很容易知晓的。一般情况下，这些化合物成人每天的服用量大概在1-5000mg之间，可以一次，也可以多次服用，当然，根据治疗疾病的需要和患者的体重或疾病状态可进行必要的个体化调整，以达到最佳疗效。但是，最适合的剂量水平应该在0.1-500mg/kg，优选为5-100mg/kg，但是根据要治疗的患者的体重、情况及它们对所述药物的反应灵敏度，以及所选择的药物制剂的类型和在进行使用时的时间和间隔期，可以进行改变。有时，低于上述范围下限的剂量水平或高于上限的剂量水平也可以，只要不产生任何影响治疗的副作用。
本发明的化合物可以制成各种药物剂型，其性质取决于给药途径,可以通过常规方法，使用相容的、药学可接受的赋形剂或载体来制备这些药物组合物。这些组合物剂型可以是片剂、胶囊、颗粒剂、喷雾剂、透皮贴剂、糖锭、锭剂、糖浆、粉末、凝胶、栓剂等等，制备临时溶液、可注射制剂、直肠、眼部、阴道制剂等等，优选的给药途经是口服和直肠给药。
当用于口服时，可以使用各种赋形剂例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸以及各种崩解剂如淀粉、海藻酸钠和某些复合硅酸盐、以及粒状粘合剂例如聚乙烯吡啰烷酮、蔗糖、明胶和阿拉伯胶。此外，为进行压片可以使用润滑剂如硬脂酸镁、月桂硫酸钠和滑石、相似类型的固体组合物也可以在胶囊中使用填充剂，与其相关的优选物质还包括乳糖或牛奶糖以及高分子量聚乙二醇。当希望水性混悬液用于口服时，活性成分可以与增甜剂或调味剂、着色物质和乳化剂和/或悬浮剂组合，与稀释剂例如水、乙醇、丙二醇、甘油及其各种组合在一起。
可以将剂型设计为缓慢释放、控制释放、立即释放、延迟释放或靶向延迟释放。这些术语的定义是本领域技术人员所共知的。
当胃肠外使用时，可以使用活性化合物的芝麻或花生油或水性丙二醇溶液，如果必要，水性溶液应当是适当缓冲的（优选pH大于8），液体稀释剂首先是等张的，水性溶液适合静脉注射的目的。在无菌条件下制备所有这些溶液都是通过本领域普通技术人员公知的标准制药技术即可完成的。
实验结果表明，本发明化合物具有优秀的抗炎作用，而且未发现明显的胃肠道损伤。并且本发明中的化合物由于会释放出适量的硫化氢，会减少心血管事件的发生 [陈雯,谢晓华.医学综述, 2008,14(24):3704]。因此，本发明中的化合物有可能避免临床正在应用的非甾体抗炎药所致的胃肠道损伤和/或心血管不良事件或其它毒副反应，有可能取代现有的临床用药，有着十分广阔的应用前景。
下面的实施例进一步描述，并使本领域的普通技术人员能够实施和使用本发明。然而，应当认识到，这些实施方案是用于解释本发明的目的，而不应理解为限制由权利要求所定义的本发明的范围。
附图说明
图1是部分YLXYⅢ和Ⅳ类化合物对二甲苯致小鼠耳肿胀的影响。
图2是部分YLXYⅢ和Ⅳ类化合物对巴豆油致小鼠耳肿胀的影响。
图3是部分受试YLXYⅢ和Ⅳ类化合物对肿瘤细胞MCF-7、HT-29增殖作用的影响。
图4是受试化合物单次给药对大鼠胃肠道的影响。
图5是受试化合物连续给药对大鼠胃肠道的影响。
具体实施方式
化合物制备
实施例一：
1、5-(4-羟基苯基)- 3H-1,2-二硫环戊基-4-烯-3-硫酮(ADT-OH)合成
（1）5-(4-甲氧基苯基)- 3H-1,2-二硫杂环戊烯-3-硫酮（ADT-OCH3）的合成
将茴香脑(3.17g,0.021mol)，硫(4.70g,0.146mol)和DMF30mL加入烧瓶中，搅拌回流6h。反应完毕倒入冷水中，析出大量沉淀，过滤，乙醇-水重结晶，得到红色晶体，产率78%，mp: 110~111℃。
1H NMR (400MHz, DMSO-d6), δ(ppm): 7.62 (d, 2H, J = 8.9 Hz, ArH), 7.40 (s, 1H, =CH), 6.98 (d, 2H, J = 8.8 Hz, ArH), 3.88 (s, 3H, OCH3)。
（2）5-(4-羟基苯基)- 3H-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)的合成
将ADT-OCH3 (20.6g, 0.1mol)和盐酸吡啶(69.0g, 0.6mol)加热回流1h，冷却，变成固体，捣碎，加水洗涤数遍，过滤，滤饼用丙酮-水重结晶，产率98.0%，mp: 191~192℃。
1H NMR (400MHz, DMSO-d6), δ(ppm):10.46 (s, 1H, OH), 7.78 (d, 2H, J = 8.7 Hz, ArH), 7.66 (s, 1H, =CH), 6.90 (d, 2H, J = 8.7 Hz, ArH)。
（3）5-[4-(2-溴乙氧基)苯基]- 3H-1,2-二硫杂环戊烯-3-硫酮(3a)的合成
将ADT-OH(0.325g, 1.4mmol)、1,2-二溴乙烷(0.50mL, 5.8mmol)和无水K2CO3 (0.396g, 2.8mmol)加至10mL干燥的DMF中，120℃反应2h。冷却后加20mL乙酸乙酯稀释，水洗(3×20mL)，合并有机相，无水Na2SO4干燥，蒸干溶剂，丙酮-水重结晶，得到黑褐色产物0.388g，产率81.5%，mp：126.0~127.0℃。
1H NMR(400MHz, CDCl3), δ(ppm): 7.59(d, 2H, J = 8.9 Hz, ArH), 7.36(s, 1H, =CH), 6.96(d, 2H, J = 8.9 Hz, ArH), 4.33(t, 2H, CH2), 3.65(t, 2H, CH2) .
13C NMR(400MHz, CDCl3), δ(ppm): 212.554, 170.180, 158.775, 132.260, 126.120, 122.226, 113.014, 65.455, 26.026。
（4）5-[4-(3-溴丙氧基)苯基]- 3H-1,2-二硫杂环戊烯-3-硫酮(3b)的合成
参照3a的合成方法由ADT-OH和1,3-二溴丙烷制备，黑褐色产物，产率83.2%，mp：79.0~80.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 7.00(d, 2H, J = 8.7 Hz, ArH), 4.19(t, 2H, CH2), 3.62(t, 2H, CH2), 2.36(p, 2H, CH2).
13C NMR (400MHz, CDCl3), δ(ppm): 212.460, 170.437, 159.454, 132.073, 126.065, 121.751, 112.886, 63.118, 29.453, 27.178。
（5）5-[4-(4-溴丁氧基)苯基]- 3H-1, 2-二硫杂环戊烯-3-硫酮(3c)的合成
参照3a的合成方法由ADT-OH和1, 4-二溴丙烷制备，黑褐色固体，产率79.4%，mp：70.0~71.0℃。
1H NMR (400MHz,CDCl3),δ(ppm): 7.60(d, 2H, J = 8.7 Hz, ArH), 7.38(s, 1H, =CH), 6.96(d, 2H, J = 8.7 Hz, ArH), 4.07(t, 2H, CH2), 3.50(t, 2H, CH2), 2.08(m, 2H, CH2), 1.99(m, 2H, CH2).
13C NMR (400MHz, CDCl3), δ(ppm): 212.439, 170.554, 159.670, 132.006, 126.057, 121.553, 112.834, 64.759, 30.795, 26.729, 25.133。
、齐墩果酸中间体的合成
（1）齐墩果酸-2-溴乙酯(9a)的合成
将齐墩果酸(0.228g, 0.5mmol)，1,2-二溴乙烷(0.17mL, 2.0mmol)和三乙胺 (0.14mL, 1.0mmol)加至10mL丙酮中，回流搅拌10h。冷却后减压蒸干溶剂，柱层析[石油醚(60~90℃):乙酸乙酯=5:1(v/v)]，得到白色固体，产率68.1%，mp: 150.0~ 152.0℃(与文献一致，张奕华, 陈莉, 田季德, 等. 齐墩果酸偶联衍生物及其药物用途[P] . CN 200410041376.3，产率：65.0%)。
（2）齐墩果酸-3-溴丙酯(9b)的合成
参照9a的制备方法由齐墩果酸和1, 3-二溴丙烷制备，白色粉末，产率69.6%，mp：151.6~152.6℃。
1H NMR (400 MHz, CDCl3), δ:5.21 (brs, 1H, C12-H), 4.25 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.12 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 1.35 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.73 (s, 3H, CH3), 0.65 (s, 3H, CH3)。
（3）齐墩果酸-4-溴丁酯(9c)的合成
参照9a的制备方法由齐墩果酸和1, 4-二溴丁烷制备，白色粉末，产率70.6%，mp：101.1~102.1℃。
1H NMR (400 MHz, CDCl3) δ:5.28 (brs, 1H, C12-H), 4.12 (t, 2H, OCH2), 4.08 (t, 2H, OCH2), 3.20 (dd, 1H, 4.5 Hz, 3α-H), 2.87 (dd, 1H, C18-H), 1.88 (m, 7H, CH2 & CH), 1.63 (m, 13H, CH2 & CH), 1.44 (d, 1H, CH), 1.34 (t, 2H, CH2), 1.27 (d, 1H, CH), 1.18 (d, 1H, CH), 1.13 (s, 3H, CH3), 1.06 (d, 2H, CH2), 0.98 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.73 (s, 3H, CH3)。
（4）3-乙酰基-O-齐墩果酸的合成
将齐墩果酸(1.82g, 4.0mmol)溶于10mL吡啶中，室温搅拌，滴加乙酸酐(3.78mL, 40.0mmol)，反应12h后倒入冰水中，析出固体，过滤，干燥，丙酮-水重结晶得到白色固体1.92g，产率96.5%，mp: 266.0~268.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.27 (brs, 1H, C12-H) 2.81 (dd, 1H, C18-H), 2.04 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.11-1.03 (m, 2H, CH2), 0.93 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.85 (s, 3H, CH3), 0.74 (s, 3H, CH3)。
（5）3-O-(2-哌啶基乙酰基)齐墩果酸(10)的合成
将齐墩果酸(1.37g, 3.0mmol)溶于10mL四氢呋喃中，加入吡啶(0.36mL, 4.5mmol)，室温搅拌下滴加氯乙酰氯(0.29mL, 3.9mmol)，反应4h。然后倒入40mL水中，过滤，干燥，得到白色固体3- (2-氯乙酰基) -O-齐墩果酸1.53g，产率95.7%，mp：281.2~281.6℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.28 (brs, 1H, C12-H), 4.06 (s, 2H, CH2), 2.88-2.78 (m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.75 (s, 3H, CH3).
将上述产物 (1.066g, 1.95mmol)溶于15mL四氢呋喃中，加入三乙胺(0.28mL, 1.95mmol)，室温搅拌下加入哌啶(0.252mL, 2.54mmol)，加热回流10h。蒸去大部分四氢呋喃，加水20mL，出现大量固体，过滤，干燥，丙酮-水重结晶，得到白色固体（10）1.03g，产率89.2%，mp：243.5~244.4℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.34-5.21 (s, 1H, C12-H), 3.21 (s, 2H, CH2), 2.90-2.74 (m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.93 (s, 6H, CH3), 0.90 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.75 (s, 3H, CH3)。
（6）3-氧代齐墩果酸的合成
将齐墩果酸(2.0g, 4.4mmol)加入50 mL二氯甲烷和50mL丙酮混合液中，冰浴下滴加Jones’试剂2.0mL，保持温度0～5℃反应15min。然后加入200mL二氯甲烷，依次用饱和NaHCO3水溶液100 mL和饱和NaCl水溶液洗涤，无水Na2S04干燥，蒸干溶剂，甲醇重结晶，得到针状白色结晶，产率100%。mp：178.0~179.0℃.
1H NMR (400MHz, CDCl3), δ(ppm): 5.30 (s, 1H, C12-H), 2.88-2.79 (m, 1H, C18-H), 2.60-2.50 (m, 1H, C2-H), 2.41-2.33 (m, 1H, C2-H), 1.14 (s, 3H, CH3), 1.08 (s, 3H CH3), 1.05 (s, 3H CH3), 1.03 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.81 (s, 3H, CH3).
HR-MS: Calcd. For C30H47O3 [M+H]+ 455.3520, Found: 455.3521。
（7）2-羟基-3-氧代齐墩果酸(11)的合成
将3-氧代齐墩果酸（0.227g，0.5mmol）、催化量浓H2SO4加至10mL甲醇和5mL二氯甲烷混合液中，然后加入mCPBA(0.224g, 0.65mmol)，室温搅拌6h，加水20mL，然后依次用饱和NaHCO3(30mL×3)和饱和NaCl(30mL×3)洗涤，无水MgSO4干燥。蒸干溶剂，柱层析[石油醚(60~90℃):乙酸乙酯=2:1(v/v)]，得到白色固体，产率68.1%，mp:64.2~65.2℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.25 (s, 1H, C12-H), 4.53-4.44 (m, 1H), 2.83-2.74 (m, 1H, C18-H), 2.39-2.31 (m, 1H, C2-H), 1.21 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.05 (d, J = 2.35 Hz, 6H, CH3), 0.88 (s, 3H, CH3), 0.87 (d, J = 10.99 Hz, 6H, CH3).
HR-MS: Calcd. For C30H47O4 [M+H]+, 471.3469 Found: 471.3468。
（8）3,11-二羰基齐墩果烷-12-烯-28-酸(12)的合成
将齐墩果酸(1.37g, 3.0mmol)溶解于100mL 含5%乙酸酐的乙酸溶液中，加入GrO3(0.90g, 3.0mmol)，室温搅拌。4h后加入60mL水和60mL二氯甲烷。水层用二氯甲烷萃取（40mL×2），合并有机相，用饱和Na2CO3溶液洗至微碱性，无水MgSO4干燥。蒸干溶剂，柱层析[石油醚(60~90℃):乙酸乙酯=10:1(v/v)]，得到白色无定形固体0.92g，产率65.8%，mp: 145.8~146.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.67 (s, 1H, C12-H), 3.04~2.92 (m, 2H, C1-H, C18-H), 2.42~2.32 (m, 1H, C9-H), 1.37 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.94 (s, 3H, CH3).
HR-MS: Calcd. For C30H45O4 [M+H]+, 469.3312 Found: 469.3313。
（9）N-(3-氧代齐墩果酰)甘氨酸(13)的合成
将3-氧代齐墩果酸(0.311g, 0.685mmol)溶于10mL干燥的二氯甲烷中，冰浴下滴加草酰氯(0.26mL, 2.74mmol)，搅拌2h后蒸干，得到白色固体3-氧代齐墩果酸酰氯，产率100%。
将3-氧代齐墩果酸酰氯(53mg, 0.11mmol)溶于5mL干燥的二氯甲烷中，冷却至0℃，加入甘氨酸甲酯盐酸盐（69mg，0.55mmol）和三乙胺(111μL 1.10mmol)，搅拌4h。然后加入50mL二氯甲烷和50mL水，有机层用饱和氯化钠水溶液洗涤(30mL×3)，干燥。蒸干溶剂，硅胶柱色谱[石油醚(60~90℃):乙酸乙酯=15:1(v/v)]，得到淡黄色固体N-(3-氧代齐墩果酰)甘氨酸甲酯55.3mg，收率93.0%，mp:101.0~102.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 6.54-6.48 (m, 1H, NH), 5.48 (s, 1H, C12-H), 3.77 (s, 3H, CH3), 2.67-2.60 (m, 1H, C18-H), 2.58-2.50 (m, 1H, C2-H), 2.41-2.32 (m, 1H, C2-H), 1.17 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.04 (s, 6H, CH3), 0.92 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.76 (s, 3H, CH3).
HR-MS: Calcd. For C33H52NO4 [M+H]+, 526.3891, Found: 526.3878。
将N-(3-氧代齐墩果酰)甘氨酸甲酯（262.5mg, 0.5mmol）溶于2mL四氢呋喃：水(v:v=4:1)的混合溶液中，再加入4mol.L-1的氢氧化钠水溶液（500μL，2.0mmol)，室温搅拌4h。加入50mL水，用1.0mol.L-1的稀盐酸调pH=2后，用二氯甲烷萃取(50mL×3)，合并有机层，用饱和氯化钠水溶液洗涤(30mL×2)，无水MgSO4干燥。蒸干溶剂，硅胶柱色谱[石油醚(60~90℃):乙酸乙酯=8:1(v/v)]，得到白色固体13，收率为95.0%，mp:140.8~141.8℃。
1H NMR (400MHz, CDCl3) δ(ppm): 6.69 (m, 1H, NH), 5.48 (s, 1H, C12-H), 2.57-2.50 (m, 1H, C18-H), 2.43-2.33 (m, 1H, C2-H), 1.17 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.92 (s, 6H, CH3), 0.77 (s, 3H, CH3)。
实施例二：
YLXYⅢ和Ⅳ类化合物的合成
（1）齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯 (YLXYⅢ-1)的合成
将ADT-OH(0.147g, 0.65mmol)、齐墩果酸-2-溴乙酯(9a)(0.365g, 0.65mmol)、无水K2CO3(0.178g, 1.30mmol)和催化量KI加至10mL干燥的DMF中，室温搅拌12h，然后加10mL乙酸乙酯稀释，水洗(3×10mL)，无水Na2SO4干燥，蒸干溶剂，柱层析[石油醚(60-90):乙酸乙酯=20:1(v/v)]，得到红色固体0.259g，产率56.2%，mp：101.0~102.0℃。
1H NMR (400 MHz, CDCl3) , δ: 7.62 (d, 2H, J = 8.8 Hz, ArH), 7.39 (s, 1H, =CH), 6.97 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.41 (m, 2H, OCH2), 4.21 (t, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.86 (d, 1H, C18-H), 1.11 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.75 (s, 3H, CH3), 0.62 (s, 3H, CH3).
13C NMR (300 MHz, CDCl3), δ: 209.85, 172.46, 167.53, 156.64, 138.25, 129.49, 123.36, 122.84, 117.28, 110.29, 73.71, 61.03, 56.93, 49.89, 42.27, 41.58, 40.53, 36.40, 36.00, 34.03, 33.48, 33.14, 31.72, 28.55, 27.83, 27.19, 25.44, 24.45, 22.86, 22.35, 21.88, 20.61, 18.37, 18.13, 17.70, 13.05, 11.75, 10.36, 10.02.
IR(KBr, cm-1): 3443.1 (OH), 1734.8 (C=O), 1659.8, 1636.1, 1602.9, 1489.9 (C=C), 1175.9 (C=S).
HR-MS: Calcd. For C41H57O4S3 [M+H]+ 709.3413, Found: 709.3392。
（2）齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (YLXYⅢ-2)的合成
参照YLXYⅢ-1的合成方法由9b和ADT-OH制备，红色粉末，产率62.3%，mp：124.0~125.0℃。
1H NMR (400 MHz, CDCl3), δ:7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.27 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.10 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 1.37 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.74 (s, 3H, CH3), 0.59 (s, 3H, CH3).
13C NMR (300 MHz, CDCl3) δ: 209.79, 172.45, 167.63, 156.93, 138.49, 129.34, 123.34, 118.97, 117.14, 110.11, 73.75, 59.28, 55.23, 49.83, 42.25, 41.54, 40.53, 36.39, 36.05, 33.93, 33.44, 33.12, 31.68, 28.56, 27.83, 27.27, 25.45, 24.46, 23.09, 22.84, 22.33, 21.84, 20.64, 18.38, 18.08, 17.75, 13.09, 11.58, 10.34, 10.00.
IR(KBr, cm-1): 3420.7 (OH), 1728.7 (C=O), 1653.2, 1635.6, 1604.0, 1468.8 (C=C), 1176.4 (C=S).
HR-MS: Calcd. For C42H59O4S3 [M+H]+ 723.3575, Found: 723.3553。
（3）齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅢ-3)的合成
参照YLXYⅢ-1的合成方法由9c和ADT-OH制备，红色粉末，产率66.7%，mp：134.5~135.5℃。
1H NMR (400 MHz, CDCl3) δ: 7.61 (d, 2H, J = 8.8 Hz, ArH), 7.39 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.28 (brs, 1H, C12-H), 4.10 (t, 2H, OCH2), 4.06 (t, 2H, OCH2), 3.21 (dd, 1H, 3α-H), 2.87 (dd, 1H, C18-H), 1.34 (t, 2H, CH2), 1.13 (s, 3H, CH3), 0.98 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.77 (s, 3H, CH3), 0.72 (s, 3H, CH3).
13C NMR (300MHz, CDCl3), δ: 209.81, 172.48, 167.78, 157.05, 138.52, 129.34, 123.34, 118.85, 117.15, 110.18, 73.71, 62.50, 58.35, 49.92, 42.32, 41.49, 40.58, 36.47, 36.11, 34.08, 33.49, 33.18, 31.76, 28.61, 27.86, 27.49, 27.27, 25.47, 22.87, 22.40, 21.93, 20.64, 20.53, 20.07, 18.40, 18.16, 17.78, 13.08, 11.83, 10.36, 10.07.
IR(KBr, cm-1): 3443.4 (OH), 1717.7 (C=O), 1652.9, 1602.5, 1490.9 (C=C), 1177.2 (C=S).
HR-MS: Calcd. For C43H61O4S3 [M+H]+ 737.3726, Found: 737.3717。
（4）3-乙酰-O-齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (YLXYⅢ-4)的合成
参照YLXYⅢ-1的合成方法由3-乙酰-O-齐墩果酸和3b制备，红色粉末，产率78.6%，mp：135.6~ 136.6℃。
1H NMR (400 MHz, CDCl3) δ:7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.27 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.10 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 2.04(s, 3H, CH3), 1.37 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.74 (s, 3H, CH3), 0.59 (s, 3H, CH3).
IR(KBr, cm-1): 1733.0 (C=O), 1698.9 (C=O), 1603.2, 1554.2, 1492.4, 1468.5, (C=C), 1177.5 (C=S).
HR-MS: Calcd. For C44H61O5S3 [M+H]+ 765.3575, Found: 765.3649。
（5）3-乙酰-O-齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯 (YLXYⅢ-5)的合成
参照YLXYⅢ-1的合成方法由3-乙酰-O-齐墩果酸和3c制备，红色粉末，产率79.7%，mp：106.8~107.8℃。
1H NMR (400 MHz, CDCl3) δ: 7.61 (d, 2H, J = 8.5Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.6 Hz, ArH), 5.28 (brs, 1H, C12-H), 4.16-4.00 (m, 4H, CH2), 2.87 (m, 1H, C18-H), 2.05 (s, 3H, CH3), 1.13 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 6H, CH3), 0.86 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.72 (s, 3H, CH3).
13C NMR (300MHz, CDCl3), δ: 215.282, 177.969, 173.272, 171.304, 162.523, 144.004, 134.804, 128.812, 124.307, 122.531, 115.635, 81.077, 67.958, 63.796, 55.451, 47.697, 46.950, 46.000, 41.912, 41.560, 39.538, 38.297, 37.883, 37.109, 34.066, 33.323, 32.873, 32.721, 30.934, 28.258, 27.838, 26.054, 25.984, 25.531, 23.866, 23.724, 23.619, 23.228, 21.584, 18.417, 17.279, 16.928, 15.595.
HR-MS: Calcd. For C45H63O5S3 [M+H]+ 779.3832, Found: 779.3849。
（6）3-[(2-哌啶基乙酰基)]-O-齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅢ-6)的合成
参照YLXYⅢ-1的合成方法由10和3b制备，白色粉末，产率78.6%，mp：119.8~ 121.4℃。
1H NMR (400MHz, CDCl3), δ(ppm):7.62 (d, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H, CH=CH), 6.96 (d, 2H, J = 8.7 Hz, ArH), 5.27-5.22 (s, 1H, C12-H), 3.19 (s, 2H, CH2), 2.88-2.81 (m, 1H, C18-H), 1.09 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.82 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.80 (s, 3H, CH3).
IR(KBr, cm-1): 1741.0 (C=O), 1719.1 (C=O), 1603.3, 1576.1, 1529.2, 1492.6 (C=C), 1175.1 (C=S).
HR-MS: Calcd. For C49H70O5S3 [M+H]+ 848.4411, Found: 848.4360。
（7）3-[(2-哌啶基乙酰基)]-O-齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅢ-7)的合成
参照YLXYⅢ-1的合成方法由10和3c制备，白色粉末，产率80.0%，mp：77.5~ 78.5℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.61 (d, 2H, J = 8.2 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.3 Hz, ArH), 5.34-5.23 (s, 1H, C12-H), 4.17-3.96 (m, 4H, CH2), 3.19 (s, 2H, CH2), 2.85(m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 6H, CH3), 0.85 (s, 6H, CH3), 0.72 (s, 3H, CH3).
IR(KBr, cm-1): 1740.8 (C=O), 1723.4 (C=O), 1653.2, 1601.8, 1576.4, 1491.2 (C=C), 1177.6 (C=S).
HR-MS: Calcd. For C50H72O5S3 [M+H]+ 862.4567, Found: 862.4567。
实施例三：
（1）3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-1)的合成
参照YLXYⅢ-1的合成方法由3-氧代齐墩果酸和3b制备，红色粉末，产率82.6%，mp：91.6~ 92.5℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62 (d, 2H, J = 8.7 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.7 Hz, ArH), 5.26 (s, 1H, C12-H), 4.30-4.16 (m, 2H, OCH2), 4.15-4.05 (m, 2H, OCH2), 2.88 (m, 1H, C18-H), 2.57-2.47 (m, 1H, C2-H), 2.39-2.28 (m, 1H, C2-H), 2.15 (p, 2H, CH2), 1.10 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.66 (s, 3H, CH3).
IR(KBr, cm-1): 1716.7 (C=O), 1701.0 (C=O), 1662.4, 1601.0, 1576.8, 1490.3 (C=C), 1177.5 (C=S).
HR-MS: Calcd. For C42H57O4S3 [M+H]+ 721.3413, Found: 721.3413。
（2）3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-2)的合成
参照YLXYⅢ-1的合成方法由3-氧代齐墩果酸和3c制备，红色粉末，产率83.0%，mp：141.8~ 142.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62 (d, 2H,J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H,J = 8.76 Hz, ArH), 5.31 (s, 1H, C12-H), 4.11 (t, 2H, OCH2), 4.06 (t, 2H, OCH2), 2.89 (m, 1H, C18-H), 2.61-2.47 (m, 1H, C2-H), 2.42-2.32 (m, 1H, C2-H), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.78 (s, 3H, CH3).
IR(KBr, cm-1): 1728.1 (C=O), 1703.9 (C=O), 1653.2, 1601.1, 1576.8, 1487.6 (C=C), 1184.9 (C=S).
HR-MS: Calcd. For C43H59O4S3 [M+H]+ 735.3570, Found: 735.3570。
（3）2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-3)的合成
参照YLXYⅢ-1的合成方法由11和3b制备，红色粉末，产率82.5%，mp：68.0~ 69.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 8.02 (s, 1H, OH), 7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.93 (d, 2H, J = 8.8 Hz, ArH), 5.26 (s, 1H, C12-H), 4.61-4.43 (m, 1H), 4.30-4.16 (m, 2H, OCH2), 4.11 (t, 2H, OCH2), 2.86(m, 1H, C18-H), 2.36 (s, 2H, C2-H), 2.21-2.09 (m, 2H, CH2), 1.28 (s, 3H, CH3), 1.13 (d, 6H, CH3), 1.10-1.05 (d, 6H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3).
IR(KBr, cm-1): 3446.6 (OH), 1716.9( C=O), 1704.8 (C=O), 1662.2, 1653.2, 1601.1, 1576.4 (C=C), 1177.8 (C=S).
HR-MS: Calcd. For C42H57O5S3 [M+H]+ 737.3363, Found: 737.3363。
（4）2-羟基-3-氧代齐墩果酸4-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-4)的合成
参照YLXYⅢ-1的合成方法由11和3c制备，红色粉末，产率82.5%，mp：49.9~52.1℃。
1H NMR (400MHz, CDCl3), δ(ppm): 8.02 (s, 1H, OH), 7.61 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H, J = 8.8 Hz, ArH), 5.30 (s, 1H, C12-H), 4.56-4.51 (m, 1H), 4.13-4.09 (m, 2H, OCH2), 4.09-4.05 (m, 2H, OCH2), 2.86(m, 1H, C18-H), 1.23 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.10 (s, 6H, CH3), 0.98 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.90 (s, 3H, CH3).
IR(KBr, cm-1): 3446.6 (OH), 1719.4( C=O), 1701.6 (C=O), 1668.5, 1653.2, 1601.9, 1570.4 (C=C), 1176.8 (C=S).
HR-MS: Calcd. For C43H59O5S3 [M+H]+ 751.3519, Found: 751.3520。
（5）3,11-二羰基齐墩果烷-12-烯-28-酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-5)的合成
参照YLXYⅢ-1的合成方法由12和3b制备，红色粉末，产率82.5%，mp：141.2~142.1℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.63(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 6.96(d, 2H, J = 8.8 Hz, ArH), 5.66 (s, 1H, C12-H), 4.12~4.05(m, 2H, CH2), 3.04~2.92 (m, 2H, C1-H, C18-H), 2.42~2.32 (m, 1H, C9-H), 2.19~2.13(m, 2H, CH2), 1.34 (s, 3H, CH3), 1.14 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.85 (s, 3H, CH3).
IR(KBr, cm-1): 1719.9( C=O), 1710.2 (C=O), 1704.0 (C=O), 1662.2, 1658.2, 1576.4 (C=C), 1177.8 (C=S).
HR-MS: Calcd. For C42H55O5S3 [M+H]+, 735.3206 Found: 735.3204。
（6）3,11-二羰基齐墩果烷-12-烯-28-酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-6)的合成
参照YLXYⅢ-1的合成方法由12和3c制备，红色粉末，产率82.5%，mp：86.7~87.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.61(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 6.96(d, 2H, J = 8.8 Hz, ArH), 5.68(s, 1H, C12-H), 4.06(t, 2H, J = 5.6 Hz, CH2), 3.05 ~2.94(m, 2H, C1-H, C18-H), 2.34 ~2.39(m, 1H, C9-H), 1.37(s, 3H, CH3), 1.21(s, 3H, CH3), 1.10(s, 3H, CH3), 1.05(s, 3H, CH3), 0.95(s, 3H, CH3), 0.94(s, 6H, CH3)
IR(KBr, cm-1): 1716.0( C=O), 1709.5 (C=O), 1704.0 (C=O), 1662.2, 1649.2, 1601.9, 1576.4 (C=C), 1177.6 (C=S).
HR-MS: Calcd. For C43H57O5S3 [M+H]+, 749.3363 Found: 749.3365。
(7) N-(3-氧代齐墩果酰)-甘氨酸4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酯(YLXYⅣ-7)的合成
由13和ADT-OH制备，红色固体，产率89.1%，mp: 116.6~ 117.6℃
1H NMR (400MHz, CDCl3), δ(ppm): 7.56 (d, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H, J = 8.4 Hz, ArH), 6.58 (m, 1H, NH), 5.49 (s, 1H, C12-H), 3.78 (s, 2H, CH2), 2.59-2.51 (m, 1H C18-H), 2.43-2.32 (m, 1H, C2-H), 1.18 (s, 3H, CH3), 1.09 (s, 3H CH3), 1.05 (s, 6H, CH3), 0.92 (d, 6H, CH3), 0.77 (s, 3H, CH3).
IR(KBr, cm-1): 1772.3 (C=O), 1699.3 (C=O), 1628.7, 1576.7, 1527.4, 1490.5 (C=C), 1170.2 (C=S).
HR-MS: Calcd. For C41H53NNaO4S3 [M+Na]+, 742.3029, Found: 742.3026.
实施例四：部分药理学实验及结果：
一、抗炎作用
1 二甲苯致小鼠耳肿胀试验
昆明种小鼠，购于中国科学院上海实验动物中心，体重18-22g，雄性。温度20-24℃，湿度（65-70%），标准饲料喂养，每天及时更换垫料和食物，保持鼠笼清洁。
受试化合物均用0.5% CMC-Na溶液配制成混悬液，给药前禁食12h，自由饮水。小鼠灌胃给药，给药容量为0.2mL/10g体重。给药1h后将小鼠右耳廓两侧用微量进样器均匀涂布二甲苯20μL致炎，左耳廓做对照。致炎1h后将小鼠脱颈椎处死，沿耳廓基线取下两耳，用打孔器（直径7mm）于同一部位各取下一耳片用电子天平称重。致炎耳片重量减去对照侧耳片重量即为肿胀度。按下式计算肿胀抑制率，并将对照组与给药组的肿胀度进行统计学处理：
肿胀抑制率（%）= （模型组平均肿胀度 - 给药组平均肿胀度）/模型组平均肿胀度×100%。
部分YLXYⅢ和Ⅳ类化合物对二甲苯致小鼠耳肿胀的影响
用二甲苯致小鼠耳肿胀模型评价了部分YLXYⅢ和Ⅳ类化合物的抗炎活性，结果见图1。
从图1中可以看出受试化合物都表现出较好的耳肿胀抑制作用，最高抑制率达到65%，超过阳性药十几个百分点，表明本组的化合物有较强的抗炎活性。
巴豆油致耳肿胀实验
将巴豆油按照如下比例配成混合溶液，巴豆油：乙醇：乙醚：水=2:20:73:5(v/v),用作致炎剂。选用健康成年雄性ICR种小鼠，购于南通大学动物实验中心，体重18-22g，将动物分为溶媒组、阳性对照组、受试药组。标准饲料喂养，每天及时更换垫料和鼠食，保持鼠笼清洁。
受试化合物均用0.5% CMC-Na溶液配制成混悬液，给药前禁食12h，自由饮水。小鼠灌胃给药，给药容量为0.2mL/10g体重。给药0.5h后将小鼠右耳廓两侧用微量进样器均匀涂布巴豆油致炎剂0.1mL致炎，左耳廓做对照。致炎4h后将小鼠脱颈椎处死，沿耳廓基线取下两耳，用打孔器于同一部位各取下一耳片用电子天平称重。致炎耳片重量减去对照侧耳片重量即为肿胀度。按下式计算肿胀抑制率，并将对照组与受试药组的肿胀度进行统计学处理：
肿胀抑制率（%）= （模型组平均肿胀度 - 给药组平均肿胀度）/模型组平均肿胀度×100%。
部分YLXYⅢ和Ⅳ类化合物对巴豆油致小鼠耳肿胀的影响
用巴豆油致小鼠耳肿胀模型评价了部分YLXYⅢ和Ⅳ类化合物的抗炎活性，结果见图2。
从图2中可以看出受试化合物都表现出较好的耳肿胀抑制作用，最高抑制率大于70%，超过阳性药二十几个百分点，表明本组的化合物有优秀的抗炎活性。
二、抗肿瘤作用
材料
MCF-7、HT-29细胞株（中国科学院上海细胞库），经复苏后传代培养。RPMI1640(或DMEM)培养液，四甲基偶氮唑蓝(MTT，Sigma公司)，胰蛋白酶(吉诺生物医药技术有限公司)，胎牛血清(杭州四季青公司)，二甲基亚砜(DMSO，广州化学试剂厂)，SDS，96孔板。
样品处理
将受试化合物溶于DMSO中，配成高浓度的溶液，然后用培养液稀释至所需浓度，备用。用培养液配制DMSO，均是现配现用。
细胞培养
将肿瘤细胞株接种于含10％灭活胎牛血清的RPMI1640(或DMEM)培养液中，在5％ CO2 37℃充分湿化条件下的培养箱中培养，每周更换2~3次培养液。
法癌细胞体外增殖抑制试验方法
取对数生长期状态良好的细胞一瓶，加入0.25%胰蛋白酶消化，使贴壁细胞脱落，制成每毫升含5×106~6×106个细胞的悬液。取细胞悬液种于96孔板上，置恒温CO2培养箱中培养24h。换液，加入受试化合物(化合物用DMSO溶解后用培养液稀释，受试化合物浓度分别为10，20，40，80，160 μmol.L-1，部分化合物浓度为5，10，20，40，80 μmol.L-1)，培养48小时。将MTT加入96孔板中，每孔20 μL，培养箱中反应4h。然后加入SDS，用酶联免疫测试仪在波长570nm处测定每孔的吸收度，计算细胞抑制率。
抑制率(%)=(对照孔平均OD值-实验孔平均OD值)/对照空平均OD值×100%。
部分受试YLXYⅢ和Ⅳ类化合物对肿瘤细胞MCF-7、HT-29增殖作用的影响见图3。由图可知大部分受试化合物的抗肿瘤活性显著强于OA，并且有的可强约至50多倍。
三、胃肠道损伤实验
1 受试化合物单次给药对大鼠胃肠道的影响
取健康雄性SD大鼠，购于上海斯莱特实验动物中心，体重（平均100g），随机分组，实验前禁食24h，不禁水。标准饲料喂养，每天及时更换垫料和鼠粮，保持鼠笼清洁。实验时，分别设溶媒对照组，双氯芬酸组，受试药物组。溶媒对照组每只动物溶媒灌胃给药；双氯芬酸对照组，每只动物按20mg/kg的剂量灌胃双氯芬酸钠溶液；受试药物组，每组动物按62.8μmol/kg灌胃给药，每组动物给药6h后处死，按以下方法观察、比较药物对大鼠胃肠道的影响，并计算相关指数。沿胃大弯侧将胃剪开展平，按Guth标准计算胃溃疡指数(UI)：溃疡面的长度小于1mm为1 分，1～2mm为2分，2～3mm为3 分，3～4mm为4分，大于4mm将其分割为若干段，每段按上法计算。溃疡宽度> 1mm 则分值×2，点状出血点按每个0.5分计算，每只大鼠的累积相加得分即为该大鼠的总胃溃疡指数。采用t检验, 分析各组间胃溃疡指数有无显著性差异。实验结果见图4。
图4的结果显示，与双氯芬酸组比较，各受试物组的胃溃疡指数非常小，有极显著性差异（P<0.01）。同时，我们解剖后发现，双氯芬酸组大鼠胃部有不同程度的颜色改变，主要呈黄白或苍白色，而受试物各组大鼠，胃部肉眼未观察到上述变化，其它的异样变化也未明显察觉。
受试化合物连续给药对大鼠胃肠道的影响
取健康雄性SD大鼠，购于上海斯莱特实验动物中心，体重（平均100g），随机分组，实验前禁食24h，不禁水。标准饲料喂养，每天及时更换垫料和鼠粮，保持鼠笼清洁。实验时，分别设溶媒对照组，双氯芬酸组，受试药物组。溶媒对照组每只动物溶媒灌胃给药；双氯芬酸对照组，每只动物按40 μmol/kg的剂量灌胃双氯芬酸钠溶液；受试药物组，每组动物按40 μmol/kg灌胃给药，每日一次，连续5天。给药期间对食物和饮水不加控制。第5天时，每组动物给药6h后将动物处死，按上述方法观察、比较药物对大鼠胃肠道的影响，并计算相关指数。采用t检验, 分析各组间胃溃疡指数有无显著性差异。实验结果如图5所示:
图5的结果显示，与双氯芬酸组比较，各受试物组的胃溃疡指数非常小，有极显著性差异（P<0.01）。同时，实验过程中我们发现双氯芬酸组大鼠大鼠腹部胀大，剪开腹腔有黄色甚至褐色腹水流出。覆盖于腹腔的粘膜变硬，胃粘膜弹性很小，有糜烂，有的大鼠实验过程中已经不能进食。以上两个实验显示，不论是单次给药还是连续给药，受试物均未发现明显的线状胃肠道出血性损伤，而双氯芬酸在试验过程中所致胃损伤十分明显，表明受试物的胃肠道安全性非常好。
Claims (8)
1.一种具有下列通式的化合物或其盐：
式YLXYⅢ
其中R代表氢，乙酰基， 
；Y=氮，氧；Z= (CH2)n、CH2CO，其中n=2-4；S是
。
2.根据权利要求1所述的的化合物，其特征在于所述化合物是：齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯，齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯，齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯。
3.一种具有下列通式的化合物或其盐：
式YLXYⅣ
其中R代表氢，羟基；X=氢，氧；Y=氮，氧；Z= (CH2)n、CH2CO，其中n=2-4；S是
。
4.根据权利要求3所述的化合物，其特征在于所述化合物是：3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯，3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯，2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯。
5.一种药物组合物，由治疗上有效剂量的权利要求1-2之一的化合物和药学上可接受的载体或辅料组成。
6.一种药物组合物，由治疗上有效剂量的权利要求3-4之一的化合物和药学上可接受的载体或辅料组成。
7.权利要求1所述的通式YLXYⅢ类化合物在制备预防和治疗炎症及肿瘤药物中的用途。
8.权利要求3所述的通式YLXYⅣ类化合物在制备预防和治疗炎症及肿瘤药物中的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110312179.0A CN102504005B (zh) | 2011-10-14 | 2011-10-14 | 一类具有新型结构的化合物及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110312179.0A CN102504005B (zh) | 2011-10-14 | 2011-10-14 | 一类具有新型结构的化合物及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102504005A CN102504005A (zh) | 2012-06-20 |
| CN102504005B true CN102504005B (zh) | 2014-03-26 |
Family
ID=46216148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110312179.0A Expired - Fee Related CN102504005B (zh) | 2011-10-14 | 2011-10-14 | 一类具有新型结构的化合物及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102504005B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243182B (zh) * | 2016-07-29 | 2018-11-23 | 广西师范大学 | 甘草次酸-硫化氢供体试剂衍生物及其合成方法和应用 |
| CN106243183B (zh) * | 2016-07-29 | 2018-11-23 | 广西师范大学 | 熊果酸-硫化氢供体试剂衍生物及其合成方法 |
| CN114409721B (zh) * | 2022-01-24 | 2023-07-18 | 大连理工大学 | 一类含有亲电弹头的五环三萜衍生物、其制备方法和应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1594354A (zh) * | 2004-07-14 | 2005-03-16 | 中国药科大学 | 齐墩果酸偶联衍生物及其药物用途 |
| CN1724556A (zh) * | 2005-03-11 | 2006-01-25 | 南京大学 | 齐墩果酸及其衍生物、制法及用途 |
| CN101235072A (zh) * | 2004-12-29 | 2008-08-06 | 浙江大学 | A环和c环含多个含氧取代基的齐墩果酸三萜及用途 |
-
2011
- 2011-10-14 CN CN201110312179.0A patent/CN102504005B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1594354A (zh) * | 2004-07-14 | 2005-03-16 | 中国药科大学 | 齐墩果酸偶联衍生物及其药物用途 |
| CN101235072A (zh) * | 2004-12-29 | 2008-08-06 | 浙江大学 | A环和c环含多个含氧取代基的齐墩果酸三萜及用途 |
| CN1724556A (zh) * | 2005-03-11 | 2006-01-25 | 南京大学 | 齐墩果酸及其衍生物、制法及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102504005A (zh) | 2012-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103880842B (zh) | 具HDAC抑制活性的β-咔啉类衍生物及制备方法和用途 | |
| CN103275051B (zh) | 一种7,3’,4’-三羟基黄酮衍生物及其在制备治疗肝癌药物中的应用 | |
| CN102702300B (zh) | 一种预防或治疗自身免疫性糖尿病的化合物及其制备方法和用途 | |
| CN102504005B (zh) | 一类具有新型结构的化合物及其制备方法和用途 | |
| CN111499608B (zh) | 苯并[c]苯并吡喃酮类衍生物及其应用 | |
| CN102241726B (zh) | 甘草次酸衍生物及其作为抗肿瘤药物的应用 | |
| CN101591318A (zh) | 3,5,7-三羟基黄酮类衍生物、其制备方法和用途 | |
| CN102827116B (zh) | 含α-芳基-γ-亚甲基丁烯内酯类化合物及其合成方法和用途 | |
| CN101332198B (zh) | 6-芳基-3-取代羰基吡啶类化合物的药物用途 | |
| CN112574172B (zh) | 一种没食子酸硫化氢衍生物及其制备方法及医药用途 | |
| WO2009059448A1 (fr) | Dérivé styrène-acide et utilisation dans la fabrication de médicaments de type agent ciblé sur les vaisseaux sanguins | |
| CN109761898B (zh) | 一种双靶点抑制剂及其制备方法和用途 | |
| CN104771392B (zh) | 一类组蛋白去乙酰化酶抑制剂及应用 | |
| CN111808062A (zh) | 一种蛇床子素磺酸酯类化合物及其应用 | |
| CN106188209A (zh) | 一种兼具抗肿瘤和抗肿瘤转移活性的二甲双胍偶联物及其应用 | |
| CN114349695B (zh) | 一种大麻二酚-2-烟酸酯及其应用 | |
| CN109020942A (zh) | 具有抗肿瘤活性的异色满酮类化合物、其制备方法及用途 | |
| CN104144919A (zh) | 茶氨酸衍生物与羧酸香豆素衍生物的缩合产物及其中间体、其制备方法和用途 | |
| CN115417877A (zh) | 组蛋白去乙酰化酶抑制剂及其制备和在制备抗癌症药物上的应用 | |
| CN115894437B (zh) | 一种丁香酚硫化氢衍生物及其制备方法与应用 | |
| KR20090061034A (ko) | 신규 페닐초산 유도체 | |
| CN107434770B (zh) | 对硝基苯胺类化合物及其制法和药物组合物与用途 | |
| CN103012394A (zh) | 一种罗丹宁衍生物及其制备方法 | |
| CN114292224B (zh) | 一种大麻二酚-2-（n-乙酰基）哌啶酸酯及其应用 | |
| CN118319907B (zh) | 一种噁二唑化合物的新用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140326 Termination date: 20191014 |