CN102746292B - Cyclized berberine derivatives, preparation method and uses thereof - Google Patents
Cyclized berberine derivatives, preparation method and uses thereof Download PDFInfo
- Publication number
- CN102746292B CN102746292B CN201210101607.XA CN201210101607A CN102746292B CN 102746292 B CN102746292 B CN 102746292B CN 201210101607 A CN201210101607 A CN 201210101607A CN 102746292 B CN102746292 B CN 102746292B
- Authority
- CN
- China
- Prior art keywords
- dioxole
- dihydro
- isoquino
- phenanthridines
- cde
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000003832 berberine derivatives Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- -1 nitro, cyano, amino, hydroxy Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical group 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 7
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 50
- 239000003814 drug Substances 0.000 claims description 39
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 33
- 229940093265 berberine Drugs 0.000 claims description 33
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 30
- 150000001263 acyl chlorides Chemical class 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000003981 vehicle Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 9
- 208000014018 liver neoplasm Diseases 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004442 acylamino group Chemical group 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- FZAGOOYMTPGPGF-UHFFFAOYSA-N Lambertine Chemical compound C1=C2C3=CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 FZAGOOYMTPGPGF-UHFFFAOYSA-N 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000006332 fluoro benzoyl group Chemical group 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- GLGSZERYOLHNML-UHFFFAOYSA-N $l^{1}-oxidanyl(phenyl)methanone Chemical compound [O]C(=O)C1=CC=CC=C1 GLGSZERYOLHNML-UHFFFAOYSA-N 0.000 claims description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229940015043 glyoxal Drugs 0.000 claims description 2
- 125000006331 halo benzoyl group Chemical group 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 239000012453 solvate Substances 0.000 abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000005257 alkyl acyl group Chemical group 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 230000001766 physiological effect Effects 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 153
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 132
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 92
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 82
- 239000007787 solid Substances 0.000 description 64
- 239000000047 product Substances 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 230000015572 biosynthetic process Effects 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- 238000000746 purification Methods 0.000 description 50
- 229960001866 silicon dioxide Drugs 0.000 description 49
- 230000006837 decompression Effects 0.000 description 48
- 238000000926 separation method Methods 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- 125000001309 chloro group Chemical group Cl* 0.000 description 47
- 238000012544 monitoring process Methods 0.000 description 42
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 41
- 238000001816 cooling Methods 0.000 description 40
- 238000010792 warming Methods 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 29
- 239000000203 mixture Substances 0.000 description 29
- 238000004821 distillation Methods 0.000 description 23
- 239000000463 material Substances 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical group C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 102000003915 DNA Topoisomerases Human genes 0.000 description 5
- 108090000323 DNA Topoisomerases Proteins 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 230000001028 anti-proliverative effect Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 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 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 235000011194 food seasoning agent Nutrition 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000000452 restraining effect Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 description 3
- RLQYRXCUPVKSAW-UHFFFAOYSA-M 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium;chloride Chemical compound [Cl-].COC1=C(OC)C=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=C1 RLQYRXCUPVKSAW-UHFFFAOYSA-M 0.000 description 3
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical compound FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010019695 Hepatic neoplasm Diseases 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
- 239000004480 active ingredient Substances 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- RIDQRIPSFYHEGL-UHFFFAOYSA-N fibrauretin Natural products CC12CC=C3C(=O)OC(CC3(C)C1C(=O)C=CC2=O)c4cocc4 RIDQRIPSFYHEGL-UHFFFAOYSA-N 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 210000000582 semen Anatomy 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 0 *Oc(c(O*)c1cc2)cc(CC*3cc4c5O*)c1c3c2c4ccc5ON Chemical compound *Oc(c(O*)c1cc2)cc(CC*3cc4c5O*)c1c3c2c4ccc5ON 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- XHQZJYCNDZAGLW-UHFFFAOYSA-N 3-methoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1 XHQZJYCNDZAGLW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 208000004429 Bacillary Dysentery Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 201000005113 shigellosis Diseases 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- RHBGITBPARBDPH-ZPUQHVIOSA-N (E,E)-piperic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=C2OCOC2=C1 RHBGITBPARBDPH-ZPUQHVIOSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- IBLMYGXJKQIGSN-UHFFFAOYSA-N 1-(bromomethyl)-2,4-difluorobenzene Chemical compound FC1=CC=C(CBr)C(F)=C1 IBLMYGXJKQIGSN-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- JSWRVDNTKPAJLB-UHFFFAOYSA-N 2,4-difluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(F)=C1 JSWRVDNTKPAJLB-UHFFFAOYSA-N 0.000 description 1
- MGKPFALCNDRSQD-UHFFFAOYSA-N 2-(4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1 MGKPFALCNDRSQD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 1
- MXNBDFWNYRNIBH-UHFFFAOYSA-N 3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1 MXNBDFWNYRNIBH-UHFFFAOYSA-N 0.000 description 1
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 1
- BBEWSMNRCUXQRF-UHFFFAOYSA-N 4-methyl-3-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1[N+]([O-])=O BBEWSMNRCUXQRF-UHFFFAOYSA-N 0.000 description 1
- RYAQFHLUEMJOMF-UHFFFAOYSA-N 4-phenoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=CC=C1 RYAQFHLUEMJOMF-UHFFFAOYSA-N 0.000 description 1
- IODMEDPPCXSFLD-UHFFFAOYSA-N 5-nitrofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)O1 IODMEDPPCXSFLD-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- DFXQXFGFOLXAPO-UHFFFAOYSA-N 96-99-1 Chemical compound OC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 DFXQXFGFOLXAPO-UHFFFAOYSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 1
- 101100190268 Caenorhabditis elegans pah-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 201000002014 Suppurative Otitis Media Diseases 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 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
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-O ethylaminium Chemical compound CC[NH3+] QUSNBJAOOMFDIB-UHFFFAOYSA-O 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000000451 gelidium spp. gum Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000001457 metallic cations Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 150000003810 morphinanes Chemical class 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- NTQYXUJLILNTFH-UHFFFAOYSA-N nonanoyl chloride Chemical compound CCCCCCCCC(Cl)=O NTQYXUJLILNTFH-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KGCNHWXDPDPSBV-UHFFFAOYSA-N p-nitrobenzyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CCl)C=C1 KGCNHWXDPDPSBV-UHFFFAOYSA-N 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 229960001553 phloroglucinol Drugs 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to cyclized berberine derivatives, a preparation method and uses thereof. The present invention specifically relates to compounds represented by a formula I or a pharmaceutically-acceptable salt or a solvate thereof, wherein X is a halogen, R is selected from hydrogen, C1-6 alkyl, phenyl substituted C1-6 alkyl, C1-18 alkylacyl, benzoyl, benzenesulfonyl, and 3,4-C1-3alkylidene dioxybenzoyl, the phenyl is optionally substituted by 1-4 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, nitro, cyano, amino, hydroxy, C1-4 alkyl acylamino. The compounds of the present invention have beneficial physiological activities.
Description
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to the compound that can be used as antineoplastic agent that a class is new, in particular to class cyclisation berberinc derivate with anti-tumor activity and preparation method thereof, and this compounds as medicine particularly as the application in the medicine of antitumor drug such as anti-liver neoplasm.
Background technology
Tumour and cancer are one of most major diseases of harm humans health.Tumour be body under various carcinogenic factor effect, some cells of local organization lose the normal regulation to its growth on gene level, cause its clonal abnormality hyperplasia and the true tumor that formed.It is generally acknowledged, tumour cell is monoclonicity, and all oncocytes namely in a tumour are all offsprings of the cell of a sudden change.Generally tumour is divided into optimum and pernicious two large classes.All malignant tumours are generically and collectively referred to as cancer.Physician points out that cancer is because being: body causes the result of health normal cell generation canceration under the effect of environmental pollution, chemical pollution (chemical toxicant), ionizing rays, free radical toxin, microorganism (bacterium, fungi, virus etc.) and the various carcinogenic substance of metabolic toxicities, hereditary property, endocrine imbalance, immunologic function disorder etc. thereof, carcinogenic factor, often shows as: the cellular abnormality hyperplasia of local organization and the local lump formed.Cancer is that organism normal cell is in many reasons, multistage and a caused large class disease of repeatedly suddenling change.
Know, Berberine (Berberine, BBR), is also called berberine, and be a kind of common morphinane alkaloid, its molecular formula is [C
20h
18nO
4]
+.It is present in many plants of four sections ten genus such as Berberidaceae, and M.-E. Xia Waliai in 1826 and G. Pei Ertan obtain first first from Xanthoxylonclava bark.Berberine is a kind of quartermary ammonium alkaloids, can separate out yellow needle-like crystals from ether; Fusing point 145 DEG C; Water-soluble, be insoluble in benzene, EC.The solubleness of its esters in water is all smaller, and such as hydrochloride is 1: 500, and vitriol is 1: 30.Berberine has restraining effect to dysentery bacterium, intestinal bacteria, pneumococcus, S. aureus L-forms, suis, Corynebacterium diphtheriae and ameba.Clinical conventional berberine hydrochloride is its 2 hydrate, is mainly used in intestinal tract infections and bacillary dysentery etc.Recently also find that Berberine has antiarrhythmic effect and may be used for treating diabetes.The has a broad antifungal spectrum of Berberine, external to multiple gram-positive and the equal tool bacteriostatic action of negative bacterium, wherein to Hemolytic streptococcus, S. aureus L-forms, vibrio cholerae.Meningococcus, shigella, Corynebacterium diphtheriae, diphtheria corynebacterium etc. have stronger restraining effect, antibacterial during lower concentration, sterilization during high density.Infected by influenza, ameba, Leptospira, some dermatophytes also have certain restraining effect.Experiment in vitro confirms that berberine can strengthen the phagocytic activity of white corpuscle and liver reticuloendothelial system.Dysentery bacterium, Hemolytic streptococcus, S. aureus L-forms etc. very easily produce resistance to this product.Berberine and penicillin, Streptomycin sulphate etc. there is no cross resistance.Current Berberine is mainly used in intestinal tract infections such as treatment gastro-enteritis, bacillary dysentery etc. clinically, effective for eye conjunctivitis, suppurative otitis media etc.
People still expect to have novelty and the medicine of effective antitumour medicine such as anti-liver neoplasm for clinical.
Summary of the invention
The object of the invention is to find the new compound with effective antitumour such as anti-liver neoplasm.The wonderful discovery of the present inventor, the cyclisation berberinc derivate with formula I structure has wonderful effect.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides with compounds of Formula I:
Or its pharmacologically acceptable salts or solvate, wherein
X is halogen;
R
1be selected from: hydrogen, C
1-6the C that alkyl, phenyl replace
1-6alkyl, C
1-18alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C
1-3alkylenedioxy group benzoyl, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-6alkyl, C
1-6alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino;
R
2and R
3be selected from independently of one another: hydrogen, C
1-6alkyl, benzoyl, wherein said phenyl is optionally by 1 to 4 halogen substiuted; Or R
2and R
3be-CH together
2-(i.e. R
2and R
3the ring of a dioxole is formed) together with the Sauerstoffatom that they connect.
Compound according to a first aspect of the present invention, wherein R
2and R
3be selected from independently of one another: hydrogen, C
1-4alkyl, Halobenzoyl; Or R
2and R
3be-CH together
2-(i.e. R
2and R
3the ring of a dioxole is formed) together with the Sauerstoffatom that they connect.
Compound according to a first aspect of the present invention, it is the compound with Formula Il:
Or its pharmacologically acceptable salts or solvate, wherein
X is halogen;
R is selected from: hydrogen, C
1-6the C that alkyl, phenyl replace
1-6alkyl, C
1-18alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C
1-3alkylenedioxy group benzoyl, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-6alkyl, C
1-6alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino.
Compound according to a first aspect of the present invention, wherein X is selected from fluorine, chlorine, bromine, iodine.In one embodiment, X is selected from chlorine, bromine, iodine.
Compound according to a first aspect of the present invention, wherein R is selected from hydrogen, C
1-4the C that alkyl, phenyl replace
1-4alkyl, C
1-16alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C
1-2alkylenedioxy group benzoyl, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-4alkyl, C
1-4alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino.
Compound according to a first aspect of the present invention, wherein R is selected from hydrogen, C
1-4the C that alkyl, phenyl replace
1-4alkyl, C
1-16alkyl acyl, benzoyl, benzenesulfonyl, 3,4-methylene-dioxy benzoyls, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-4alkyl, C
1-4alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino.
Compound according to a first aspect of the present invention, it is following formula: compound,
Wherein R
1, R
2, R
3with X, there is implication described in following any one of numbering (No1 to No51):
Compound according to a first aspect of the present invention, it is be selected from following compound:
9,10-dimethoxy-5,6-dihydro-[1,3] dioxole is [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate also;
9-hydroxyl-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate also;
9-oxyethyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide also;
9-butoxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-iodide also;
9-benzyloxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide also;
9-(2,4 difluorobenzene base) methoxyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-ethanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to anisoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluorine m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methoxyl group m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4-methylene-dioxy benzoyl oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4,5-trimethoxybenzoy oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Adjacent fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1, the 3] dioxole of 9-also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Adjacent chlorobenzene formacyl Oxy-1 0-methoxyl group-5,6-dihydro-[1, the 3] dioxole of 9-also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(2,4 difluorobenzene formyl radical oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to acetamido benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-decanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-lauroyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hexadecanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Or its pharmacologically acceptable salts or solvate.
Compound according to a first aspect of the present invention, it is compound prepared by the embodiment of the present invention or its pharmacologically acceptable salts or solvate.
Second aspect present invention provides the method preparing formula I described in any one of first aspect present invention, and it comprises the following steps:
A) in solvent (such as methyl alcohol), under alkali (such as salt of wormwood, sodium hydroxide etc. or its combination) exists, sodium borohydride and Berberine are reacted, obtains dihydroberberine;
B) in solvent (such as acetonitrile), such as, under acid (such as organic acid, acetic acid) exists, make dihydroberberine and glyoxal reaction, obtain the cyclisation Berberine shown in formula Ia:
Optional, c) make formula Ia cyclisation Berberine at vacuum (such as 10-60mmHg, such as 20-40mmHg) under, such as, under high temperature (such as 150 ~ 250 DEG C, 180 ~ 230 DEG C) process obtain the 9-Hydroxy Cyclization Berberine shown in formula Ib:
Optional, d) in organic solvent (such as DMF), under alkali (such as sodium hydroxide, potassium hydroxide) exists, make the 9-Hydroxy Cyclization Berberine of formula Ib and suitable reagent (such as halohydrocarbon, the halogenated alkane that such as halogenated alkane, phenyl replace) reaction, obtain 9-alkyl oxy cyclisation Berberine, alkyl wherein is optionally replaced by the phenyl of phenyl or replacement;
Optional; e) in organic solvent (such as acetonitrile); under reagent (such as pyridine) exists; the 9-Hydroxy Cyclization Berberine of formula Ib and acyl chlorides or SULPHURYL CHLORIDE are reacted; obtain 9-acyloxy cyclisation Berberine or the cyclization Berberine of 9-alkylsulfonyl oxygen, acyl group is wherein alkyloyl or benzoyl.
In the preparation method of second aspect present invention, where necessary, in formula I preparation process; undesirable reaction is there is for preventing some group (as amino, hydroxyl etc.); need to be protected these groups, meanwhile, removed protecting group in due course.These embodiments are too numerous to enumerate, and the use of the protecting group specifically do not mentioned and the method for deprotection also belong within scope of the present invention.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention relates to formula I described in any one of first aspect present invention for the preparation of the purposes treated and/or prevented in the medicine of Mammals (comprising people) tumour or cancer disease (such as liver cancer).
Fifth aspect present invention relates to a kind of method treating and/or preventing Mammals (comprising people) tumour or cancer disease (such as liver cancer) in Mammals in need, and the method comprises to the formula I described in any one of first aspect present invention of administration treatment significant quantity in need.
Sixth aspect present invention relates to the pharmaceutical composition being used for the treatment of and/or preventing Mammals (comprising people) tumour or cancer disease (such as liver cancer), this pharmaceutical composition comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Seventh aspect present invention also relates to the formula I described in any one of first aspect present invention being used for the treatment of and/or preventing Mammals (comprising people) tumour or cancer disease (such as liver cancer).
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Those skilled in the art know, and the main ring of Berberine and annular atoms can by serial numbers exemplary as follows:
Similarly, for formula I, such as, for for formula Ia compound, wherein corresponding five rings and part annular atoms numbering can example as follows:
Therefore in the present invention, when mentioning " cyclisation Berberine ", refer to the berberinc derivate of above formula Ia.Further, when mentioning " 9-Hydroxy Cyclization Berberine ", refer to the berberinc derivate shown in following formula Ib:
Again such as, refer to that 9-position is the compounds of this invention of oxyethyl group when mentioning " 9-oxyethyl group cyclisation Berberine ".
In the present invention, term " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.In the present invention, group " 3,4-C
1-3alkylenedioxy group benzoyl " in radical moiety " C
1-3alkylidene group " refer to the alkylidene group with 1 to 3 carbon atom.
In the present invention, when mentioning, the term " alkyl " adopted comprises alkyl, thiazolinyl and alkynyl, and cyclic group, such as the group of aromatic ring (as phenyl ring) or non-aromatic ring (such as cyclohexane ring).In the present invention, C is mentioned
1-6during alkyl, it comprises its random subset, such as, comprise C
1-5alkyl, C
1-4alkyl, C
1-3alkyl, and methyl, ethyl, n-propyl, sec.-propyl, normal-butyl etc.
In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.
Formula I of the present invention can use with other active ingredient combinations, as long as it does not produce other detrimental actions, and such as anaphylaxis.
Active compound shown in formula I can be used as unique antitumor/cancer therapy drug uses, or can with one or more other antibacterials conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.In the present invention, term " composition " can exchange with " pharmaceutical composition " and use.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al., J.Pharmaceutical Sciences, has been described in detail pharmacologically acceptable salts in 1977,66:1.Described salt, by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, is prepared at the final abstraction and purification process situ of the compounds of this invention or prepares separately.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, Basic nitrogen-containing groups can be quaternized with following material: elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halide as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to be formed the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid is as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt by make the compounds of this invention containing carboxylic moiety and suitable alkali reaction, in the final abstraction and purification process situ preparation of the compounds of this invention, the oxyhydroxide of the acceptable metallic cation of described alkali such as pharmacy, carbonate and supercarbonate, or ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to that positively charged ion based on basic metal or alkaline-earth metal is as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the representative organic amines that can be used for being formed base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Formula I also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.
Below the structure of exemplary compounds more of the present invention and the activity of anti-HepG2 cell proliferation thereof are listed in, antiproliferative activity measuring method is wherein shown in test example 1.
| Embodiment number | Compound numbers | Inhibiting rate % |
| Embodiment 1 | A | 33.4±3.2 a |
| Embodiment 2 | A-30 | 50.0±3.1 a |
| Embodiment 3 | A-31 | 41.9±3.3 a |
| Embodiment 4 | A-32 | 62.6±1.8 a |
| Embodiment 5 | A-33 | 53.3±11.5 a |
| Embodiment 6 | A-43 | 50.7±11.7 a |
| Embodiment 7 | A-34 | 88.7±1.1 a |
| Embodiment 8 | A-35 | 86.6±2.4 a |
| Embodiment 9 | A-38 | 63.7±2.0 a |
| Embodiment 10 | A-40 | 84.5±1.9 a |
| Embodiment 11 | A-39 | 70.3±2.6 a |
| Embodiment 12 | A-44 | 69.6±2.5 a |
| Embodiment 13 | A-45 | 50.9±4.3 a |
| Embodiment 14 | A-46 | 53.6±2.2 a |
| Embodiment 15 | A-56 | 88.6±10.8 a |
| Embodiment 16 | A-49 | 86.5±10.6 a |
| Embodiment 17 | A-55 | 93.7±16.1 a |
| Embodiment 18 | A-37 | 62.3±2.0 a |
| Embodiment 19 | A-58 | 92.5±11.4 a |
| Embodiment 20 | A-41 | 8.9±5.1 a |
| Embodiment 21 | A-42 | 56.2±2.0 a |
| Embodiment 22 | A-50 | 87.3±55.5 a |
| Embodiment 23 | A-53 | 87.6±9.8 a |
| Embodiment 24 | A-54 | 93.5±2.5 a |
| Embodiment 25 | A-61 | 86.5±10.6 a |
| Embodiment 26 | A-64 | 79.0±9.9 a |
| Embodiment 27 | A-67 | 70.5±2.5 a |
| Embodiment 28 | A-68 | 63.7±6.1 a |
| Embodiment 29 | A-69 | 88.6±9.1 a |
| Embodiment 30 | A-70 | 76.5±8.4 a |
| Embodiment 31 | A-71 | 58.6±5.3 b |
| Embodiment 32 | A-72 | 49.7±6.1 b |
| Embodiment 33 | A-73 | 58.0±5.6 b |
| Embodiment 34 | A-74 | 59.3±5.1 b |
| Embodiment 35 | A-75 | 57.6±3.6 b |
| Embodiment 36 | A-76 | 52.4±2.3 b |
| Embodiment 37 | A-77 | 52.8±4.1 b |
| Embodiment 38 | A-78 | 50.9±3.5 b |
| Embodiment 39 | A-79 | 48.5±4.3 b |
| Embodiment 40 | A-80 | 49.5±6.0 b |
| Embodiment 41 | A-81 | 57.3±3.6 b |
| Embodiment 42 | A-82 | 43.4±3.2 b |
| Embodiment 43 | A-83 | 56.6±1.2 b |
| Embodiment 44 | A-84 | 53.5±5.6 b |
| Embodiment 45 | A-85 | 60.6±1.2 b |
| Embodiment 46 | A-86 | 54.1±6.0 b |
| Embodiment 47 | A-87 | 13.0±1.3 b |
| Embodiment 48 | A-36 | 32.9±3.0 a |
| Embodiment 49 | A-60 | 5.4±0.9 a |
| Embodiment 50 | A-65 | 87.3±55.5 a |
| Embodiment 51 | A-66 | 87.6±9.8 a |
Note a:0.6 μ g/mL b:0.1 μ g/mL
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment and/or prevention.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
The pharmaceutical carrier using those skilled in the art to be familiar with can be prepared into the pharmaceutical composition of the compounds of this invention containing effective dose.Therefore the present invention goes back the pharmaceutical composition of providing package containing the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.Described pharmaceutical composition can to become with solid or liquid form is for oral administration, for parental injection or for rectal administration by particular formulation especially.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, such as, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding injection water before the injection can use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and need, also containing disintegrating agent, as starch, agar, Lalgine or its salt, normally sodiun alginate, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., the matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, locally (as by powder, ointment or drops), mouth cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.
The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee the effect preventing microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials in suspensoid.
In some cases, be the effect of prolong drug, expect absorption that is subcutaneous or intramuscular injection of drugs of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can by oral method or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and parenteral preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to the auxiliary material manufacturing tablet, capsule, Drug coating used is conventional auxiliary material, such as starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).Other auxiliary material, such as tensio-active agent is also had, lubricant, disintegrating agent, sanitas, correctives and pigment etc. containing in the preparation of the compounds of this invention.In tablet, capsule, Drug coating, injection and suppository containing the dosage of formula I be with unit dosage form in the compound gauge that exists calculate.In unit dosage form, the general content of formula I is 0.01-5000mg, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can accept vehicle or carrier such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least one inertia and mix: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agents is as paraffin; F) accelerator is absorbed as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, in described formulation, also buffer reagent can be comprised.
The solids composition of similar type uses excipients as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill can be prepared with the solid dosage of granule together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages optionally can contain opalizer, and its composition also can make its just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into microencapsulated form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form is except the inert diluent also can commonly used containing this area containing active ingredient beyond the region of objective existence, such as water or other solvents, the fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and sorbitan and their mixture.Oral compositions also can comprise auxiliary material except comprising inert diluent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
Composition for rectum or vagina administration is preferably suppository.Suppository is prepared by being mixed with suitable non-irritating excipient or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax by the compounds of this invention, they are at room temperature solid, but be then liquid under body temperature, therefore can melt in rectal cavity or vaginal canal and discharge active compound.
Compound of the present invention and composition thereof are also considered for topical.The dosage form giving the compounds of this invention for local comprises powder, sprays, ointment and inhalation.Aseptically by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposomal form administration.As known in the art, liposome obtains with phosphatide or other lipid materials usually.Liposome formed by the single or multiple lift aquation liquid crystal be scattered in water-bearing media.Any nontoxic, physiology that can form liposome can to accept and metabolizable lipid all can use.The present composition of liposomal form, except containing except the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide that is natural and that synthesize and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method forming liposome is well known in the art.See such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
The present inventor is surprised to find, and the propagation of cyclisation berberinc derivate to HepG2 cell shown in structural formula I creates obvious restraining effect.Therefore, compound of the present invention can be used for treating and/or preventing Mammals (comprising people) tumour or cancer disease (such as liver cancer).
Accompanying drawing explanation
Fig. 1 depicts the determination of activity result of the compounds of this invention to cells of resistant tumors.
Fig. 2 depicts the cell cycle analysis measurement result of the compounds of this invention.
Fig. 3 depicts the inhibit activities measurement result of the compounds of this invention to topoisomerase I.
Embodiment
Further illustrate the present invention below by concrete preparation embodiment and biological test example, but should be understood to, these embodiments and test example are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
Embodiment 1: the synthesis of compd A
Sodium borohydride (1.2g will be dissolved with, 5% sodium hydroxide solution (10ml) 32mmol) is dropwise added to containing Berberine (7.4g, 20mmol) with salt of wormwood (8.3g, in methyl alcohol (250ml) solution system 60mmol), stirring at room temperature 2 hours, the greenish yellow solid that collected by suction is separated out, filter cake uses distilled water (100ml) and 80% ethanol (100ml) washing successively, obtain intermediate dihydroberberine (4.2g, 62%).By intermediate dihydroberberine (4.0g, 12mmol) be dissolved in acetonitrile (160ml), then the oxalic dialdehyde (2ml) of acetic acid (40ml) and 40% is added, be heated to 85 ~ 95 DEG C of backflows 5 hours, flaggy monitoring reacts completely, and is concentrated by reaction solution, obtains dark red oil, add 2% hydrochloric acid soln (200ml), stirring at room temperature 1 hour, filters, filtrate stirring at room temperature 5 days, reaction solution is concentrated, use 95% ethyl alcohol recrystallization, products therefrom washed with diethylether, obtain orange solids A (1.8g, 38%), fusing point: 185 ~ 187 DEG C.
HRMS-ESI(M/Z)：360.1216【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.12(s，3H)，4.16(s，3H)，5.24(t，J＝6.8Hz，2H)，6.39(s，2H)，7.59(s，1H)，8.21(d，J＝9.2Hz，1H)，8.31(d，J＝9.6Hz，1H)，8.85(d，J＝9.6Hz，1H)，8.89(d，J＝9.2Hz，1H)，10.14(s，1H).
Embodiment 2: the synthesis of compd A-30
By A (3.6g, 9.1mmol) be placed in 250ml round-bottomed flask, maintenance vacuum tightness is 30 ~ 40mmHg, be heated to 195 ~ 210 DEG C of reactions 30 minutes, solid color is deepened gradually, finally all becomes scarlet, and acidic alcohol (5ml: 95ml) acidifying obtains red product A-30 (3.2g, 92%), fusing point: 269 ~ 271 DEG C.
HRMS-ESI(M/Z)：346.1069【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.56(t，J＝6.8Hz，2H)，4.03(s，3H)，5.10(t，J＝6.8Hz，2H)，6.36(s，2H)，7.52(s，1H)，8.02(d，J＝8.8Hz，1H)，8.10(d，J＝9.2Hz，1H)，8.26(d，J＝8.4Hz，1H)，8.75(d，J＝9.2Hz，1H)，9.96(s，1H).
Embodiment 3: the synthesis of compd A-31
By A-30 (198mg, 0.52mmol) be dissolved in DMF (10ml), then potassium hydroxide (the 60mg of porphyrize is added, 1.04mmol) with monobromethane (2ml, 27mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, resistates dilute hydrochloric acid adjusts PH to 3, and the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain red product A-31 (52mg, 22%), fusing point: 216 ~ 218 DEG C.
HRMS-ESI(M/Z)：374.1397【M-Br】
+
1H NMR(CD
3SOCD
3，400MHz)：δ1.49(t，J＝7.2Hz，3H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.44(q，J＝7.2Hz，2H)，5.26(t，J＝6.8Hz，2H)，6.39(s，2H)，7.58(s，1H)，8.20(d，J＝9.2Hz，1H)，8.29(d，J＝9.2Hz，1H)，8.83(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，10.05(s，1H).
Embodiment 4: the synthesis of compd A-32
By A-30 (198mg, 0.52mmol) be dissolved in DMF (10ml), then potassium hydroxide (the 60mg of porphyrize is added, 1.04mmol) with 1-butyl iodide (236 μ l, 2.08mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, resistates dilute hydrochloric acid adjusts PH to 3, and the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain red product A-32 (75mg, 27%), fusing point: 202 ~ 204 DEG C.
HRMS-ESI(M/Z)：402.1702【M-I】
+
1H NMR(CD
3SOCD
3，400MHz)：δ1.00(t，J＝7.2Hz，3H)，1.51-1.57(m，2H)，1.87-1.94(m，2H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.37(t，J＝6.8Hz，2H)，5.25(t，J＝6.8Hz，2H)，6.40(s，2H)，7.59(s，1H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝9.2Hz，1H)，8.84(d，J＝9.2Hz，1H)，8.89(d，J＝9.2Hz，1H)，9.98(s，1H).
Embodiment 5: the synthesis of compd A-33
By A-30 (99mg, 0.26mmol) be dissolved in DMF (5ml), then potassium hydroxide (the 30mg of porphyrize is added, 0.52mmol) with cylite (124 μ l, 1.04mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, resistates dilute hydrochloric acid adjusts PH to 3, and the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain orange product A-33 (81mg, 60%), fusing point: 131 ~ 133 DEG C.
HRMS-ESI(M/Z)：436.1562【M-Br】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.14(s，3H)，5.22(t，J＝6.8Hz，2H)，5.43(s，2H)，6.39(s，2H)，7.35-7.43(m，3H)，7.59(s，1H)，7.62(d，J＝6.8Hz，2H)，8.21(d，J＝9.2Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.86(t，J＝9.2Hz，2H)，9.98(s，1H).
Embodiment 6: the synthesis of compd A-43
By A-30 (99mg, 0.26mmol) be dissolved in DMF (5ml), then potassium hydroxide (the 30mg of porphyrize is added, 0.52mmol) He 2,4-difluorobenzyl bromide (134 μ l, 1.04mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, and resistates dilute hydrochloric acid adjusts PH to 3, the solid that collected by suction is separated out, take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain red product A-43 (79mg, 55%), fusing point: 138 ~ 140 DEG C.
HRMS-ESI(M/Z)：472.1347【M-Br】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.11(s，3H)，5.22(t，J＝6.8Hz，2H)，5.47(s，2H)，6.40(s，2H)，7.14-7.19(m，1H)，7.28-7.33(m，1H)，7.60(s，1H)，7.81(q，J＝8.4Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.88(d，J＝4.4Hz，1H)，8.90(d，J＝4.0Hz，1H)，9.93(s，1H).
Embodiment 7: the synthesis of compd A-34
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), Acetyl Chloride 98Min. (74 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-34 (70mg, 64%), fusing point: 183 ~ 185 DEG C.
HRMS-ESI(M/Z)：388.1188【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ2.56(s，3H)，3.64(t，J＝6.8Hz，2H)，4.09(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.15(s，1H).
Embodiment 8: the synthesis of compd A-35
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), Benzoyl chloride (120 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-35 (84mg, 67%), fusing point: 228 ~ 230 DEG C.
HRMS-ESI(M/Z)：450.1336【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.07(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.71(t，J＝7.6Hz，2H)，7.86(t，J＝7.6Hz，1H)，8.26-8.31(m，3H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.15(d，J＝9.2Hz，1H)，10.24(s，1H).
Embodiment 9: the synthesis of compd A-38
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add methyl benzoyl chloride (139 μ l, 1.04mmol), continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-38 (53mg, 41%), fusing point: 221 ~ 223 DEG C.
HRMS-ESI(M/Z)：464.1489【M-Cl】
+
1H NMR(CD
3OD，400MHz)：δ2.47(s，3H)，3.60(t，J＝6.8Hz，2H)，4.06(s，3H)，5.17(t，J＝6.8Hz，2H)，6.29(s，2H)，7.40(s，1H)，7.43(d，J＝8.0Hz，2H)，8.19(d，J＝8.0Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.76(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.89(s，1H).
Embodiment 10: the synthesis of compd A-40
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), anisoyl chloride (141 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-40 (69mg, 51%), fusing point: 202 ~ 204 DEG C.
HRMS-ESI(M/Z)：480.1442【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，3.92(s，3H)，4.06(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.22(d，J＝8.8Hz，2H)，7.59(s，1H)，8.24(d，J＝8.8Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 11: the synthesis of compd A-39
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add fluorobenzoyl chloride (123 μ l, 1.04mmol), continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-39 (40mg, 31%), fusing point: 218 ~ 220 DEG C.
HRMS-ESI(M/Z)：468.1256【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.08(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(t，J＝8.8Hz，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.35-8.39(m，2H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 12: the synthesis of compd A-44
Fluoro-for 4-3-nitrobenzoic acid (193mg, 1.04mmol) be added in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-44 (35mg, 25%), fusing point: 187 ~ 189 DEG C.
HRMS-ESI(M/Z)：513.1083【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.93-7.98(m，1H)，8.29(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.67-8.68(m，1H)，8.94(dd，J＝2.0，7.2Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.29(s，1H).
Embodiment 13: the synthesis of compd A-45
Be added to by 4-methyl-3-nitro phenylformic acid (188mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains scarlet product A-45 (36mg, 25%), fusing point: 165 ~ 167 DEG C.
HRMS-ESI(M/Z)：509.1343【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ2.70(s，3H)，3.62(t，J＝6.8Hz，2H)，4.08(s，3H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.87(d，J＝8.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.47(d，J＝9.2Hz，2H)，8.79(d，J＝1.2Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.17(d，J＝9.2Hz，1H)，10.27(s，1H).
Embodiment 14: the synthesis of compd A-46
Be added to by 4-methoxyl group-3-nitrobenzoic acid (205mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains scarlet product A-46 (22mg, 15%), fusing point: 158 ~ 160 DEG C.
HRMS-ESI(M/Z)：525.1295【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.68(d，J＝8.8Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.51(dd，J＝2.4，8.8Hz，1H)，8.74(d，J＝2.4Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H).
Embodiment 15: the synthesis of compd A-56
Be added to by piperinic acid (173mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-56 (29mg, 21%), fusing point: 192 ~ 194 DEG C.
HRMS-ESI(M/Z)：494.1239【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.25(s，2H)，6.41(s，2H)，7.22(d，J＝8.0Hz，1H)，7.60(s，1H)，7.73(d，J＝1.6Hz，1H)，7.91(dd，J＝1.6，8.4Hz，1H)，8.27(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.97(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.19(s，1H).
Embodiment 16: the synthesis of compd A-49
Be added to by 3,4,5-trimethoxybenzoic acid (221mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-49 (31mg, 21%), fusing point: 210 ~ 212 DEG C.
HRMS-ESI(M/Z)：540.1685【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，3.83(s，3H)，3.92(s，6H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(s，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 17: the synthesis of compd A-55
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), o-fluoro-benzoyl chloride (124 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-55 (35mg, 27%), fusing point: 181 ~ 183 DEG C.
HRMS-ESI(M/Z)：468.1247【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.51-7.57(m，2H)，7.60(s，1H)，7.88-7.92(m，1H)，8.28(d，J＝9.2Hz，1H)，8.30-8.32(m，1H)，8.46(d，J＝9.2Hz，1H)，8.98(d，J＝9.2Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H).
Embodiment 18: the synthesis of compd A-37
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), o-chlorobenzoyl chloride (132 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-37 (31mg, 23%), fusing point: 164 ~ 166 DEG C.
HRMS-ESI(M/Z)：484.0952【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.63(t，J＝6.8Hz，2H)，4.11(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.66-7.69(m，1H)，7.79-7.81(m，2H)，8.28(d，J＝9.2Hz，1H)，8.45-8.48(m，2H)，8.99(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.24(s，1H).
Embodiment 19: the synthesis of compd A-58
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add 2,4-difluoro benzoyl chloride (128 μ l, 1.04mmol), continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-58 (23mg, 17%), fusing point: 191 ~ 193 DEG C.
HRMS-ESI(M/Z)：486.1151【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.10(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.41-7.46(m，1H)，7.61(s，1H)，7.62-7.68(m，1H)，8.28(d，J＝9.2Hz，1H)，8.39(q，J＝8.4Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 20: the synthesis of compd A-41
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), 4-acetamido benzene sulfonyl chloride (243mg, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-41 (23mg, 15%), fusing point: 205 ~ 207 DEG C.
HRMS-ESI(M/Z)：543.1203【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ2.12(s，3H)，3.60(t，J＝6.4Hz，2H)，3.81(s，3H)，5.18(t，J＝6.4Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.86(s，4H)，8.28(d，J＝9.2Hz，1H)，8.34(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.15(d，J＝9.6Hz，1H)，9.74(s，1H)，10.61(s，1H).
Embodiment 21: the synthesis of compd A-42
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), benzene sulfonyl chloride (133 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-42 (38mg, 28%), fusing point: 223 ~ 225 DEG C.
HRMS-ESI(M/Z)：486.1001【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，3.76(s，3H)，5.20(t，J＝6.8Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.73(t，J＝8.0Hz，2H)，7.91(t，J＝7.6Hz，1H)，7.97(d，J＝7.2Hz，2H)，8.28(d，J＝9.6Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，9.79(s，1H).
Embodiment 22: the synthesis of compd A-50
Be added to by n-capric acid (179mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-50 (25mg, 18%), fusing point: 180 ~ 182 DEG C.
HRMS-ESI(M/Z)：500.2444【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.85-0.88(m，3H)，1.23-1.49(m，12H)，1.73-1.80(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.11(s，1H).
Embodiment 23: the synthesis of compd A-53
Lauric acid (208mg, 1.04mmol) be added in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-53 (21mg, 14%), fusing point: 184 ~ 186 DEG C.
HRMS-ESI(M/Z)：528.2718【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.85(t，J＝6.8Hz，3H)，1.25-1.47(m，16H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H).
Embodiment 24: the synthesis of compd A-54
Be added to by palmitinic acid (267mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-54 (52mg, 32%), fusing point: 184 ~ 186 DEG C.
HRMS-ESI(M/Z)：584.3337【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.84(t，J＝6.8Hz，3H)，1.23-1.47(m，24H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H).
Embodiment 25: the synthesis of compd A-61
By A-30 (99mg, 0.26mmol) be dissolved in DMF (5ml), then potassium hydroxide (the 30mg of porphyrize is added, 0.52mmol) He 1,2-ethylene dibromide (90 μ l, 1.04mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, and resistates dilute hydrochloric acid adjusts PH to 3, the solid that collected by suction is separated out, take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain red product A-61 (40mg, 29%), fusing point: 142 ~ 144 DEG C.
HRMS-ESI(M/Z)：452.0476【M-Br】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.65(t，J＝6.4Hz，2H)，4.02(t，J＝6.0Hz，2H)，4.13(s，3H)，4.70(t，J＝6.0Hz，2H)，5.25(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.24(d，J＝9.2Hz，1H)，8.34(d，J＝9.2Hz，1H)，8.90(d，J＝8.8Hz，1H)，8.92(d，J＝8.8Hz，1H)，10.11(s，1H).
Embodiment 26: the synthesis of compd A-64
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), bromoacetyl bromide (91 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-64 (42mg, 30%), fusing point: 154 ~ 156 DEG C.
HRMS-ESI(M/Z)：466.0293【M-Br】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.65(t，J＝6.8Hz，2H)，4.10(s，3H)，4.78(s，2H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.62(s，1H)，8.27(d，J＝9.2Hz，1H)，8.42(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.17(s，1H).
Embodiment 27: the synthesis of compd A-67
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), caproyl chloride (144 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-67 (54mg, 43%), fusing point: 125 ~ 127 DEG C.
HRMS-ESI(M/Z)：444.1824【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.94(t，J＝7.2Hz，3H)，1.38-1.46(m，4H)，1.76-1.79(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.10(s，1H).
Embodiment 28: the synthesis of compd A-68
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), oenanthyl chloro (161 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-68 (46mg, 36%), fusing point: 117 ~ 119 DEG C.
HRMS-ESI(M/Z)：458.1953【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.91(t，J＝7.2Hz，3H)，1.34-1.38(m，4H)，1.46-1.50(m，2H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.25(d，J＝9.2Hz，1H)，8.39(d，J＝9.2Hz，1H)，8.94(d，J＝9.6Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.13(s，1H).
Embodiment 29: the synthesis of compd A-69
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), capryl(yl)chloride (178 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains orange product A-69 (69mg, 52%), fusing point: 118 ~ 120 DEG C.
HRMS-ESI(M/Z)：472.2121【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.89(t，J＝6.8Hz，3H)，1.31-1.39(m，6H)，1.45-1.49(m，2H)，1.75-1.79(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.11(s，1H).
Embodiment 30: the synthesis of compd A-70
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), pelargonyl chloride (195 μ l, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-70 (39mg, 29%), fusing point: 126 ~ 128 DEG C.
HRMS-ESI(M/Z)：486.2262【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ0.88(t，J＝6.8Hz，3H)，1.23-1.47(m，10H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.25(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，8.23(d，J＝9.2Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.06(d，J＝9.6Hz，1H)，10.14(s，1H).
Embodiment 31: the synthesis of compd A-71
Be added to by 3-nitro-4-chloro-benzoic acid (209mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-71 (63mg, 46%), fusing point: 211 ~ 213 DEG C.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.19(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.15(d，J＝8.4Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.53(dd，J＝2.0，8.4Hz，1H)，8.91(d，J＝1.6Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.28(s，1H).
Embodiment 32: the synthesis of compd A-72
By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), 4-cyanobenzenesulfonyl chloride (210mg, 1.04mmol) is then added, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-72 (74mg, 56%), fusing point: 216 ~ 219 DEG C.
HRMS-ESI(M/Z)：511.09638【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.64(t，J＝6.4Hz，2H)，3.75(s，3H)，5.25(t，J＝6.4Hz，2H)，6.42(s，2H)，7.64(s，1H)，8.16-8.24(m，4H)，8.28(d，J＝9.2Hz，1H)，8.33(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，9.88(s，1H).
Embodiment 33: the synthesis of compd A-73
Bromo-for 2-5-nitrobenzoic acid (254mg, 1.04mmol) be added in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.By A-30 (99mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), dividing cooling, the solid that collected by suction is separated out, take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain red product A-73 (62mg, 46%), fusing point: 180 ~ 183 DEG C.
HRMS-ESI(M/Z)：573.02972【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.23(d，J＝7.8Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.51(dd，J＝1.6，7.8Hz，1H)，8.93(d，J＝1.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.36(s，1H).
Embodiment 34: the synthesis of compd A-74
Be added to by 2-fluorine-5-nitro benzoic acid (192mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-74 (40mg, 30%), fusing point: 209 ~ 211 DEG C.
HRMS-ESI(M/Z)：513.11096【M-Cl】
+
1H NMR(CD3SOCD
3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.42(s，2H)，7.61(s，1H)，7.89(t，J＝10.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.74-8.76(mm，1H)，8.99(d，J＝9.2Hz，1H)，9.02(d，J＝3.2Hz，1H)，9.19(d，J＝9.6Hz，1H)，10.30(s，1H).
Embodiment 35: the synthesis of compd A-75
Be added to by 2-furancarboxylic acid (117mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-75 (29mg, 26%), fusing point: 186 ~ 188 DEG C.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，6.93(q，J＝1.6Hz，1H)，7.59(s，1H)，7.77(d，J＝3.6Hz 1H)，8.21-8.25(m，2H)，8.42(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.11(d，J＝9.2Hz，1H)，10.22(s，1H).
Embodiment 36: the synthesis of compd A-76
Be added to by 3-nitrobenzoic acid (174mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-76 (52mg, 41%), fusing point: 221 ~ 223 DEG C.
HRMS-ESI(M/Z)：495.12041【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，8.01-8.05(m，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.69-8.71(m，2H)，8.97-9.0(m，2H)9.18(d，J＝9.2Hz，1H)，10.32(s，1H).
Embodiment 37: the synthesis of compd A-77
Be added to by 4-chloro-benzoic acid (163mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-77 (48mg, 38%), fusing point: 198 ~ 201 DEG C.
HRMS-ESI(M/Z)：484.09596【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.21(t，J＝6.4Hz，2H)，6.30(s，2H)，7.60(s，1H)，7.80(d，J＝8.4Hz，2H)，8.24(d，J＝9.2Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.25(s，1H).
Embodiment 38: the synthesis of compd A-78
Be added to by 3-tolyl acid (141mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-78 (57mg, 48%), fusing point: 205 ~ 208 DEG C.
HRMS-ESI(M/Z)：464.15097【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ2.49(s，3H)，3.62(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.62-769.(m，2H)，8.09-8.13(m，2H)，8.23(d J＝8.4Hz，1H)，8.43(d，J＝8.4Hz，1H)，8.94(d，J＝8.4Hz，1H)，9.11(d，J＝8.4Hz，1H)，10.24(s，1H).
Embodiment 39: the synthesis of compd A-79
Be added to by 2-tolyl acid (141mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-79 (50mg, 42%), fusing point: 200 ~ 202 DEG C.
HRMS-ESI(M/Z)：464.15110【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ2.66(s，3H)，3.62(t，J＝6.0Hz，2H)，4.09(s，3H)，5.24(t，J＝6.0Hz，2H)，6.40(s，2H)，7.51-7.54(m，2H)，7.59(s，1H)，7.69(t，J＝7.6Hz，1H)，8.24(d J＝9.2Hz，1H)，8.37(d J＝7.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.6Hz，1H)，9.11(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 40: the synthesis of compd A-80
Be added to by 5-nitro-2-furancarboxylic acid (163mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-80 (29mg, 27%), fusing point: 190 ~ 192 DEG C.
HRMS-ESI(M/Z)：485.09969【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.02-8.06(m，2H)，8.25(d，J＝8.4Hz，1H)，8.46(d，J＝8.4Hz，1H)，8.96(d，J＝8.4Hz，1H)，9.17(d，J＝8.4Hz，1H)，10.30(s，1H).
Embodiment 41: the synthesis of compd A-81
Be added to by 4-phenoxy benzoic acid (222mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-81 (59mg, 42%), fusing point: 199 ~ 202 DEG C.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，7.20-7.23(m，4H)，7.30(t，J＝7.6Hz，1H)，7.52(t，J＝8Hz，2H)，7.59(s，1H)，8.22(d，J＝8.8Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.42(d，J＝9.2Hz，1H)，8.92(d，J＝8.8Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.22(s，1H).
Embodiment 42: the synthesis of compd A-82
Be added to by 4-fluorophenylacetic acid (160mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-82 (43mg, 34%), fusing point: 195 ~ 198 DEG C.
HRMS-ESI(M/Z)：482.14194【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.66(t，J＝6.8Hz，2H)，4.08(s，3H)，4.31(s，2H)，5.26(t，J＝6.8Hz，2H)，6.41(s，2H)，7.23-7.30(m，2H)，7.51-7.55(m，2H)，7.62(s，1H)，8.26(d，J＝9.6Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.94(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 43: the synthesis of compd A-83
Be added to by 3-chloro-benzoic acid (162mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-83 (63mg, 50%), fusing point: 183 ~ 185 DEG C.
HRMS-ESI(M/Z)：484.09598【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.22(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，7.74-7.79(m，1H)，7.94-7.97(m，1H)，8.22-8.26(m，2H)，8.30(s，1H)，8.43(d，J＝9.2Hz，1H)，8.93(d，J＝9.2Hz，1H)，9.12(d，J＝9.2Hz，1H)，10.28(s，1H).
Embodiment 44: the synthesis of compd A-84
Be added to by 3-methoxybenzoic acid (162mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-84 (40mg, 32%), fusing point: 205 ~ 208 DEG C.
HRMS-ESI(M/Z)：484.14417【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.90(s，3H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.74-7.79(m，1H)，7.60-7.65(m，2H)，7.76(s，1H)，7.89(d，J＝7.6Hz，1H)8.26(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.14(d，J＝9.2Hz，1H)，10.23(s，1H).
Embodiment 45: the synthesis of compd A-85
Be added to by 3-fluorobenzoic acid (146mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-85 (46mg, 38%), fusing point: 198 ~ 201 DEG C.
HRMS-ESI(M/Z)：468.12509【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.39(s，2H)，7.59(s，1H)，7.75-7.79(m，2H)，8.09(d，J＝9.2Hz，1H)，8.14-8.19(m，2H)，8.40(d，J＝9.2Hz，1H)，8.87(d，J＝9.2Hz，1H)，9.07(d，J＝9.6Hz，1H)，10.27(s，1H).
Embodiment 46: the synthesis of compd A-86
Be added to by O-Anisic Acid (162mg, 1.04mmol) in thionyl chloride (5ml), reflux 2 hours, underpressure distillation removes unnecessary solvent thionyl chloride.A-30 (99mg, 0.26mmol) is suspended in dry acetonitrile (5ml), is warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add above-mentioned acyl chlorides, continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains red product A-86 (30mg, 24%), fusing point: 183 ~ 185 DEG C.
HRMS-ESI(M/Z)：484.14358【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.93(s，3H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.40(s，2H)，7.18-7.22(m，1H)，7.33-7.35(m，1H)，7.59(s，1H)，7.75-7.79(m，1H)，8.21-8.26(m，2H)，8.43(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.10(d，J＝9.2Hz，1H)，10.12(s，1H).
Embodiment 47: the synthesis of compd A-87
By A-30 (99mg, 0.26mmol) be dissolved in DMF (5ml), then potassium hydroxide (the 30mg of porphyrize is added, 0.52mmol) with 4-nitrobenzyl chlorine (134 μ l, 1.04mmol), be heated to 60 DEG C of reactions 12 hours, concentrating under reduced pressure is except desolventizing, resistates dilute hydrochloric acid adjusts PH to 3, and the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtain orange product A-87 (72mg, 57%), fusing point: 208 ~ 210 DEG C.
HRMS-ESI(M/Z)：481.13863【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.11(s，3H)，5.24(t，J＝6.4Hz，2H)，5.57(s，2H)，6.40(s，2H)，7.60(s，1H)，7.92(d，J＝8.4Hz，2H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝8.8Hz，2H)，8.34(d，J＝9.2Hz，1H)，8.88-8.91(m，2H)，10.10(s，1H).
Embodiment 48: the synthesis of compd A-36
By Phloroglucinol (3.0g at 90 DEG C, 18.5mmol) be repeatedly added to 60% sulfuric acid (60ml in batches, v/v) until form colorless cleared solution in, then add A (3.0g in batches, 7.6mmol) form scarlet suspension, after adding material, insulation continues reaction 10 hours, and flaggy monitoring reacts completely.Under vigorous stirring, reacting liquor while hot is inclined in saturated aqueous common salt (50ml), stirring at room temperature 2 hours, then put into negative 20 DEG C of refrigerators and fully cool.Suction filtration, solid distilled water wash, and it is dissolved in 1NNaOH (100ml), use 2N HCl (100ml) that system furnishing is acid subsequently, abundant stirring, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, gained solid uses ethanol again: concentrated hydrochloric acid (V: V=95: 5) system recrystallization, obtain red product A-36 (1.8g, 62%), fusing point: 225 ~ 227 DEG C.
HRMS-ESI(M/Z)：348.1240【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.54(t，J＝6.4Hz，2H)，4.11(s，3H)，4.15(s，3H)，5.21(t，J＝6.4Hz，2H)，7.34(s，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.77(d，J＝9.6Hz，1H)，8.82(d，J＝9.2Hz，1H)，9.61(s，1H)，10.07(s，1H)，10.36(s，1H).
Embodiment 49: the synthesis of compd A-60
By A-36 (100mg, 0.26mmol) be suspended in dry acetonitrile (5ml), be warming up to the basic dissolving of backflow, add anhydrous pyridine (84 μ l, 1.04mmol), then add fluorobenzoyl chloride (185 μ l, 1.56mmol), continue backflow 6 hours, flaggy monitoring reacts completely.Abundant cooling, the solid that collected by suction is separated out take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, obtains yellow product A-60 (18mg, 11%), fusing point: 169 ~ 171 DEG C.
HRMS-ESI(M/Z)：592.1569【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.80(t，J＝6.4Hz，2H)，4.14(s，3H)，4.20(s，3H)，5.38(t，J＝6.4Hz，2H)，7.34-7.44(m，4H)，8.03(s，1H)，8.07(dd，J＝5.6，8.8Hz，2H)，8.23(dd，J＝5.2，8.8Hz，2H)，8.37(d，J＝9.2Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.31(s，1H).
Embodiment 50: the synthesis of compd A-65
Sodium borohydride (1.2g will be dissolved with, 5% sodium hydroxide solution (10ml) 32mmol) is dropwise added to containing Fibrauretin (7.8g, 20mmol) with salt of wormwood (8.3g, in methyl alcohol (250ml) solution system 60mmol), stirring at room temperature 2 hours, the greenish yellow solid that collected by suction is separated out, filter cake uses distilled water (100ml) and 80% ethanol (100ml) washing successively, obtain intermediate dihydro Fibrauretin (4.4g, 62%).By intermediate dihydro Fibrauretin (4.2g, 12mmol) be dissolved in acetonitrile (160ml), then the oxalic dialdehyde (2ml) of acetic acid (40ml) and 40% is added, be heated to 85 ~ 95 DEG C of backflows 5 hours, flaggy monitoring reacts completely, reaction solution is concentrated, obtain dark red oil, add 2% hydrochloric acid soln (200ml), stirring at room temperature 1 hour, filter, filtrate stirring at room temperature 5 days, reaction solution is concentrated, use 95% ethyl alcohol recrystallization, products therefrom washed with diethylether, obtain yellow product A-65 (2.9g, 59%), fusing point: 105 ~ 107 DEG C.
HRMS-ESI(M/Z)：376.1564【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.67(t，J＝6.8Hz，2H)，3.97(s，3H)，4.06(s，3H)，4.12(s，3H)，4.17(s，3H)，5.27(t，J＝6.8Hz，2H)，7.72(s，1H)，8.32(d，J＝9.2Hz，1H)，8.45(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，8.92(d，J＝9.6Hz，1H)，10.15(s，1H).
Embodiment 51: the synthesis of compd A-66
A-65 (2.0g, 4.9mmol) is placed in 250ml round-bottomed flask, and maintenance vacuum tightness is 30 ~ 40mmHg, and be heated to 195 ~ 210 DEG C of reactions 30 minutes, solid color is deepened gradually, finally all becomes scarlet.Take methylene chloride/methanol as moving phase, with the separation and purification of decompression silicagel column, ethanol: concentrated hydrochloric acid (V: V=95: 5) system acidifying obtains red product A-66 (1.5g, 77%), fusing point: 110 ~ 112 DEG C.
HRMS-ESI(M/Z)：362.1395【M-Cl】
+
1H NMR(CD
3SOCD
3，400MHz)：δ3.56(t，J＝6.4Hz，2H)，3.94(s，3H)，3.95(s，3H)，4.02(s，3H)，5.02(t，J＝6.4Hz，2H)，7.61(s，1H)，7.79(d，J＝8.0Hz，1H)，7.92(s，1H)，8.27(d，J＝9.2Hz，1H)，8.66(d，J＝9.2Hz，1H)，9.74(s，1H).
Test example 1: the compounds of this invention antiproliferative activity measures
Materials and methods
1, test medicine: some exemplary compounds of the present invention, contrast medicine is hydroxycamptothecine (10-hydroxycamptothecin, HCPT).
2, cell strain: HepG2 cell.
3, liquor strength is 0.6 μ g/mL.
4, method: be inoculated in 96 well culture plates, 5000/hole/200 μ L, dosing after 24h after being counted by the HepG2 cell dissociation of logarithmic phase, often organizes medicine and establishes 5 multiple holes, and establish DMSO Vehicle controls hole and acellular zeroing hole.In 37 DEG C, 5%CO
2cultivate 48h under condition, after PBS washing, every hole adds 200 μ L PBS again, drips trichoroacetic acid(TCA) (TCA) fixed cell of 50 μ L 50% (m/v), and TCA final concentration is 10%, 4 DEG C and places 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in air.Every hole adds the Sulforhodamine solution of 50 μ L, and ambient temperatare puts 10-30min.Remove supernatant, the acetic acid with 1% washs 5 times, dry air.Finally add Tris solution (pH=10.5) the 150 μ L of 10mmol/l, oscillator plate vibrates 5min.Measure OD value at enzyme-linked immunosorbent assay instrument (Model3550, Bio-Rad), with blank zeroing, wavelength used is 570nm.Calculate the inhibiting rate of growth of tumour cell as follows:
Inhibiting rate=[(OD
570 control wells-OD
570 dosing holes)/OD
570 control wells] × 100%.
More than test in triplicate, obtain average inhibition.
Under same measured condition, the inhibiting rate of contrast medicine HCPT is 85.4%.Result shows that the compounds of this invention has positive effect in antiproliferative.
Test example 2: by MCF-7, Hela, HT1080 and HCT116 tetra-kinds of tumour cell SCREENED COMPOUND
Materials and methods
1, test medicine: some exemplary compounds of the present invention, contrast medicine is hydroxycamptothecine (10-hydroxycamptothecin, HCPT).
2, cell strain: MCF-7, Hela, HT1080 and HCT116.
3, liquor strength is 0.6 μ g/mL.
4, method: be inoculated in 96 well culture plates, 5000/hole/200 μ L, dosing after 24h after being counted by the cell dissociation of logarithmic phase, often organizes medicine and establishes 5 multiple holes, and establish DMSO Vehicle controls hole and acellular zeroing hole.In 37 DEG C, cultivate 48h under 5%CO2 condition, after PBS washing, every hole adds 200 μ L PBS again, drips trichoroacetic acid(TCA) (TCA) fixed cell of 50 μ L 50% (m/v), and TCA final concentration is 10%, 4 DEG C and places 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in air.Every hole adds the Sulforhodamine solution of 50 μ L, and ambient temperatare puts 10-30min.Remove supernatant, the acetic acid with 1% washs 5 times, dry air.Finally add Tris solution (pH=10.5) the 150 μ L of 10mmol/l, oscillator plate vibrates 5min.Measure OD value at enzyme-linked immunosorbent assay instrument (Model3550, Bio-Rad), with blank zeroing, wavelength used is 570nm.Calculate the inhibiting rate of growth of tumour cell as follows:
Inhibiting rate=[(OD570 control wells-OD570 dosing holes)/OD570 control wells] × 100%.
More than test in triplicate, obtain average inhibition.The activity of part of compounds of the present invention to tumor cell proliferation sees the following form:
Result shows, under same measured condition, the compounds of this invention has positive effect in antiproliferative.
Test example 3: compd A-35, A-55, A-40 and A-56 are to the IC of cell HepG2 and HCT116
50measure
Materials and methods
1, test medicine: some exemplary compounds of the present invention.
2, cell strain: HepG2 and HCT116.
3, liquor strength is 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL and 0.125 μ g/mL.
4, method: be inoculated in 96 well culture plates, 5000/hole/200 μ L, dosing after 24h after being counted by the cell dissociation of logarithmic phase, often organizes medicine and establishes 5 multiple holes, and establish DMSO Vehicle controls hole and acellular zeroing hole.In 37 DEG C, cultivate 48h under 5%CO2 condition, after PBS washing, every hole adds 200 μ L PBS again, drips trichoroacetic acid(TCA) (TCA) fixed cell of 50 μ L 50% (m/v), and TCA final concentration is 10%, 4 DEG C and places 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in air.Every hole adds the Sulforhodamine solution of 50 μ L, and ambient temperatare puts 10-30min.Remove supernatant, the acetic acid with 1% washs 5 times, dry air.Finally add Tris solution (pH=10.5) the 150 μ L of 10mmol/l, oscillator plate vibrates 5min.Measure OD value at enzyme-linked immunosorbent assay instrument (Model3550, Bio-Rad), with blank zeroing, wavelength used is 570nm.Calculate the inhibiting rate of growth of tumour cell as follows:
IC50 adopts the IC in sigmaplot
50calculation formula obtains.
More than test in triplicate, obtain IC
50.Part of compounds of the present invention is to the IC of tumour cell
50be listed in the table below:
The IC of the compounds of this invention
50all lower, numerical value all, below 1 μM, has positive effect in antiproliferative.
Test example 4: compd A-35 couples of mdr cell IC
50mensuration
Materials and methods
1, test medicine: compd A-35 of the present invention and Zorubicin.
The cell strain MCF-7/DOX of 2, cell strain: MCF-7 and adriamycin-resistant.
3, liquor strength is 0.5 μ g/mL, 1 μ g/mL, 2 μ g/mL, 4 μ g/mL, 8 μ g/Ml, 16 μ g/mL, 32 μ g/mL and 64 μ g/mL.
4, method: be inoculated in 96 well culture plates, 5000/hole/200 μ L, dosing after 24h after being counted by the cell dissociation of logarithmic phase, often organizes medicine and establishes 5 multiple holes, and establish DMSO Vehicle controls hole and acellular zeroing hole.In 37 DEG C, cultivate 48h under 5%CO2 condition, after PBS washing, every hole adds 200 μ L PBS again, drips trichoroacetic acid(TCA) (TCA) fixed cell of 50 μ L 50% (m/v), and TCA final concentration is 10%, 4 DEG C and places 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in air.Every hole adds the Sulforhodamine solution of 50 μ L, and ambient temperatare puts 10-30min.Remove supernatant, the acetic acid with 1% washs 5 times, dry air.Finally add Tris solution (pH=10.5) the 150 μ L of 10mmol/l, oscillator plate vibrates 5min.Measure OD value at enzyme-linked immunosorbent assay instrument (Model3550, Bio-Rad), with blank zeroing, wavelength used is 570nm.Calculate the inhibiting rate of growth of tumour cell as follows:
IC50 adopts the IC in sigmaplot
50calculation formula obtains.
More than test in triplicate, obtain IC
50.The results are shown in Figure 1.
From result, the resistance of the cell of the compounds of this invention reversible adriamycin-resistant.
Test example 5: cell cycle analysis
Materials and methods
1, test medicine: compd A-35 of the present invention.
2, cell strain: HCT116 cell.
3, liquor strength is 0.5 μ g/mL.
4, method: with 0.5 μ g/mL process HCT116 cell, cell respectively after 4h, 12h and 24h collect drug treating, PBS washes twice, and add 75% ethanol of precooling ,-20 DEG C are fixedly spent the night, centrifugal removing ethanol, PBS washes twice, adds 200mgmL-1RNA enzyme, 37 DEG C of digestion 30min, add Propidium iodide 25mgmL-1,4 DEG C of lucifuges.
The results are shown in Figure 2.Result shows the compounds of this invention by cell block in the G2/M phase.
Test example 6: topoisomerase is tested
Materials and methods
1, test medicine: compd A-35 of the present invention.
2, experimental subjects: topoisomerase I and its substrate pBR322DNA.
3, liquor strength is 30 μ g/mL, 3 μ g/mL and 0.3 μ g/mL.
4, method: being determined in the reaction system of 20 μ l containing 10 × reaction buffer (350mmol/L Tris-HCl pH8.0mmol/L of topoisomerase I activity, 720mmol/L Repone K, 5mmol/L magnesium chloride, 50mmol/L DTT, 50mmol/L Spermidine) 2 μ l, 0.1%BAS 2 μ l, PBR3220.36 μ g, positive control pipe (hydroxycamptothecine) final concentration is 212.5 μ g/ml, 10.6 μ g/ml.Each test tube adds the A-35 (final concentration is respectively 30 μ g/mL, 3 μ g/mL and 0.3 μ g/mL) of different concns respectively.Topoisomerase I, each effective distilled water is supplemented to 20 μ l, mixes rearmounted 37 DEG C of reaction 30min, adds 5 μ l stop buffers (SDD of 5%, the sucrose of 40%, 0.25mg/ml bromjophenol blue) termination reaction.Agarose electrophoresis is carried out in TBE electrophoretic buffer, under 40V voltage, electrophoresis 4h.Dye Ethidum Eremide solution (1 μ g/ μ l) 30min, puts the electrophoresis zone of 260nm viewed under ultraviolet radiation DNA, and take the photograph sheet record.
The results are shown in Figure 3.Result shows that the compounds of this invention is inhibited to topoisomerase I.
Claims (11)
1. formula I:
Or its pharmacologically acceptable salts, wherein
X is halogen;
R
1be selected from: hydrogen, C
1-6the C that alkyl, phenyl replace
1-6alkyl, C
1-18alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C
1-3alkylenedioxy group benzoyl, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-6alkyl, C
1-6alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino;
R
2and R
3be selected from independently of one another: hydrogen, C
1-6alkyl, benzoyl, wherein said phenyl is optionally by 1 to 4 halogen substiuted; Or R
2and R
3be-CH together
2-.
2. the compound of claim 1, wherein X is selected from fluorine, chlorine, bromine, iodine.
3. the compound of any one of claim 1 to 2, wherein R
1be selected from hydrogen, C
1-4the C that alkyl, phenyl replace
1-4alkyl, C
1-16alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C
1-2alkylenedioxy group benzoyl, wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-4alkyl, C
1-4alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino.
4. the compound of any one of claim 1 to 2, wherein R
2and R
3be selected from independently of one another: hydrogen, C
1-4alkyl, Halobenzoyl; Or R
2and R
3be-CH together
2-.
5. the compound of any one of claim 1 to 2, it is following formula: compound,
Wherein R
1, R
2, R
3with X, there is implication described in following any one of numbering No1 to No51:
。
6. the compound of any one of claim 1 to 2, it is be selected from following compound:
9,10-dimethoxy-5,6-dihydro-[1,3] dioxole is [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate also;
9-hydroxyl-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate also;
9-oxyethyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide also;
9-butoxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-iodide also;
9-benzyloxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole is [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide also;
9-(2,4 difluorobenzene base) methoxyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-ethanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to anisoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluorine m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methoxyl group m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4-methylene-dioxy benzoyl oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4,5-trimethoxybenzoy oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Adjacent fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1, the 3] dioxole of 9-also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Adjacent chlorobenzene formacyl Oxy-1 0-methoxyl group-5,6-dihydro-[1, the 3] dioxole of 9-also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(2,4 difluorobenzene formyl radical oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to acetamido benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-decanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-lauroyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hexadecanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4', 5':6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Or its pharmacologically acceptable salts.
7. a following formula: compound,
Wherein R
1, R
2, R
3with X have following numbering No:25,26,35, implication described in any one of 40-42:
。
8. prepare the method for cyclisation berberinc derivate, it comprises the following steps:
A) in a solvent, in the presence of a base, sodium borohydride and Berberine are reacted, obtains dihydroberberine;
B) in a solvent, in presence of an acid, make dihydroberberine and glyoxal reaction, obtain the cyclisation Berberine shown in formula Ia:
Optional, c) make formula Ia cyclisation Berberine under vacuo, at 195 ~ 210 DEG C process obtain the 9-Hydroxy Cyclization Berberine shown in formula Ib:
Optional, d) in organic solvent, in the presence of a base, make the 9-Hydroxy Cyclization Berberine of formula Ib and suitable reagent react, obtain 9-C
1-6alkyl oxy cyclisation Berberine, alkyl wherein is optionally replaced by the phenyl of phenyl or replacement, and wherein said phenyl is optionally selected from following substituting group by 1 to 4 and replaces: halogen, C
1-6alkyl, C
1-6alkoxyl group, nitro, cyano group, amino, hydroxyl, C
1-4alkyl acylamino;
Optional, e) in organic solvent, under reagent exists, the 9-Hydroxy Cyclization Berberine of formula Ib and acyl chlorides or SULPHURYL CHLORIDE are reacted, and obtain 9-acyloxy cyclisation Berberine or the cyclization Berberine of 9-alkylsulfonyl oxygen, acyl group is wherein C
1-18alkyloyl or benzoyl.
9. a pharmaceutical composition, it comprises compound described in any one of claim 1 to 7, and one or more optional pharmaceutically acceptable carriers or vehicle.
10. compound described in any one of claim 1 to 7 is for the preparation of the purposes treated and/or prevented in the medicine of mammal tumor.
The purposes of 11. claims 10, wherein said tumour is liver cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210101607.XA CN102746292B (en) | 2011-04-18 | 2012-04-09 | Cyclized berberine derivatives, preparation method and uses thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110096343 | 2011-04-18 | ||
| CN2011100963439 | 2011-04-18 | ||
| CN201110096343.9 | 2011-04-18 | ||
| CN201210101607.XA CN102746292B (en) | 2011-04-18 | 2012-04-09 | Cyclized berberine derivatives, preparation method and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102746292A CN102746292A (en) | 2012-10-24 |
| CN102746292B true CN102746292B (en) | 2015-03-18 |
Family
ID=47026840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210101607.XA Expired - Fee Related CN102746292B (en) | 2011-04-18 | 2012-04-09 | Cyclized berberine derivatives, preparation method and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102746292B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188035B (en) * | 2016-06-30 | 2017-11-17 | 合肥华方医药科技有限公司 | The Preparation method and use of the double-functional group berberinc derivate of 9 substitutions |
| WO2018068769A1 (en) * | 2016-10-14 | 2018-04-19 | 中国医学科学院药物研究所 | Use of dihydroberberine type compounds in preparation of product for treating tumour diseases associated with stat3 signaling pathway |
| CN107722000A (en) * | 2017-11-03 | 2018-02-23 | 中国药科大学 | The preparation of the berberinc derivate of 9-substitution and its medical usage |
| CN107892689A (en) * | 2017-11-28 | 2018-04-10 | 中国医学科学院医药生物技术研究所 | One kind cyclisation berberinc derivate and its production and use |
| CN108822095B (en) * | 2018-07-25 | 2020-05-01 | 山东大学 | Benzo [ h ] chromene compound and application thereof as AcrB efflux pump inhibitor in antibiosis |
| CN114736202A (en) * | 2022-04-20 | 2022-07-12 | 四川大学 | Preparation and application of berberine derivative with IDO1/TDO inhibitory activity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211252A (en) * | 1996-02-12 | 1999-03-17 | 新泽西州州立大学(拉特格斯) | Coralyne analogs as topoisomerase inhibitors |
| CN101255158A (en) * | 2008-03-28 | 2008-09-03 | 中山大学 | 9-N-substituted berberine derivatives as well as preparation method and use as anti-cancer drugs |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8188109B2 (en) * | 2009-07-20 | 2012-05-29 | Naxospharma S.R.L. | Benzoquinolizinium salt derivatives as anticancer agents |
-
2012
- 2012-04-09 CN CN201210101607.XA patent/CN102746292B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211252A (en) * | 1996-02-12 | 1999-03-17 | 新泽西州州立大学(拉特格斯) | Coralyne analogs as topoisomerase inhibitors |
| CN101255158A (en) * | 2008-03-28 | 2008-09-03 | 中山大学 | 9-N-substituted berberine derivatives as well as preparation method and use as anti-cancer drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102746292A (en) | 2012-10-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102746292B (en) | Cyclized berberine derivatives, preparation method and uses thereof | |
| KR101530721B1 (en) | Compounds and methods for inhibiting the interaction of bcl proteins with binding partners | |
| CA2736097C (en) | Carbazole compounds for inhibition of nf-kb activity | |
| EP2970145B1 (en) | Compounds and compositions for the treatment of cancer | |
| CN102485721B (en) | 2，3-benzodiazine ketone compound replaced and uses thereof | |
| DE69831877T2 (en) | NEW PIPERAZINYL-SUBSTITUTED PYRIDYL ALKAN, ALKEN AND ALKINE CARBOXAMIDE | |
| DE69830855T2 (en) | ARYL-SUBSTITUTED PYRIDYL ALKAN, ALKENE, AND ALKINE CARBOXAMIDE DERIVATIVES USEFUL AS CYTOSTATIC AND IMMUNOSUPPRESSIVE AGENTS | |
| DE69834269T2 (en) | PIPERIDINYL SUBSTITUTED PYRIDYL ALKANE, ALKALINE AND ALKINCARBOXYLIC ACIDS AS CYTOSTATICS AND IMMUNOSUPPRESSIVES | |
| JP7027393B2 (en) | Benzamide and nicotinamide compounds and methods of using them | |
| CN101268048A (en) | Carbazole derivatives | |
| WO2008118802A1 (en) | Therapeutic compounds | |
| KR20090040923A (en) | Compounds and methods for inhibiting the interaction of bcl proteins with binding partners | |
| WO2016155545A1 (en) | Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals | |
| CN102746291B (en) | 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs | |
| CN101374807B (en) | Compounds and methods for inhibiting the interaction of BCL proteins with binding partners | |
| CN103319402B (en) | Diphenyl thiourea derivatives, preparation method and applications thereof | |
| BRPI0712483A2 (en) | 6-Methoxy-8- [4-1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline hydrochloric acid salts | |
| JPH024771A (en) | Arylpyperadinylalkoxy derivative of cyclic imide and predetermined thereof | |
| CN101503394A (en) | High piperazine acetydrazide derivatives, and preparation and use thereof | |
| CN102838567B (en) | Benzenesulfonyl piperazine compounds or benzoyl piperazine compounds, preparation methods and uses thereof | |
| JPH01294670A (en) | 2-(piperadinyl)-2-oxoethylene-substituted flavonoid derivative, its production and pharmaceutical composition containing said derivative | |
| BRPI0713107A2 (en) | 6-Methoxy-8- [4- (1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline siccinate salts, and crystalline forms thereof | |
| CN101987835A (en) | Homopiperazine acethydrazide derivatives | |
| CN101381371A (en) | Dithiolopyrrolones compounds and preparation method and application thereof | |
| CN1034074C (en) | Heterocycle-substituted benzenemethanamine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| 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: 20150318 |