CN105384736B - 一种ⅳ型胶原酶抑制剂及合成方法 - Google Patents
一种ⅳ型胶原酶抑制剂及合成方法 Download PDFInfo
- Publication number
- CN105384736B CN105384736B CN201510709786.9A CN201510709786A CN105384736B CN 105384736 B CN105384736 B CN 105384736B CN 201510709786 A CN201510709786 A CN 201510709786A CN 105384736 B CN105384736 B CN 105384736B
- Authority
- CN
- China
- Prior art keywords
- water
- type
- thiadiazoles
- dichloro benzene
- round
- 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
- 102000004266 Collagen Type IV Human genes 0.000 title claims abstract description 12
- 108010042086 Collagen Type IV Proteins 0.000 title claims abstract description 12
- 239000002532 enzyme inhibitor Substances 0.000 title claims abstract description 11
- 229940125532 enzyme inhibitor Drugs 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 4
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- FFMXLRXJGJMUDC-UHFFFAOYSA-N C(=O)O.ClC1=CC=CC(=C1)Cl Chemical compound C(=O)O.ClC1=CC=CC(=C1)Cl FFMXLRXJGJMUDC-UHFFFAOYSA-N 0.000 claims description 2
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 150000002240 furans Chemical group 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 2
- 150000003384 small molecules Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000013382 Gelatinases Human genes 0.000 description 5
- 108010026132 Gelatinases Proteins 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 4
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)c1*(*)c(C)c(*)c(*)c1* Chemical compound CC(C)c1*(*)c(C)c(*)c(*)c1* 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- ZMJRUUBDMPKHJS-UHFFFAOYSA-N 2-phenyl-1,3,4-thiadiazole Chemical class S1C=NN=C1C1=CC=CC=C1 ZMJRUUBDMPKHJS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- ZIVOKOPGPJWHMY-UHFFFAOYSA-N NN(C(N)=O)S(O)(=O)=O Chemical compound NN(C(N)=O)S(O)(=O)=O ZIVOKOPGPJWHMY-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种Ⅳ型胶原酶抑制剂，化学通式如下，R1=呋喃环，苯环；X=CH2，O；n=0,1；m=0，1；R2，R3，R4，R5为F，Cl，I，NO2，OCH3,1至5个碳原子的直链或支链烷烃。本发明还涉及到该Ⅳ型胶原酶抑制剂的合成方法，所设计的化合物均为小分子拟肽类化合物，合成工艺路线短，原材料易得，生产成本低。
Description
技术领域
本发明涉及一种Ⅳ型胶原酶抑制剂及合成方法。
背景技术
基质金属蛋白酶是一类典型的含金属锌离子的蛋白酶，其活性催化中心含有催化锌离子。基质金属蛋白酶可由成纤维细胞、软骨细胞、成骨细胞、中性粒细胞或巨噬细胞产生，也可由肿瘤细胞产生。内源性组织抑制剂通过调节金属蛋白酶的活性而维持机体的内环境稳定。因此，基质金属蛋白酶表达增加或基质金属蛋白酶与组织抑制剂失衡将导致疾病，如肿瘤转移、类风湿性关节炎多发性硬化症等。研究发现基质金属蛋白酶抑制剂能抑制肿瘤的生长及转移。基底膜主要由Ⅳ型胶原组成并能阻止肿瘤细胞的侵袭。Ⅳ型胶原酶通过分解基底膜血管而使肿瘤细胞发生侵袭和转移。所以Ⅳ型胶原酶抑制剂能有效的阻止肿瘤细胞的侵袭和转移，Ⅳ型胶原酶抑制剂是寻找和开发抗肿瘤物的新领域。
发明内容
本发明的目的是提供一种Ⅳ型胶原酶抑制剂及合成方法。
本发明是这样来实现的，其化学通式如下，
R1＝呋喃环，苯环；X＝CH2，O；n＝0,1；m＝0，1；R2，R3，R4，R5为F，Cl，I，NO2，OCH3,1至5个碳原子的直链或支链烷烃。
本发明的合成方法步骤是：
(1)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：将2,4-二氯苯甲酸、硫代氨基脲、POCl3放于带有回流装置的圆底烧瓶中，回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入水，回流反应4h，冷却至室温，用氢氧化钠溶液调PH值，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得目的物。
(2)N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：将糠酸、氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次。冰浴下缓慢滴入含有5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、无水三乙胺，二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/L HCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶，得固体目的物。
本发明的优点是：所设计的化合物均为小分子拟肽类化合物，合成工艺路线短，原材料易得，生产成本低。
具体实施方式
实施例：
(1)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：
将9.74g(50mmol)2,4-二氯苯甲酸、4.65g(50mmol)硫代氨基脲、13ml POCl3放于带有回流装置的圆底烧瓶中，在75℃下回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入55ml水，于110℃回流反应4h,冷却至室温，用50％氢氧化钠溶液调PH值至8，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得浅黄色目的物6.21g，产率：50.36％；mp:154-156℃.
(2)N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：
将1.71g(15mmol)糠酸、12ml氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次。冰浴下缓慢滴入含有3.7g(15mmol)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、9ml无水三乙胺，二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/L HCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶，得白色固体2.9g，产率：56.86％，mp:294-295℃。IR(KBr,cm-1):3126,1680,1533,1507,1321,1091；1HNMR(400MHz,DMSO)δ13.25(s,1H),8.17(d,J＝8.4Hz,1H),8.08(s,1H),7.92(d,J＝24.4Hz,1H),7.76(s,1H),7.62(d,J＝8.5Hz,1H),6.78(d,J＝1.6Hz,1H)；ESI-MS:m/z[M+H]+340.3.
(3)(2R)-N-[2-[5-苯基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺的制备
将1.52g(10mmol)(R)-(-)-扁桃酸、1.7mL(20.5mmol)吡啶、20mL二氯甲烷和催化剂DMAP置于干燥的圆底烧瓶中，待完全溶解后逐滴加入2.6mL(20.5mmol)三甲基氯硅烷，室温搅拌4h。冷却至0℃，加入0.75mL(10.3mmol)二氯亚砜和两滴DMF，0℃搅拌1h，室温搅拌30min。冷却至0℃，加入1.95g(11mmol)5-苯基-1,3,4-噻二唑-2-胺和2.7mL(33mmol)吡啶，室温搅拌2h。将2.11g(11mmol)柠檬酸用20mL甲醇溶解，加入到反应瓶中，室温搅拌30min后倒入分液漏斗，用乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠溶液和饱和食盐水各洗两遍，将有机相溶剂蒸除，用乙酸乙酯重结晶，干燥后得目标化合物。黄色固体，产率80.6％,m.p.232-234℃；IR(KBr,ν):3300,2730,1703,1676,1549,1501cm-1；1H NMR(DMSO-d6,400MHz)δ:12.75(1H,s,NH),7.94–7.89(2H,m,Ar-H),7.53(5H,dd,J＝9.8,5.8Hz,Ar-H),7.38(2H,t,J＝7.3Hz,Ar-H),7.31(1H,dd,J＝8.4,6.1Hz,Ar-H),6.42(1H,d,J＝4.8Hz,OH),5.38(1H,d,J＝4.6Hz,7-CH)；ESI-MS m/z 312.1(M)+。
体外抑酶活性
底物MOCAc-Pro-Leu-Gly-Leu-Dap(Dnp)-Ala-Arg-NH2中具有荧光物质MOCAc，可用荧光分光光度计检测，底物中的Dap(Dnp)为荧光熄灭物，在没有明胶酶加入的情况下底物不显荧光，当在适宜的条件下加入明胶酶，明胶酶能分解底物，底物分解后Dap(Dnp)对MOCAc的荧光熄灭作用消失，释放出的荧光物MOCAc发出荧光，可通过荧光分光光度计检测其荧光的强度，从而可以确定明胶酶的活性，通过加入对明胶酶有抑制作用的目标化合物间接的反应Ⅳ型胶原酶抑制剂的活性大小。
96孔黑色酶标板，每孔加入20uL(5nmol/L)酶，然后加入5uL(100umol/L)化合物，混匀，37℃孵育15分钟。然后加入10uL(50umol/L)底物，再加入15uL缓冲液(50mmol/LHEPES,pH 7.5,150mmol/L NaCl,5mmol/L CaCl2,0.01％Brij-35,1％DMSO)，混匀，37℃孵育15分钟。用酶标仪检测荧光信号，激发波长为328nm，发射波长为393nm。目标化合物对酶的抑制率＝{1-[(Flu化合物-Flu本底)/(Flu酶-Flu本底)]}×100％。
表1化合物的体外抑酶活性
表2化合物的体外抑酶活性
Claims (2)
1.一种Ⅳ型胶原酶抑制剂：
.
。
2.一种Ⅳ型胶原酶抑制剂N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的合成方法，其特征是合成方法步骤为：
(1) 5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：将2,4-二氯苯甲酸、硫代氨基脲、POCl3放于带有回流装置的圆底烧瓶中，回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入水，回流反应4h，冷却至室温，用氢氧化钠溶液调PH值，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得目的物；
(2) N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：将糠酸、氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次；冰浴下缓慢滴入含有5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、无水三乙胺，二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/L HCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶，得固体目的物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510709786.9A CN105384736B (zh) | 2015-10-28 | 2015-10-28 | 一种ⅳ型胶原酶抑制剂及合成方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510709786.9A CN105384736B (zh) | 2015-10-28 | 2015-10-28 | 一种ⅳ型胶原酶抑制剂及合成方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105384736A CN105384736A (zh) | 2016-03-09 |
| CN105384736B true CN105384736B (zh) | 2018-11-02 |
Family
ID=55417559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510709786.9A Expired - Fee Related CN105384736B (zh) | 2015-10-28 | 2015-10-28 | 一种ⅳ型胶原酶抑制剂及合成方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105384736B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527225B (zh) * | 2021-07-15 | 2022-11-18 | 南昌大学 | 一种丙烯酰噻二唑衍生物及其制备方法和应用 |
| CN115925572A (zh) * | 2022-12-12 | 2023-04-07 | 南京安杰新生物医药有限公司 | 一锅法合成米拉贝隆杂质 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646505A (zh) * | 2002-02-22 | 2005-07-27 | 弗奈利斯(牛津)公司 | 噁二唑和噻二唑及其作为金属蛋白酶抑制剂的用途 |
| WO2008107677A2 (en) * | 2007-03-07 | 2008-09-12 | Senexis Limited | Thiadiazole and oxadiazole derivatives for the treatment of neurodegenerative disorders |
| CN101279956A (zh) * | 2008-04-25 | 2008-10-08 | 南昌大学 | 一种基质金属蛋白酶抑制剂及合成方法 |
-
2015
- 2015-10-28 CN CN201510709786.9A patent/CN105384736B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646505A (zh) * | 2002-02-22 | 2005-07-27 | 弗奈利斯(牛津)公司 | 噁二唑和噻二唑及其作为金属蛋白酶抑制剂的用途 |
| WO2008107677A2 (en) * | 2007-03-07 | 2008-09-12 | Senexis Limited | Thiadiazole and oxadiazole derivatives for the treatment of neurodegenerative disorders |
| CN101279956A (zh) * | 2008-04-25 | 2008-10-08 | 南昌大学 | 一种基质金属蛋白酶抑制剂及合成方法 |
Non-Patent Citations (2)
| Title |
|---|
| 李敏.苹果酸类基质金属蛋白酶抑制剂的合成及体外活性测定.《中国优秀硕士学位论文全文数据库（电子期刊）》.2012,(第5期),E079-1页；正文第9-10页1.8部分，正文第25页表3.1. * |
| 苹果酸类基质金属蛋白酶抑制剂的合成及体外活性测定;李敏;《中国优秀硕士学位论文全文数据库（电子期刊）》;20120515(第5期);E079-1页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105384736A (zh) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9108932B2 (en) | Preparation of haloalkoxyarylhydrazines and intermediates therefrom | |
| CN105384736B (zh) | 一种ⅳ型胶原酶抑制剂及合成方法 | |
| KR20220027958A (ko) | 나프탈렌술폰아미드계 화합물, 제조 방법 및 응용 | |
| CN104592144B (zh) | 制备噁唑衍生物的新方法 | |
| CN111699184B (zh) | 噁唑烷酮化合物的制造方法 | |
| AU2006312801A1 (en) | Styrylsulfonamides, their manufacture and use as pharmaceutical agents | |
| CN105949136A (zh) | 一种1,5-取代-1,2,3-三氮唑类化合物的合成方法 | |
| CN113563265A (zh) | 一种合成On-DNA N,N-单取代吲唑酮类化合物的方法 | |
| KR100519010B1 (ko) | 히스톤 디아세틸라제 저해활성을 갖는 벤즈히드록시아미드유도체 및 그의 제조방법 | |
| CN105272952A (zh) | 苯并呋喃类化合物中间体及其制备方法和应用 | |
| CN105418518B (zh) | 一种吩嗪羧酸酯类化合物及其用途 | |
| Li et al. | The synthesis and preliminary activity assay in vitro of peptide-like derivatives as APN inhibitors | |
| JP2014151285A (ja) | 新規光学活性イミダゾリン−リン酸触媒とその誘導体 | |
| JP2007091596A (ja) | ベンゾイソチアゾリン誘導体及び農園芸用植物病害防除剤 | |
| GUO et al. | Synthesis and herbicidal activity of novel sulfonylureas containing thiadiazol moiety | |
| CN105294697B (zh) | 2-氨基-5,8-二甲氧基[1,2,4]三唑并[1,5-c]嘧啶的合成方法 | |
| CN103193715A (zh) | 一种5,6-二氢嘧啶酮衍生物的制备方法 | |
| KR101037052B1 (ko) | 5-클로로-ｎ-(((5ｓ)-2-옥소-3-(4-(5,6-디하이드로-1,2,4-트리아진-1(4ｈ)-일)페닐)-1,3-옥사졸리딘-5-일)메틸)티오펜-2-카르복사미드 유도체의 제조방법 및 그 제조중간체 | |
| CN105481779A (zh) | 抗癌药物Rociletinib及其中间体制备 | |
| CN106554345A (zh) | 一种五氯化磷氯化副产物的回收和利用的方法 | |
| CN104788398A (zh) | 苯并恶唑类化合物及其制备方法和用途 | |
| CN102924375B (zh) | Talnetant中间体及其制备方法和应用 | |
| CN112979507A (zh) | 一种茜素磺酸酯的合成方法 | |
| CN102115466B (zh) | 一类磺内酰胺类化合物及其制备方法和中间体 | |
| JP2000169458A (ja) | 農園芸用殺菌剤の製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181102 |