CN101735217B - 咪唑[4,5-f][1,10]菲咯啉及其衍生物在制备抗肿瘤药物中的应用 - Google Patents
咪唑[4,5-f][1,10]菲咯啉及其衍生物在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN101735217B CN101735217B CN200910213817A CN200910213817A CN101735217B CN 101735217 B CN101735217 B CN 101735217B CN 200910213817 A CN200910213817 A CN 200910213817A CN 200910213817 A CN200910213817 A CN 200910213817A CN 101735217 B CN101735217 B CN 101735217B
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- Prior art keywords
- phenanthroline
- imidazoles
- compounds
- phenyl
- verivate
- 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.)
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- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 title claims abstract description 143
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 14
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract description 13
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 9
- 150000002460 imidazoles Chemical class 0.000 claims description 89
- 210000004027 cell Anatomy 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 8
- JVCBVNUOEFLXGK-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1h-imidazole Chemical class COC1=CC=CC=C1C1=NC=CN1 JVCBVNUOEFLXGK-UHFFFAOYSA-N 0.000 claims description 6
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 6
- ZEVQPQCOLBCVSA-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1h-imidazole Chemical class C1=CC(OC)=CC=C1C1=NC=CN1 ZEVQPQCOLBCVSA-UHFFFAOYSA-N 0.000 claims description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 5
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 5
- NEJHPXADNMJLGB-UHFFFAOYSA-N 2-(2-nitrophenyl)-1h-imidazole Chemical class [O-][N+](=O)C1=CC=CC=C1C1=NC=CN1 NEJHPXADNMJLGB-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000012010 growth Effects 0.000 claims description 4
- IRIGPPDONXVEHU-UHFFFAOYSA-N 2-(4-bromophenyl)-1h-imidazole Chemical class C1=CC(Br)=CC=C1C1=NC=CN1 IRIGPPDONXVEHU-UHFFFAOYSA-N 0.000 claims description 3
- QBXIGUJIZJQJQP-UHFFFAOYSA-N 2-(4-butoxyphenyl)-1h-imidazole Chemical class C1=CC(OCCCC)=CC=C1C1=NC=CN1 QBXIGUJIZJQJQP-UHFFFAOYSA-N 0.000 claims description 3
- GTIYLLQEFVPNTN-UHFFFAOYSA-N 2-(4-fluorophenyl)-1h-imidazole Chemical class C1=CC(F)=CC=C1C1=NC=CN1 GTIYLLQEFVPNTN-UHFFFAOYSA-N 0.000 claims description 3
- QHNDFWPCDITBSG-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-imidazole Chemical class C1=CC(C)=CC=C1C1=NC=CN1 QHNDFWPCDITBSG-UHFFFAOYSA-N 0.000 claims description 3
- KVSDTOUXJILXIN-UHFFFAOYSA-N 2-(4-propoxyphenyl)-1h-imidazole Chemical class C1=CC(OCCC)=CC=C1C1=NC=CN1 KVSDTOUXJILXIN-UHFFFAOYSA-N 0.000 claims description 3
- ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 2-phenyl-1h-imidazole Chemical compound C1=CNC(C=2C=CC=CC=2)=N1 ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 0.000 claims description 3
- QWZSAEUNIBEKIZ-UHFFFAOYSA-N 4-(1h-imidazol-2-yl)pyridine Chemical class C1=CNC(C=2C=CN=CC=2)=N1 QWZSAEUNIBEKIZ-UHFFFAOYSA-N 0.000 claims description 3
- PFNAKDGBCFZGGM-UHFFFAOYSA-N 5-(1h-imidazol-2-yl)-2-methoxyphenol Chemical class C1=C(O)C(OC)=CC=C1C1=NC=CN1 PFNAKDGBCFZGGM-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005341 metaphosphate group Chemical group 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 2
- 229960000658 sumatriptan succinate Drugs 0.000 claims description 2
- 150000005041 phenanthrolines Chemical class 0.000 claims 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 238000009395 breeding Methods 0.000 claims 1
- 230000001488 breeding effect Effects 0.000 claims 1
- 230000000452 restraining effect Effects 0.000 claims 1
- 229950004288 tosilate Drugs 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 abstract description 5
- 125000002541 furyl group Chemical group 0.000 abstract description 4
- 125000000335 thiazolyl group Chemical group 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 2
- 125000000168 pyrrolyl group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 26
- 238000000921 elemental analysis Methods 0.000 description 24
- 238000002474 experimental method Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- 206010013786 Dry skin Diseases 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 244000144992 flock Species 0.000 description 7
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- 229910002027 silica gel Inorganic materials 0.000 description 7
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- 229960001866 silicon dioxide Drugs 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- -1 substituted-phenyl Chemical group 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- GJKIAPNNPWBCOF-UHFFFAOYSA-N 2-(4-nitrophenyl)-1h-imidazole Chemical class C1=CC([N+](=O)[O-])=CC=C1C1=NC=CN1 GJKIAPNNPWBCOF-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000003935 benzaldehydes Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- GUKULMCQRHXQPR-UHFFFAOYSA-N 2-(2-methylphenyl)-1h-imidazole Chemical class CC1=CC=CC=C1C1=NC=CN1 GUKULMCQRHXQPR-UHFFFAOYSA-N 0.000 description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 208000029742 colonic neoplasm Diseases 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 2
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- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
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- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical compound O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 description 1
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- GQXXBWDAABZSHM-UHFFFAOYSA-N 8,11,15,17-tetrazatetracyclo[8.7.0.01,14.04,9]heptadeca-2,4(9),5,7,10,12,14,16-octaene Chemical class C1=C2C=CC34C(C=CN=C3C2=NC=C1)=NC=N4 GQXXBWDAABZSHM-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了咪唑[4,5-f][1,10]菲咯啉及其衍生物在制备抗肿瘤药物中的应用,咪唑[4,5-f][1,10]菲咯啉的结构式如式I所示:
Description
技术领域
本发明涉及化学药物应用领域,具体涉及咪唑[4,5-f][1,10]菲咯啉及其衍生物在制备抗肿瘤药物中的应用。
背景技术
咪唑[4,5-f][1,10]菲咯啉及其取代衍生物是一类优良的金属螯合试剂,常被作为配体用于制备各种具有抗肿瘤活性的金属配合物,特别是钌多吡啶配合物。吴建忠等报道了咪唑[4,5-f][1,10]菲咯啉、2-苯基咪唑[4,5-f][1,10]菲咯啉、2-(4-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-硝基苯基)咪唑[4,5-f][1,10]菲咯啉及其钌配合物,并研究了它们对DNA分子的识别能力(Polyhedron,16(1),103-107,1997)。Mei报道了2-(4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉的制备(Inorganica Chimica Acta 357,2004,285-293)以及2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-氯苯基)咪唑[4,5-f][1,10]菲咯啉和2-(2-硝基苯基)咪唑[4,5-f][1,10]菲咯啉的制备方法(Transition Metal Chemistry,2006,31:277-285)。Mei报道了2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉和2-(3-羟苯基)咪唑[4,5-f][1,10]菲咯啉的制备(Dalton Trans.,2003,1352-1359)以及2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉的制备(Transition Met Chem,2008,33:499-503),并报道了这些化合物用于制备手性钌(II)多吡啶配合物及其对DNA分子的识别。Liu等人报道了2-(4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-硝基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-氯苯基)咪唑[4,5-f][1,10]菲咯啉和2-(2-硝基苯基)咪唑[4,5-f][1,10]菲咯啉对肿瘤细胞的体外抑制实验,在实验条件下这些化合物对实验的肿瘤细胞生长并不表现出明显的抑制作用。
中国专利NO:200680023377.2中报道了2-吲哚基咪唑并[4,5-d]菲咯啉衍生物及其在癌症治疗中的用途;国际专利申请NO:PCT/IB04/052433(WO2005/047266)记载了很宽类别的2,4,5-三取代的咪唑化合物,包括一些1,10-菲咯啉取代化合物。目前,尚未有咪唑[4,5-f][1,10]菲咯啉及其衍生物在抗肿瘤活性方面的具体研究,因此,值得进一步探讨。
发明内容
本发明目的在于根据现有技术的不足,提供一种用于制备抗肿瘤药物的咪唑[4,5-f][1,10]菲咯啉及其衍生物。
本发明上述目的通过以下技术方案予以实现:
咪唑[4,5-f][1,10]菲咯啉的结构式如下式所示:
其中,式中的R选自氢,碳原子数为1~6的烷基或碳原子为1~6的取代烷基,苯基或取代苯基,吡啶基或取代吡啶基,呋喃基或取代呋喃基,吡咯基或取代吡咯基,噻唑或取代噻唑基。
上述苯基、吡啶基、呋喃基、噻唑的取代基均选自羟基、硝基、卤素、氨基、羧基、氰基、巯基、碳原子数为3~8的环烷基、SO3H、碳原子数为1~6的烷基、碳原子数为2~6的链烯基、碳原子为2~6的链炔基、碳原子数为1~6的羟烷基、碳原子数为1~6的氨烷基、CO2R’、CONR’R’、COR’、SO2R’R’、碳原子数为1~6的烷氧基、碳原子数为1~6的烷硫基、-N=NR’、NR’R’或三氟甲基;其中,所述R’选自H、碳原子数为1~6的烷基或苯基。
具体地,本发明咪唑[4,5-f][1,10]菲咯啉化合物可以选自如下化合物:
咪唑[4,5-f][1,10]菲咯啉、2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-羟基-4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-硝苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-甲氧基-4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-硝基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-氟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-溴苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-苯基咪唑[4,5-f][1,10]菲咯啉、2-(3,4-二羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-乙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-丙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-异丙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-丁氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-羧基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-二甲氨基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-硝基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-羧基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-吡啶基)咪唑[4,5-f][1,10]菲咯啉、2-(2-呋喃)咪唑[4,5-f][1,10]菲咯啉、2-(2-吡咯)咪唑[4,5-f][1,10]菲咯啉、2-(2-噻唑)咪唑[4,5-f][1,10]菲咯啉。
咪唑[4,5-f][1,10]菲咯啉可具有充分的酸性官能团、碱性官能团或同时具有酸性和碱性官能团,因此该化合物可以与有机碱、无机碱、有机酸或无机酸反应,形成药学可接受的盐,所谓药学可接受的盐即总体上药学可接受的并且只要抗衡离子对盐总体不会产物不利性质,形成的盐的特定抗衡离子不具有关键性质的盐,即咪唑[4,5-f][1,10]菲咯啉的衍生物,如咪唑[4,5-f][1,10]菲咯啉的硫酸盐、焦硫酸盐、重硫酸盐、亚硫酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、盐酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐。
上述无机酸优选盐酸、氢溴酸、氢碘酸、硫酸、碳酸或磷酸。
上述有机酸优选对甲苯磺酸、甲磺酸、草酸、对溴苯基磺酸、琥珀酸、柠檬酸、苯甲酸或乙酸。
本发明咪唑[4,5-f][1,10]菲咯啉在制备抗肿瘤药物的应用中,可将咪唑[4,5-f][1,10]菲咯啉与溶剂一起制备成药学可接受的载体、稀释剂或赋形剂。
制备咪唑[4,5-f][1,10]菲咯啉及其衍生物的方法为本领域中的常用方法,如:
具体步骤见下述文件记载:Krieg et al,Natruforsch,1967,22b,132;Sarshar et al,Tetrahedron Lett,1996,37,835-838;吴建忠等,Polyhedron,1997,16(1),103-107。Fischer等人(J.Am.Chem.Soc.,1961,83,4208-4210);Guijarro et al,J.Am.Chem.Soc.,1999,121,4155-4157;Chi et al,Synth.Comm.,1994,24(15),2119-2122;Armesto et al,Synthesis,Comm.,1994,24(15),2119-2122;Armesto et al,Synthesis,1988,799-801);Yamada et al,Bull.Soc Chem.Jpn.,1990,63(9),2710-2712);Hiortet al,J.Am.Chem.Soc.1993,115,3448-3454;Tetrahedron letters 2004,45(33),6316-6363。
具体地,上述制备方法可以是如下步骤:菲咯啉5,6-二酮0.52g,取代醛2.4mmol,乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml蒸馏水,浓氨水调节pH=7,得黄色或者白色絮状沉淀;抽滤,水洗,50℃干燥,无水乙醇溶解后,过60~100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,即得。
经体外实验证明,咪唑[4,5-f][1,10]菲咯啉及其衍生物对肿瘤细胞,尤其是对肺腺癌细胞、肝癌细胞和结肠癌细胞的生长有显著的抑制作用,因此,咪唑[4,5-f][1,10]菲咯啉及其衍生物可以用于制备治疗抗肿瘤细胞的药物。
与现有技术相比,本发明具有如下有益效果:
(1)本发明咪唑[4,5-f][1,10]菲咯啉及其衍生物用于制备抗肿瘤药物,可以抑制肿瘤细胞的发生和发展,特别是对肺腺癌细胞、肝癌细胞和结肠癌细胞的生长有显著的抑制作用;
(2)本发明咪唑[4,5-f][1,10]菲咯啉及其衍生物用于制备抗肿瘤药物的疗效显著,安全无毒,药理作用明显,有很好的药用前景。
具体实施方式
下面结合实施例来进一步解释本发明,但实施例并不对本发明做任何形式的限定。
实施例1咪唑[4,5-f][1,10]菲咯啉的制备
菲咯啉5,6-二酮0.52g(2.4mmol),甲醛0.072g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml蒸馏水,浓氨水调节pH=7,得黄色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率87%。Calculated forC13H8N4·H2O(%):C:65.5;H:3.36;N:23.5;ESI-MS(in MeOH,m/z):238.4。
实施例2 2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉的制备
菲咯啉5,6-二酮0.52g(2.4mmol),2-三氟甲基苯甲醛0.42g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml水,浓氨水调节pH=7,得黄色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率84%。元素分析结果(%):C:63.0;H:2.91;N:14.3;ESI-MS(in MeOH,m/z):364.4。
实施例3 2-(3-羟基-4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉的制备
菲咯啉5,6-二酮0.52g(2.4mmol),3-羟基-4-甲氧苯甲醛0.36g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml水,浓氨水调节pH=7,得黄色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率79%。元素分析结果(%):C:73.3;H:4.6;N:17.1;ESI-MS(in MeOH,m/z):326.5。
实施例4 2-(4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉
菲咯啉5,6-二酮0.52g(2.4mmol),4-甲氧基苯甲醛0.33g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml水,浓氨水调节pH=7,得黄色或白色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率85%。元素分析结果(%):C:69.3,H:4.09,N:16.0;ESI-MS(in MeOH,m/z):326.6。
实施例5 2-(4-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉的制备
菲咯啉5,6-二酮0.52g(2.4mmol),4-三氟甲基苯甲醛0.42g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml水,浓氨水调节pH=7,得黄色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率82%。元素分析结果(%):C:62.5;H:2.90;N:14.2;ESI-MS(in MeOH,m/z):364.4。
实施例6 2-(4-氯苯基)咪唑[4,5-f][1,10]菲咯啉
菲咯啉5,6-二酮0.52g(2.4mmol),4-氯苯甲醛0.27g(2.4mmol),乙酸铵3.8g,30ml冰乙酸于50ml圆底烧瓶中加热到110℃回流4小时,待反应混合液冷却至室温后,加入40ml水,浓氨水调节pH=7,得黄色絮状沉淀;抽滤,水洗,50℃干燥。无水乙醇溶解后,过60-100目硅胶柱,无水乙醇淋洗,得到浅黄色溶液,减压旋干,得浅黄色固体,无水乙醇重结晶,产率81%。元素分析结果(%):C:69.4;H:3.3;N:16.4;ESI-MS(in MeOH,m/z):328.5。
实施例7 2-(4-羟苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-羟基苯甲醛0.29g(2.4mmol)。产率81%。元素分析结果(%):C:68.9;H:3.7;N:16.8;ESI-MS(inMeOH,m/z):330.1。
实施例8 2-(3-甲氧基-4-羟苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为3-甲氧基-4-羟基苯甲醛0.36g(2.4mmol)。产率78%。元素分析结果(%):C:73.2;H:4.5;N:17.0;ESI-MS(in MeOH,m/z):326.5。
实施例9 2-(3-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为3-三氟甲基苯甲醛0.42g(2.4mmol)。产率87%。元素分析结果(%):C:62.6;H:2.90;N:14.4;ESI-MS(inMeOH,m/z):364.4。
实施例10 2-(2-硝苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-硝基苯甲醛0.36g(2.4mmol)。产率81%。元素分析结果(%):C:63.2;H:3.3;N:19.2;ESI-MS(inMeOH,m/z):341.2。
实施例11 2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-甲氧基苯甲醛0.33g(2.4mmol)。产率86%。元素分析结果(%):C:69.5,H:4.09,N:16.1;ESI-MS(inMeOH,m/z):326.6。
实施例12 2-(3-氯苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为3-氯苯甲醛0.27g(2.4mmol)。产率86%。元素分析结果(%):C:69.1;H:3.5;N:16.2;ESI-MS(inMeOH,m/z):328.5。
实施例13 2-(3-羟苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为3-羟基苯甲醛0.29g(2.4mmol)。产率85%。元素分析结果(%):C:68.8;H:3.9;N:16.7;ESI-MS(inMeOH,m/z):330.1。
实施例14 2-(2-羟苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-羟基苯甲醛0.29g(2.4mmol)。产率82%。元素分析结果(%):C:68.9;H:3.8;N:16.8;ESI-MS(inMeOH,m/z):330.7。
实施例15 2-(4-氟苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-氟苯甲醛0.30g(2.4mmol)。产率79%。元素分析结果(%):C:68.9;H:3.5;N:16.7;ESI-MS(inMeOH,m/z):312.3。
实施例16 2-(4-溴苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-溴苯甲醛0.44g(2.4mmol)。产率81%。元素分析结果(%):C:60.7;H:3.1;N:14.6;ESI-MS(inMeOH,m/z):356.5。
实施例17 2-(4-甲苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-甲基苯甲醛0.28g(2.4mmol)。产率84%。元素分析结果(%):C:73.0;H:4.5;N:16.8;ESI-MS(inMeOH,m/z):310.3。
实施例18 2-苯基咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为苯甲醛0.25g(2.4mmol).产率87%。元素分析结果(%):C:77.1;H:3.9;N:18.6;ESI-MS(in MeOH,m/z):277.7。
实施例19 2-(4-乙氧苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-乙氧基苯甲醛0.36(2.4mmol)。产率84%。元素分析结果(%):C:71.1,H:4.6,N:15.5;ESI-MS(inMeOH,m/z):340.2。
实施例20 2-(4-丙氧苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-丙氧基苯甲醛0.39(2.4mmol)。产率74%。元素分析结果(%):C:70.6,H:4.9,N:14.8;ESI-MS(inMeOH,m/z):354.3。
实施例21 2-(4-异丙氧苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-异丙氧基苯甲醛0.39(2.4mmol)。产率76%。元素分析结果(%):C:70.5,H:4.9,N:14.8;ESI-MS(inMeOH,m/z):354.3。
实施例22 2-(4-丁氧苯基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-丁氧基苯甲醛0.42(2.4mmol)。产率71%。元素分析结果(%):C:71.2,H:5.6,N:14.1;ESI-MS(inMeOH,m/z):368.5。
实施例23 2-(4-吡啶基)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为4-吡啶甲醛0.26g(2.4mmol)。产率73%。元素分析结果(%):C:68.2;H:3.8;N:22.0;ESI-MS(inMeOH,m/z):297.4。
实施例24 2-(2-呋喃)咪唑[4,5-f][1,10]菲咯啉
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-呋喃甲醛0.23g(2.4mmol)。产率77%。Calculated for C18H10N4O·H2O(%):C:71.3;H:3.5;N:19.6;ESI-MS(in MeOH,m/z):286.3。
实施例25 2-(2-咪唑)咪唑[4,5-f][1,10]菲咯啉。
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-咪唑甲醛0.23g(2.4mmol)。产率75%。元素分析结果(%):C:67.8;H:3.6;N:23.13;ESI-MS(inMeOH,m/z):293.4。
实施例26 2-(2-噻唑)咪唑[4,5-f][1,10]菲咯啉。
实验方法同实施例1,将甲醛0.072g(2.4mmol)改为2-噻唑甲醛0.20g(2.4mmol)。产率76%。元素分析结果(%):C:65.2;H:3.0;N:20.1;ESI-MS(inMeOH,m/z):284.6。
实施例27咪唑[4,5f][1,10]菲咯啉(IP)及其取代衍生物的体外抗肿瘤活性
化合物体外抗肿瘤活性用IC50值(50%细胞生长抑制所需要的浓度)来评定:将细胞按一定密度接种于含10%小牛血清的RPMI1640培养基(内含适量青、链霉素和谷氨酰胺)的96孔板中,5%CO2,37℃条件下培养24小时后,换用不同浓度受试药物(用PBS配制成1μg/mL工作液,使用时按需要用培养基稀释)的新鲜培养基,继续培养48小时;然后每孔加入50μL预冷50%三氯乙酸(TCA,终浓度为10%),静置5分钟后,蒸馏水洗涤5次,空气干燥,加入100μL MTT染液,染色处理10min,1%醋酸溶液洗涤细胞4次,除去未结合染料,空气干燥,最后加入150μL 10mmol/L Tris溶液,充分混匀后,酶标仪在490nm波长下测定OD值。每个样品每个浓度平行实验6次,取平均值。
咪唑[4,5f][1,10]菲咯啉(IP)及其取代衍生物对A549(人肺腺癌)肿瘤细胞株的抑制活性见表1。
从表1数据可以看出,咪唑[4,5f][1,10]菲咯啉(IP)及其取代衍生物对肺腺癌A549细胞生长表现出显著的抑制作用,有部分化合物对肿瘤细胞的半数致死量远远低于临床上使用的抗肿瘤药物顺铂,在肿瘤疾病的临床治疗中具有潜在的工业应用价值。
表1.咪唑[4,5f][1,10]菲咯啉(IP)及其取代衍生物的对人肺腺癌细胞A549的抑制
Claims (4)
1.咪唑[4,5-f][1,10]菲咯啉类化合物及其衍生物在制备抗肿瘤药物中的应用,其特征在于所述咪唑[4,5-f][1,10]菲咯啉类化合物及其衍生物对肿瘤细胞的生长或繁殖有抑制作用,所述肿瘤细胞是肺腺癌细胞A549;
所述咪唑[4,5-f][1,10]菲咯啉类化合物选自如下化合物:咪唑[4,5-f][1,10]菲咯啉、2-(2-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-羟基-4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-甲氧基-4-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-三氟甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-硝基苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-甲氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-氯苯基)咪唑[4,5-f][1,10]菲咯啉、2-(3-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(2-羟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-氟苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-溴苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-甲苯基)咪唑[4,5-f][1,10]菲咯啉、2-苯基咪唑[4,5-f][1,10]菲咯啉、2-(4-乙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-丙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-异丙氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-丁氧苯基)咪唑[4,5-f][1,10]菲咯啉、2-(4-吡啶基)咪唑[4,5-f][1,10]菲咯啉、2-(2-呋喃)咪唑[4,5-f][1,10]菲咯啉、2-(2-噻唑)咪唑[4,5-f][1,10]菲咯啉。
2.根据权利要求1所述的咪唑[4,5-f][1,10]菲咯啉类化合物及其衍生物在制备抗肿瘤药物中的应用,其特征在于所述咪唑[4,5-f][1,10]菲咯啉类化合物的衍生物为咪唑[4,5-f][1,10]菲咯啉类化合物在药学上可接受的盐。
3.根据权利要求2所述的咪唑[4,5-f][1,10]菲咯啉类化合物及其衍生物在制备抗肿瘤药物中的应用,其特征在于所述咪唑[4,5-f][1,10]菲咯啉类化合物的药学上可接受的盐是咪唑[4,5-f][1,10]菲咯啉类化合物与药学可接受的酸或碱反应得到的盐。
4.根据权利要求3所述的咪唑[4,5-f][1,10]菲咯啉类化合物及其衍生物在制备抗肿瘤药物中的应用,其特征在于所述咪唑[4,5-f][1,10]菲咯啉类化合物的药学上可接受的盐为咪唑[4,5-f][1,10]菲咯啉类化合物的硫酸盐、焦硫酸盐、重硫酸盐、亚硫酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氢溴酸盐、氢碘酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、盐酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐或琥珀酸盐、碳酸盐、对甲苯磺酸盐、甲磺酸盐、对溴苯基磺酸盐、柠檬酸盐。
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