CN1743330A - Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use - Google Patents
Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use Download PDFInfo
- Publication number
- CN1743330A CN1743330A CN 200410074202 CN200410074202A CN1743330A CN 1743330 A CN1743330 A CN 1743330A CN 200410074202 CN200410074202 CN 200410074202 CN 200410074202 A CN200410074202 A CN 200410074202A CN 1743330 A CN1743330 A CN 1743330A
- Authority
- CN
- China
- Prior art keywords
- preparation
- catalysis
- fmoc
- compound
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 241001225321 Aspergillus fumigatus Species 0.000 title claims abstract description 15
- 229940091771 aspergillus fumigatus Drugs 0.000 title claims abstract description 15
- 102000009784 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Human genes 0.000 title claims description 13
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 title claims description 13
- 238000000034 method Methods 0.000 title description 5
- 230000002194 synthesizing effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000002360 preparation method Methods 0.000 claims abstract description 45
- 230000002829 reductive effect Effects 0.000 claims abstract description 17
- 238000005815 base catalysis Methods 0.000 claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 8
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical class OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 claims abstract description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- 150000008575 L-amino acids Chemical group 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- -1 amino acid methyl ester hydrochlorides Chemical class 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract 2
- JSUAJTLKVREZHV-UHFFFAOYSA-N 1-[4-(1-pyrrolidinyl)but-2-ynyl]pyrrolidine Chemical compound C1CCCN1CC#CCN1CCCC1 JSUAJTLKVREZHV-UHFFFAOYSA-N 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 239000007787 solid Substances 0.000 description 36
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
- 239000002585 base Substances 0.000 description 24
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- GOLXRNDWAUTYKT-UHFFFAOYSA-N 3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(CCC(=O)O)=CNC2=C1 GOLXRNDWAUTYKT-UHFFFAOYSA-N 0.000 description 6
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 description 6
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000022131 cell cycle Effects 0.000 description 6
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 6
- 229940017219 methyl propionate Drugs 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ILGDOMACGBCIPG-UHFFFAOYSA-N 2-(ethylamino)acetaldehyde Chemical compound CCNCC=O ILGDOMACGBCIPG-UHFFFAOYSA-N 0.000 description 4
- DATPFTPVGIHCCM-UHFFFAOYSA-N 2-(ethylamino)propanoic acid Chemical compound CCNC(C)C(O)=O DATPFTPVGIHCCM-UHFFFAOYSA-N 0.000 description 4
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 4
- 230000027311 M phase Effects 0.000 description 4
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- JUOXYWXXPHUSAI-UHFFFAOYSA-N ethylamino acetate Chemical compound CCNOC(C)=O JUOXYWXXPHUSAI-UHFFFAOYSA-N 0.000 description 4
- IUCRWTOOIVSODZ-UHFFFAOYSA-N ethylaminomethyl acetate Chemical compound CCNCOC(C)=O IUCRWTOOIVSODZ-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- RPUSRLKKXPQSGP-UHFFFAOYSA-N methyl 3-phenylpropanoate Chemical class COC(=O)CCC1=CC=CC=C1 RPUSRLKKXPQSGP-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 2
- ZPGDWQNBZYOZTI-UHFFFAOYSA-N 1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- FORVAIDSGSLRPX-RGMNGODLSA-N methyl (2s)-2,6-diaminohexanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCCCN FORVAIDSGSLRPX-RGMNGODLSA-N 0.000 description 2
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 2
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 2
- DODCBMODXGJOKD-RGMNGODLSA-N methyl (2s)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(C)C DODCBMODXGJOKD-RGMNGODLSA-N 0.000 description 2
- IYUKFAFDFHZKPI-DFWYDOINSA-N methyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](C)N IYUKFAFDFHZKPI-DFWYDOINSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- IGQGXIVCGKMRAM-UHFFFAOYSA-N 4-amino-3-methylbenzenesulfonamide Chemical compound CC1=CC(S(N)(=O)=O)=CC=C1N IGQGXIVCGKMRAM-UHFFFAOYSA-N 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101100059559 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) nimX gene Proteins 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930183739 Tryprostatin Natural products 0.000 description 1
- 101100273808 Xenopus laevis cdk1-b gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
This invention discloses a new series of Aspergillus fumigatus tremorine C-likes and their preparation method and its use in medicine field. The preparation method is as follow: first, with base as catalyst, the 2-position functional groups in (1S/R, 3S)-(2, 2-dimethoxy ethyl)- 1, 2, 3, 4-tetrahydro-beta-carboline-3-carbomethoxylate are acylated by activated Fmoc-Pro-OH; then, with the presence of base catalyst, at the same time of Fmoc removal, the acylates are intramolecularly cyclized; next, after the cyclized resultants are hydrolyzed and deacetalized by heating under acid catalysis, the resultants react with amino acid methyl ester hydrochlorides to be dehydrated and condensed under base catalysis, then reduced buy reducer, and finally the reduction product is saponified under base catalysis. As shown in experiment this compound has higher anti-tumor activity.
Description
Technical field
The present invention relates to a class cell cycle inhibitor, relate in particular to a class Aspergillus fumigatus dardarin C analogue, its preparation method and use.
Background technology
Cell cycle is the cell processes that is strictly controlled, and by finishing the cell cycle, a parent cell is split into two daughter cells.The propagation ceaselessly of tumour cell depends on the circulation ceaselessly of cell generation cycle, promptly finishes around G ceaselessly
1The phase/S phase/G
2The phase/running of M phase realizes undying propagation.In a single day adjusted or control cell generation cycle, just no longer development of tumour so.In a single day be interrupted the cell generation cycle of tumour, and just developing becomes no proliferative ability cell and death (Hartwell, LH.; Weinert TA.Checkpoints Controls that ensure the order of cell cycle events, Science, 246,629-634,1989.O ' Farrel, PH.; Edgar, BA.; Lakich, D.; Lehner, CF.Directing celldivision during development, Science, 246,635-640,1989.Nurse, P.Universalcontrol mechanism regulating onset of M-phase, Nature, 344,503-508,1990.Norbury, C.; Nurse, P.Animal cell cyclesand their control.Ann.Rev.Biochem.61,441-470,1992.).Therefore cell cycle inhibitor just becomes tumor chemotherapeutic drug, and corresponding novel cell cycle inhibitor just becomes potential candidate compound (Yamashita, the K. of tumor chemotherapeutic drug; Yasuda, H.; Pines, J.; Yasumoto, K.; Nishitani, H.; Ohtsubo, M.; Hunter, T.; Sugimura T.; Nishimoto, T.Okadaic acid, a potent inhibitor of typel and type 2a proteinphosphatates, activates cdc2/H1 kinase and transiently induces a prematuremitosis-like state in BHK21 cells, EMBO J., 9,4331-4338,1990.).Nineteen ninety generation later on the Aspergillus fumigatus dardarin C of bibliographical information M phase in mammalian cell cycle had suppress active, can make the cell cycle rest on G
2The transitional period of/M.Though suppressing the mechanism of action of the M phase of cell cycle, Aspergillus fumigatus dardarin C still remains to be illustrated, but change from the morphocytology that it causes, the cellular form that it and R 17934 (nocodazole) or Omaine (colcemid) cause changes similar (Cui, CB.; Kaakeya, H.; Okada, G.; Onose R.; Osada, H.Novel mammalian cell cycle inhibitors, tryprostatins A, B, and othert diketopiperazines produced by Aspergillus fumigatus I.Taxonomy, fermentation, isolation and biological properties, J.Antibiotics, 49,527-533,1996).As the potential candidate compound of cancer chemotherapy medicine, Aspergillus fumigatus dardarin C has caused people's common concern.
Aspergillus fumigatus dardarin C
But Aspergillus fumigatus dardarin C itself remains in the not high enough defective of anti-tumor activity as antitumor drug.
Summary of the invention
Technical problem to be solved by this invention provides a class and has Aspergillus fumigatus dardarin C analogue than high anti-tumor activity.
Technical problem to be solved by this invention realizes by following technological approaches:
A kind of Aspergillus fumigatus dardarin C analogue has the structure of following general formula general formula I and I ' compound:
General formula I and I ' wherein R are amino acid whose side chain of L-or hydrogen, R
1Be OH or OCH
3
In above-mentioned general formula I and the I ' compound, described L-amino acid side chain is-CH
3,-CH
2CH (CH
3)
2,-CH
2COOH ,-CH
2C
6H
5,-CH
2OH, indol-3-yl-CH
2Or-(CH
2)
3NH
2.
The intermediate of a kind of general formula I and I ' compound has the structure of following general formula I I and II '
General formula I I and II ', wherein R=CH (OCH
3)
2Or CHO.
A kind of method for preparing general formula I and I ' compound may further comprise the steps:
1) with Fmoc-Pro-OH (not methoxycarbonyl proline(Pro)) activated state under base catalysis will (1S/R, 3S)-(2, the 2-dimethoxy-ethyl)-1; 2,3,2 acidylates of 4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester; intramolecular cyclization when the product after the acidylate taken off Fmoc under base catalysis
2) the product heating hydrolysis under acid catalysis with the step 1) gained goes acetalation,
3) with step 2) aldehyde of gained and amino acid methyl ester hydrochloride under base catalysis dehydrating condensation after reductive agent it is reduced,
4) the reduzate saponification under base catalysis with the step 3) gained promptly gets general formula I of the present invention and I ' compound.
In the above-mentioned synthetic method, wherein the activation form of Fmoc-Pro-OH can be an acyl chlorides in the step 1), and acid anhydrides or active ester are preferably acyl chlorides; Described acylation reaction is carried out under organic base catalytic, preferentially carries out under diisopropyl ethyl amine catalysis; The reagent that takes off Fmoc is the general reagent during polypeptide synthesizes, and is preferably diethylamine.
Step 2) going acetalation catalysis acid in is organic acid, is preferably tosic acid; Heating temperature is 28 ℃ to 65 ℃, is preferably 45 ℃
Catalysis alkali in the step 3) is organic bases, is preferably triethylamine; Dewatering both can also can dewater with dewatering agent by azeotropic dehydration for method commonly used, was preferably anhydrous sodium sulfate dehydration; Dewatered product reduces through reductive agent, and reductive agent is common reductive agent, is preferably POTASSIUM BOROHYDRIDE or sodium borohydride.
The alkali that saponification is used in the step 4) is mineral alkali, is preferably sodium hydroxide or potassium hydroxide.
The compounds of this invention is to be prepared from by the structure of Aspergillus fumigatus dardarin C is further modified, and has higher anti-tumor activity.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Illustrate: in the present embodiment except that glycine used amino acid be the L-configuration, reagent is commercially available chemical pure except that indicating, each degree of purity of production of intermediate is confirmed with TLC, nuclear-magnetism is gone up mensuration at VXR-300S (300MHz) or INOVA-500 (500MHz), FAB-MS measures on the ZAB-MS of Britain VG company, EI-MS measures on the Trace MS of U.S. Thermo Finnigan company System mass spectrograph, fusing point is measured (temperature is not proofreaied and correct) with the desk-top micro-fusing point instrument of XT5 heat that instrument electric light instrument plant of Beijing section produces, optically-active is measured (the long 5cm of sample pool with the POLARTRONIC D type trace polarimeter of SCHMIDT+HAENSCH company, volume 0.7ml), the compound name is a foundation with the CA systematic nomenclature mainly, the band carboline is common name in a few title, presses the IUPAC systematic naming method.
Embodiment 1 (1S/R, 3S)-1-(2, the 2-dimethoxy-ethyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester synthetic
5.0g (19.6mmol) the tryptophan methyl ester hydrochloride adds 6ml (23.6mmol) 1,1,3 after being dissolved in 50ml methyl alcohol, 3-tetramethyl Ethylene Oxide.Reaction mixture with 5N hydrochloric acid regulate PH less than 4.0, be warmed up to 45 ℃ of reactions 48 hours.TLC (CHCl
3: CH
3OH, 9: 1) show that the raw material spot disappears, add triethylamine and regulate PH greater than 8, water pump pressure reducing and steaming solvent, add 50ml chloroform and 50ml sodium carbonate solution (10%) in the resistates, water layer after the extraction with chloroform extract (30ml * 3) again, merge organic layer, anhydrous sodium sulfate drying, filtration, filtrate be evaporated to dried, resistates at 37 ℃ and get 5.4g (86%) title compound with silica gel column chromatography, is light yellow oil.EI-MS(m/e)318[M]
+。
1H-NMR (CDCl
3, 500MHz) show that product is the mixture hydrogen of a pair of diastereomer, according to the integration ratio of relevant proton extrapolate (1S/3S) and (1R/3S) relative proportion of two isomer be 1.35: 1.
Embodiment 2. (5aS, 12R, 14aS)-5,14-dioxy-12-(2, the 2-dimethoxy-ethyl)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles (2a) and (5aS, 12S, 14aS)-5,14-dioxy-12-(2, the 2-dimethoxy-ethyl)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-preparation of pyrido-[3,4-b]-indoles (2b)
Behind the middle Dropwise 5 0ml sulfur oxychloride of 10g Fmoc-Pro-OH (29.7mmol), refluxed 5 hours, cooling, concentrating under reduced pressure is removed residual sulfur oxychloride, residue is evaporated to dried with the 5ml acetic acid ethyl dissolution again, this operates triplicate, and resistates grinds with ether, leaches the acyl chlorides of shallow white solid Fmoc-Pro, without being further purified, be directly used in next step reaction.
5.4g (17.0mmol) (1S/R, 3S)-(2, the 2-dimethoxy-ethyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester dissolves with the 50ml anhydrous methylene chloride, ice-water bath cooling back adds the acyl chlorides of 9.1g (25.5mmol) Fmoc-Pro, keeping reaction mixture with diisopropyl ethyl amine is alkalescence, stirring at room 24 hours, TLC (CHCl
3: CH
3OH, 9: 1) show that the raw material spot disappears.The reaction mixture concentrating under reduced pressure removes and to desolvate, and resistates is that (1S/R, 3S)-N-(Fmoc-Pro)-1-(2, the 2-dimethoxy-ethyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester not purifiedly is directly used in next step reaction.
Top resistates adds the 5ml diethylamine after using the 50ml dissolve with methanol, and stirring at room made compound close ring, TLC (CHCl in 12 hours when removing the Fmoc protecting group
3: CH
3OH, 9: 1) show that raw material point disappears.Concentrating under reduced pressure removes and desolvates, residue decompression column chromatography (CHCl
3: CH
3OH, 20: 1) get 1.46g (21%) 2a and 2.45g (35%) 2b, be colorless solid.
2a Mp 180-183℃，EI-MS(m/e)383[M]
+.
(c＝0.33，CHCl
3/CH
3OH，1∶1)
1H-NMR(CDCl3，300MHz)：δ＝8.67(s，1H)，7.50(d，J＝7.5Hz，1H)，7.34(d，J＝7.5Hz，1H)，7.22(t，J＝7.5Hz，1H)，7.09(t，J＝7.6Hz，1H)，5.82(t，J＝6.0Hz，1H)，4.76(t，J＝6.0Hz，1H)，4.41(m，J＝5.8Hz，1H)，4.14(m，J＝5.7Hz，1H)，3.92(m，J＝4.8Hz，1H)，3.64(dd，J＝15.0Hz，J＝4.5Hz，1H)，3.46(s，3H)，3.40(s，3H)，2.86(dd，J＝16.0Hz，J＝11.1Hz，1H)，2.51(t，J＝4.3Hz，1H)，2.35(t，J＝4.3Hz，1H)，2.22(t，J＝4.8Hz，1H)，1.95(t，J＝4.6Hz，2H)。
2b Mp205-207℃，EI-MS(m/e)383[M]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.47(s，1H)，7.59(d，J＝7.5Hz，1H)，7.38(d，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，7.16(t，J＝7.4Hz，1H)，5.37(dd，J＝10.0Hz，J＝4.0Hz，1H)，4.41(dd，J＝8.0Hz，J＝4.8Hz，1H)，4.16(m，J＝5.7Hz，2H)，3.90(m，J＝4.9Hz，1H)，3.60(dd，J＝14.5Hz，J＝4.2Hz，2H)，3.49(s，3H)，3.40(s，3H)，2.91(dd，J＝12.0Hz，J＝16.0Hz，1H)，2.30(t，J＝4.3Hz，1H)，2.26(t，J＝4.3Hz，1H)，2.20(t，J＝4.8Hz，1H)，1.92(t，J＝4.6Hz，2H)。
Embodiment 3.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino acetaldehyde (3a)
200mg (0.522mmol) 2a is dissolved in the 15ml acetone, adds the 20mg tosic acid, is warmed up to 45 ℃ of insulation reaction 1 hour, TLC (CHCl
3: CH
3OH, 9: 1) show that 2a disappears.Reaction mixture is evaporated to dried, and the residue repetitiousness grinds with ether, obtains 173mg (98%) 3a, is colorless solid.
3a Mp162-163℃，EI-MS(m/e)337[M]
+.
(c＝0.33，CHCl
3/CH
3OH，1∶1)
1H-NMR(CDCl3，300MHz)：δ＝11.50(s，1H)，8.67(s，1H)，7.54(d，J＝7.6Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.30(t，J＝7.6Hz，1H)，7.15(t，J＝7.5Hz，1H)，4.74(t，J＝6.1Hz，1H)，4.44(m，J＝5.9Hz，1H)，4.18(m，J＝5.8Hz，1H)，3.94(m，J＝4.9Hz，1H)，3.62(dd，J＝15.2Hz，J＝4.6Hz，1H)，2.88(dd，J＝15.9Hz，J＝11.3Hz，1H)，2.58(d，J＝4.9Hz，2H)，2.54(t，J＝4.4Hz，1H)，2.38(t，J＝4.5Hz，1H)，2.23(t，J＝4.9Hz，1H)。
Embodiment 4.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino acetaldehyde (3b)
200mg (0.522mmol) 2b is dissolved in the 15ml acetone, adds the 20mg tosic acid, is warmed up to 45 ℃ of insulation reaction 1 hour, TLC (CHCl
3: CH
3OH, 9: 1) show that 2b disappears.Reaction mixture is evaporated to dried, and the residue repetitiousness grinds with ether, obtains 175mg (98%) 3b, is colorless solid.
3b Mp 198-200℃，EI-MS(m/e)337[M]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.36(s，1H)，8.56(s，1H)，7.72(d，J＝7.6Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.33(t，J＝7.6Hz，1H)，7.27(t，J＝7.5Hz，1H)，4.43(dd，J＝8.1Hz，J＝4.7Hz，1H)，4.18(m，J＝5.7Hz，2H)，3.92(m，J＝5.1Hz，1H)，3.62(dd，J＝14.2Hz，J＝4.4Hz，2H)，3.12(dd，J＝16.1Hz，J＝12.2Hz，1H)，2.54(t，J＝4.7Hz，2H)，2.32(t，J＝4.4Hz，1H)，2.27(t，J＝4.4Hz，1H)，2.21(t，J＝4.7Hz，2H)。
Embodiment 5.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino methyl acetate (4Aa)
The mixture stirring at room of 202mg (0.6mmol) 3a, 75mg (0.6mmol) glycine methyl ester hydrochloride, 5ml chloroform 0.5ml triethylamine and 3.0g anhydrous sodium sulphate is after 3 hours, add 5ml methyl alcohol and 100mg (1.85mmol) POTASSIUM BOROHYDRIDE stirring at room 3 hours again, TLC (CHCl
3: CH
3OH, 9: 1) show that 3a disappears.Product is a pure point, the triketohydrindene hydrate colour developing.Reaction mixture is evaporated to dried, and residue and 10ml chloroform, 10ml deionized water and a small amount of 5N mixed in hydrochloric acid are regulated pH greater than 8 with ammoniacal liquor then.Separation chloroform layer, water layer use the chloroform layer of chloroform extraction (5ml * 3), merging to wash once with saturated nacl aqueous solution again, anhydrous sodium sulfate drying, filtration, filtrate are evaporated to dried at 37 ℃, the residue silica gel column chromatography gets 242mg (98%) title compound, is colorless solid.Mp178-180℃，EI-MS(m/e)411[M]
+.
(c＝0.33，CHCl
3/CH
3OH，1∶1).
1H-NMR(CDCl
3，300MHz)δ＝8.62(s，1H)，7.53(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.28(t，J＝7.5Hz，1H)，7.13(t，J＝7.4Hz，1H)，4.76(t，J＝6.2Hz，1H)，4.65(d，J＝4.7Hz，2H)，4.21(m，J＝5.6Hz，1H)，4.10(m，J＝5.7Hz，1H)，3.92(m，J＝4.7Hz，2H)，3.60(s，3H)，3.24(m，J＝4.7Hz，1H)，3.15(dd，J＝15.9Hz，J＝11.3Hz，2H)，2.24(d，J＝4.9Hz，2H)，2.20(t，J＝4.4Hz，2H)，1.93(m，J＝4.7Hz，2H)，1.88(t，J＝4.5Hz，2H)。
Embodiment 6.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino methyl acetate (4Ab)
According to the operation of embodiment 5, obtain 242mg (98%) title compound from 202mg (0.6mmol) 3b, 75mg (0.6mmol) glycine methyl ester hydrochloride, be colorless solid.Mp 189-191℃，EI-MS(m/e)411[M]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.52(s，1H)，7.70(d，J＝7.5Hz，1H)，7.40(d，J＝7.5Hz，1H)，7.30(t，J＝7.8Hz，1H)，7.25(t，J＝7.6Hz，1H)，4.54(d，J＝5.5Hz，2H)，4.50(d，J＝5.8Hz，1H)，4.40(dd，J＝8.0Hz，J＝4.5Hz，1H)，4.36(t，J＝6.0Hz，1H)，3.95(m，J＝5.4Hz，1H)，3.92(dd，J＝14.2Hz，J＝4.4Hz，1H)，3.61(s，3H)，3.52(dd，J＝16.0Hz，J＝12.0Hz，2H)，3.20(m，J＝4.6Hz，2H)，3.12(m，J＝6.0Hz，1H)，2.24(t，J＝4.6Hz，2H)，1.96(m，J＝4.4Hz，2H)，1.91(m，J＝4.9Hz，2H)。
Embodiment 7.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino methyl propionate (4Ba)
According to the operation of embodiment 5, obtain 242mg (98%) title compound from 202mg (0.6mmol) 3a, 84mg (0.6mmol) L-alanine methyl ester hydrochloride, be colorless solid.Mp 201-203℃，EI-MS(m/e)424[M]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.60(s，1H)，7.51(d，J＝7.5Hz，1H)，7.46(d，J＝7.5Hz，1H)，7.31(t，J＝7.5Hz，1H)，7.14(t，J＝7.4Hz，1H)，4.72(m，J＝6.1Hz，1H)，4.62(d，J＝4.8Hz，1H)，4.23(m，J＝5.5Hz，1H)，4.12(m，J＝5.5Hz，1H)，3.94(m，J＝4.8Hz，2H)，3.61(s，3H)，3.20(m，J＝4.8Hz，1H)，3.14(dd，J＝15.2Hz，J＝10.3Hz，2H)，2.22(d，J＝4.8Hz，2H)，2.18(t，J＝4.6Hz，2H)，2.14(d，J＝5.2Hz，3H)，1.90(m，J＝4.7Hz，2H)，1.89(t，J＝4.5Hz，2H)。
Embodiment 8.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino methyl propionate (4Bb)
According to the operation of embodiment 5, obtain 244mg (98%) title compound from 202mg (0.6mmol) 3b, 84mg (0.6mmol) L-alanine methyl ester hydrochloride, be colorless solid.Mp 185-187℃，EI-MS(m/e)424[M]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.62(s，1H)，7.54(d，J＝7.5Hz，1H)，7.47(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.18(t，J＝7.5Hz，1H)，4.60(d，J＝4.7Hz，1H)，4.45(m，J＝6.0Hz，1H)，4.24(m，J＝5.6Hz，1H)，4.15(m，J＝5.7Hz，1H)，3.92(m，J＝4.8Hz，2H)，3.62(s，3H)，3.22(m，J＝4.7Hz，1H)，3.16(dd，J＝15.2Hz，J＝10.3Hz，2H)，2.20(d，J＝4.8Hz，2H)，2.16(t，J＝4.6Hz，2H)，2.12(d，J＝5.2Hz，3H)，1.92(m，J＝4.7Hz，2H)，1.87(t，J＝4.5Hz，2H)。
Embodiment 9.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 4-methyl-methyl valerate (4Ca)
According to the operation of embodiment 5, obtain 281mg (97%) title compound from 202mg (0.6mmol) 3a, 108mg (0.6mmol) L-leucine methyl ester hydrochloride, be colorless solid.Mp 175-177℃，ESI-MS(m/e)483[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.60(s，1H)，7.55(d，J＝7.7Hz，1H)，7.49(d，J＝7.7Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.15(t，J＝7.5Hz，1H)，4.78(t，J＝6.4Hz，1H)，4.66(t，J＝4.8Hz，1H)，4.24(m，J＝5.5Hz，1H)，4.13(m，J＝5.6Hz，1H)，3.94(m，J＝4.6Hz，2H)，3.62(s，3H)，3.20(m，J＝4.7Hz，1H)，3.18(dd，J＝15.6Hz，J＝11.0Hz，2H)，2.23(d，J＝4.9Hz，2H)，2.21(t，J＝4.5Hz，2H)，1.94(m，J＝4.6Hz，2H)，1.92(m，J＝4.2Hz，1H)，1.89(t，J＝4.5Hz，2H)，1.85(m，J＝4.6Hz，2H)，1.83(d，J＝4.3Hz，3H)，1.79(t，J＝4.4Hz，3H)。
Embodiment 10.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 4-methyl-methyl valerate (4Cb)
According to the operation of embodiment 5, obtain 286mg (98%) title compound from 202mg (0.6mmol) 3b, 108mg (0.6mmol) L-leucine methyl ester hydrochloride, be colorless solid.Mp 115-117℃，ESI-MS(m/e)483[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.50(s，1H)，7.72(d，J＝7.6Hz，1H)，7.43(d，J＝7.6Hz，1H)，7.32(t，J＝7.7Hz，1H)，7.27(t，J＝7.7Hz，1H)，4.56(t，J＝5.5Hz，1H)，4.52(d，J＝5.7Hz，1H)，4.42(dd，J＝8.0Hz，J＝4.5Hz，1H)，4.37(t，J＝6.2Hz，1H)，3.96(m，J＝5.5Hz，1H)，3.94(dd，J＝14.2Hz，J＝4.4Hz，1H)，3.62(s，3H)，3.50(dd，J＝15.8Hz，J＝11.8Hz，2H)，3.22(m，J＝4.7Hz，2H)，3.14(m，J＝6.1Hz，1H)，2.22(t，J＝4.7Hz，2H)，1.95(m，J＝4.5Hz，2H)，1.92(m，J＝4.8Hz，2H)，1.90(m，J＝4.3Hz，1H)，1.86(m，J＝4.6Hz，2H)，1.84(d，J＝4.3Hz，3H)，1.80(t，J＝4.4Hz，3H)。
Embodiment 11.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 "; 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-and pyrido-[3,4-b]-indoles-12-base ethylamino]-1, the preparation of 4-dimethyl succinate (4Da)
According to the operation of embodiment 5, obtain 281mg (97%) title compound from 202mg (0.6mmol) 3a, 127mg (0.6mmol) L-asparagus fern amino acid dimethyl ester hydrochloride, be colorless solid.Mp 175-177℃，ESI-MS(m/e)481[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.64(s，1H)，7.54(d，J＝7.6Hz，1H)，7.47(d，J＝7.6Hz，1H)，7.26(t，J＝7.6Hz，1H)，7.15(t，J＝7.5Hz，1H)，4.77(t，J＝6.1Hz，1H)，4.66(d，J＝4.6Hz，1H)，4.23(m，J＝5.7Hz，1H)，4.12(m，J＝5.7Hz，1H)，3.90(m，J＝4.8Hz，2H)，3.62(s，3H)，3.59(s，3H)，3.22(m，J＝4.7Hz，1H)，3.14(dd，J＝15.7Hz，J＝11.1Hz，2H)，2.41(d，J＝5.2Hz，2H)，2.25(d，J＝4.7Hz，2H)，2.21(t，J＝4.4Hz，2H)，1.92(m，J＝4.7Hz，2H)，1.89(t，J＝4.5Hz，2H)。
Embodiment 12.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 "; 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-and pyrido-[3,4-b]-indoles-12-base ethylamino]-1, the preparation of 4-dimethyl succinate (4Db)
According to the operation of embodiment 5, obtain 281mg (97%) title compound from 202mg (0.6mmol) 3b, 127mg (0.6mmol) L-aspartic acid dimethyl ester hydrochloride, be colorless solid.Mp 115-117℃，ESI-MS(m/e)481[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.55(s，1H)，7.72(d，J＝7.6Hz，1H)，7.43(d，J＝7.6Hz，1H)，7.32(t，J＝7.7Hz，1H)，7.28(t，J＝7.5Hz，1H)，4.52(d，J＝5.5Hz，1H)，4.51(d，J＝5.9Hz，1H)，4.42(dd，J＝8.1Hz，J＝4.4Hz，1H)，4.38(t，J＝6.2Hz，1H)，3.94(m，J＝5.5Hz，1H)，3.91(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.62(s，3H)，3.60(s，3H)，3.54(dd，J＝15.8Hz，J＝11.7Hz，2H)，3.22(m，J＝4.8Hz，2H)，3.14(m，J＝6.1Hz，1H)，2.39(d，J＝5.1Hz，2H)，2.25(t，J＝4.6Hz，2H)，1.94(m，J＝4.5Hz，2H)，1.92(m，J＝4.8Hz，2H)。
Embodiment 13.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-phenylpropionic acid methyl esters (4Ea)
According to the operation of embodiment 5, obtain 295mg (98%) title compound from 202mg (0.6mmol) 3a, 129mg (0.6mmol) L-phenylalanine methyl ester hydrochloride, be colorless solid.Mp 175-177℃，ESI-MS(m/e)501[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.64(s，1H)，7.55(d，J＝7.6Hz，1H)，7.47(d，J＝7.6Hz，1H)，7.45(d，J＝7.4Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.27(d，J＝7.4Hz，2H)，7.15(t，J＝7.5Hz，1H)，6.98(t，J＝7.5Hz，2H)，4.78(t，J＝6.1Hz，1H)，4.64(d，J＝4.6Hz，1H)，4.22(m，J＝5.5Hz，1H)，4.12(m，J＝5.6Hz，1H)，3.94(m，J＝4.6Hz，2H)，3.61(s，3H)，3.23(m，J＝4.8Hz，1H)，3.21(s，2H)，3.14(dd，J＝15.5Hz，J＝11.1Hz，2H)，2.23(d，J＝4.8Hz，2H)，2.21(t，J＝4.5Hz，2H)，1.92(m，J＝4.8Hz，2H)，1.89(t，J＝4.6Hz，2H)。
Embodiment 14.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-phenylpropionic acid methyl esters (4Eb)
According to the operation of embodiment 5, obtain 293mg (97%) title compound from 202mg (0.6mmol) 3b, 129mg (0.6mmol) L-phenylalanine methyl ester hydrochloride, be colorless solid.Mp 169-171℃，ESI-MS(m/e)501[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.54(s，1H)，7.72(d，J＝7.4Hz，1H)，7.44(d，J＝7.4Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.32(t，J＝7.7Hz，1H)，7.27(t，J＝7.5Hz，1H)，7.26(d，J＝7.4Hz，2H)，6.95(t，J＝7.5Hz，2H)，4.55(d，J＝5.6Hz，1H)，4.52(d，J＝5.7Hz，1H)，4.42(dd，J＝8.1Hz，J＝4.6Hz，1H)，4.35(t，J＝6.1Hz，1H)，3.96(m，J＝5.5Hz，1H)，3.90(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.62(s，3H)，3.54(dd，J＝15.9Hz，J＝11.7Hz，2H)，3.22(m，J＝4.5Hz，2H)，3.19(s，2H)，3.13(m，J＝6.1Hz，1H)，2.23(t，J＝4.5Hz，2H)，1.95(m，J＝4.5Hz，2H)，1.87(m，J＝4.7Hz，2H)。
Embodiment 15.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-hydroxy methyl propionate (4Fa)
According to the operation of embodiment 5, obtain 295mg (98%) title compound from 202mg (0.6mmol) 3a, 93mg (0.6mmol) L-serine methyl ester hydrochloride, be colorless solid.Mp 213-215℃，ESI-MS(m/e)441[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.61(s，1H)，7.51(d，J＝7.5Hz，1H)，7.46(d，J＝7.5Hz，1H)，7.25(t，J＝7.5Hz，1H)，7.15(t，J＝7.4Hz，1H)，4.77(t，J＝6.1Hz，1H)，4.66(d，J＝4.9Hz，1H)，4.23(m，J＝5.6Hz，1H)，4.12(m，J＝5.7Hz，1H)，4.06(s，1H)，3.94(m，J＝4.7Hz，2H)，3.78(d，J＝5.6Hz，2H)，3.62(s，3H)，3.23(m，J＝4.7Hz，1H)，3.16(dd，J＝15.7Hz，J＝11.0Hz，2H)，2.23(d，J＝4.8Hz，2H)，2.21(t，J＝4.5Hz，2H)，1.91(m，J＝4.8Hz，2H)，1.86(t，J＝4.4Hz，2H)。
Embodiment 16.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1,2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-hydroxy methyl propionate (4Fb)
According to the operation of embodiment 5, obtain 292mg (97%) title compound from 202mg (0.6mmol) 3b, 93mg (0.6mmol) L-serine methyl ester hydrochloride, be colorless solid.Mp 200-202℃，ESI-MS(m/e)441[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.55(s，1H)，7.73(d，J＝7.6Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.32(t，J＝7.7Hz，1H)，7.28(t，J＝7.5Hz，1H)，4.55(d，J＝5.5Hz，1H)，4.52(d，J＝5.7Hz，1H)，4.43(dd，J＝8.2Hz，J＝4.6Hz，1H)，4.35(t，J＝6.1Hz，1H)，4.05(s，1H)，3.94(m，J＝5.5Hz，1H)，3.90(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.75(d，J＝5.6Hz，2H)，3.63(s，3H)，3.54(dd，J＝15.6Hz，J＝11.7Hz，2H)，3.22(m，J＝4.6Hz，2H)，3.14(m，J＝6.1Hz，1H)，2.25(t，J＝4.7Hz，2H)，1.95(m，J＝4.6Hz，2H)，1.90(m，J＝4.8Hz，2H)。
Embodiment 17.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-(indol-3-yl-) methyl propionate (4Ga)
According to the operation of embodiment 5, obtain 317mg (98%) title compound from 202mg (0.6mmol) 3a, 153mg (0.6mmol) L-tryptophan methyl ester hydrochloride, be colorless solid.Mp 120-122℃，ESI-MS(m/e)540[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.66(s，1H)，8.63(s，1H)，7.57(d，J＝7.7Hz，1H)7.55(d，J＝7.6Hz，1H)，7.53(d，J＝7.8Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.35(t，J＝7.7Hz，1H)，7.32(t，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.16(t，J＝7.5Hz，1H)，6.89(s，1H)，4.77(t，J＝6.1Hz，1H)，4.67(d，J＝4.9Hz，1H)，4.23(m，J＝5.7Hz，1H)，4.14(m，J＝5.6Hz，1H)，3.94(m，J＝4.8Hz，2H)，3.78(d，J＝5.1Hz，2H)，3.63(s，3H)，3.23(m，J＝4.6Hz，1H)，3.13(dd，J＝15.1Hz，J＝10.9Hz，2H)，2.25(d，J＝4.8Hz，2H)2.21(t，J＝4.5Hz，2H)，1.94(m，J＝4.8Hz，2H)，1.89(t，J＝4.7Hz，2H)。
Embodiment 18.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-(indol-3-yl-) methyl propionate (4Gb)
According to the operation of embodiment 5, obtain 314mg (97%) title compound from 202mg (0.6mmol) 3b, 153mg (0.6mmol) L-tryptophan methyl ester hydrochloride, be colorless solid.Mp 191-193℃，ESI-MS(m/e)540[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝8.55(s，1H)，8.45(s，1H)，7.73(d，J＝7.6Hz，1H)，7.68(d，J＝7.7Hz，1H)，7.43(d，J＝7.6Hz，1H)，7.40(d，J＝7.7Hz，1H)，7.34(t，J＝7.7Hz，1H)，7.31(t，J＝7.8Hz，1H)，7.28(t，J＝7.5Hz，1H)，7.22(t，J＝7.6Hz，1H)，6.89(s，1H)，4.57(d，J＝5.4Hz，1H)，4.53(d，J＝5.7Hz，1H)，4.43(dd，J＝8.1Hz，J＝4.3Hz，1H)，4.38(t，J＝6.1Hz，1H)，3.97(m，J＝5.5Hz，1H)，3.94(dd，J＝14.0Hz，J＝4.3Hz，1H)，3.87(d，J＝5.7Hz，2H)，3.63(s，3H)，3.54(dd，J＝15.7Hz，J＝11.6Hz，2H)，3.22(m，J＝4.7Hz，2H)，3.15(m，J＝6.1Hz，1H)，2.26(t，J＝4.7Hz，2H)，1.97(m，J＝4.5Hz，2H)，1.90(m，J＝4.7Hz，2H)。
Embodiment 19.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 2-(the amino butyl of 4--1-yl) methyl acetate (4Ha)
According to the operation of embodiment 5, obtain 93mg (32%) title compound from 202mg (0.6mmol) 3a, 108mg (0.6mmol) L-lysine methyl ester hydrochloride, be colorless solid.Mp 149-151℃，ESI-MS(m/e)481[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.95(s，1H)，7.58(d，J＝7.5Hz，1H)，7.46(d，J＝7.5Hz，1H)，7.25(t，J＝7.5Hz，1H)，7.14(t，J＝7.4Hz，1H)，4.78(t，J＝6.0Hz，1H)，4.67(d，J＝4.8Hz，1H)，4.24(m，J＝5.5Hz，1H)，4.14(m，J＝5.8Hz，1H)，3.96(m，J＝4.9Hz，2H)，3.62(s，3H)，3.23(t，J＝4.9Hz，2H)，3.17(dd，J＝15.9Hz，J＝11.3Hz，2H)，2.77(s，1H)，2.26(d，J＝4.9Hz，2H)，2.24(t，J＝4.4Hz，2H)，1.94(m，J＝4.9Hz，2H)，1.92(m，J＝4.7Hz，2H)，1.85(t，J＝4.5Hz，2H)，1.76(m，J＝4.7Hz，2H)，1.66(m，J＝5.2Hz，2H)，1.63(m，J＝5.2Hz，2H)。
Embodiment 20.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 2-(the amino butyl of 4--1-yl) methyl acetate (4Hb)
According to the operation of embodiment 5, obtain 116mg (40%) title compound from 202mg (0.6mmol) 3b, 108mg (0.6mmol) L-lysine methyl ester hydrochloride, be colorless solid.Mp 155-157℃，ESI-MS(m/e)481[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝8.76(s，1H)，7.55(d，J＝7.5Hz，1H)，7.43(d，J＝7.5Hz，1H)，7.23(t，J＝7.5Hz，1H)，7.12(t，J＝7.4Hz，1H)，4.65(d，J＝4.8Hz，1H)，4.54(t，J＝6.0Hz，1H)，4.22(m，J＝5.5Hz，1H)，4.16(m，J＝5.8Hz，1H)，3.94(m，J＝4.9Hz，2H)，3.60(s，3H)，3.25(t，J＝4.9Hz，2H)，3.14(dd，J＝15.6Hz，J＝11.1Hz，2H)，2.75(s，1H)，2.24(d，J＝4.9Hz，2H)，2.21(t，J＝4.4Hz，2H)，1.96(m，J＝4.9Hz，2H)，1.93(m，J＝4.7Hz，2H)，1.86(t，J＝4.5Hz，2H)，1.74(m，J＝4.7Hz，2H)，1.65(m，J＝5.2Hz，2H)，1.61(m，J＝5.2Hz，2H)。
Embodiment 21.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino acetate (5Aa)
205mg (0.5mmol) 4Aa adds 300mg sodium hydroxide (7.5mmol), reaction mixture stirring at room 1.5 hours, TLC (CHCl after using the 5ml dissolve with methanol
3: CH
3OH, 9: 1) show that 4Aa disappears.Reaction mixture is regulated pH6.5 with Glacial acetic acid, concentrating under reduced pressure, and resistates is with the silica gel H column chromatography (CHCl that reduces pressure
3: CH
3OH, 20: 1), get 196mg (99%) title compound, be colorless solid.Mp 223-225℃，ESI-MS(m/e)397[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝10.50(s，1H)，8.97(s，1H)，7.47(d，J＝7.5Hz，1H)，7.36(d，J＝7.5Hz，1H)，7.15(t，J＝7.5Hz，1H)，7.09(t，J＝7.4Hz，1H)，4.82(t，J＝6.2Hz，1H)，4.75(d，J＝4.7Hz，2H)，4.23(m，J＝5.6Hz，1H)，4.18(m，J＝5.7Hz，1H)，3.95(m，J＝4.7Hz，2H)，3.26(m，J＝4.7Hz，1H)，3.17(dd，J＝15.9Hz，J＝11.3Hz，2H)，2.26(d，J＝4.9Hz，2H)，2.24(t，J＝4.4Hz，2H)，1.95(m，J＝4.7Hz，2H)，1.89(t，J＝4.5Hz，2H)。
Embodiment 22.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino acetate (5Ab)
According to the operation of embodiment 19, get 197mg (99%) title compound from 205mg (0.5mmol) 4Ab, be colorless solid.Mp 233-237℃，ESI-MS(m/e)397[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝10.61(s，1H)，8.67(s，1H)，7.31(d，J＝7.5Hz，1H)，7.19(d，J＝7.5Hz，1H)，7.13(t，J＝7.8Hz，1H)，7.08(t，J＝7.6Hz，1H)，4.52(d，J＝5.6Hz，2H)，4.48(d，J＝5.7Hz，1H)，4.41(dd，J＝8.1Hz，J＝4.4Hz，1H)，4.34(t，J＝6.0Hz，1H)，3.92(m，J＝5.4Hz，1H)，3.90(dd，J＝14.2Hz，J＝4.4Hz，1H)，3.52(dd，J＝15.8Hz，J＝11.8Hz，2H)，3.23(m，J＝4.6Hz，2H)，3.11(m，J＝6.0Hz，1H)，2.22(t，J＝4.6Hz，2H)，1.94(m，J＝4.4Hz，2H)，1.90(m，J＝4.9Hz，2H)。
Embodiment 23.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino propionic acid (5Ba)
According to the operation of embodiment 19, get 197mg (99%) title compound from 212mg (0.5mmol) 4Ba, be colorless solid.Mp 224-226℃，ESI-MS(m/e)411[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝10.82(s，1H)，8.87(s，1H)，7.40(d，J＝7.5Hz，1H)，7.32(d，J＝7.5Hz，1H)，7.25(t，J＝7.5Hz，1H)，7.09(t，J＝7.4Hz，1H)，4.92(m，J＝6.0Hz，1H)，4.69(d，J＝4.8Hz，1H)，4.25(m，J＝5.5Hz，1H)，4.16(m，J＝5.5Hz，1H)，3.95(m，J＝4.8Hz，2H)，3.23(m，J＝4.8Hz，1H)，3.16(dd，J＝15.2Hz，J＝10.3Hz，2H)，2.24(d，J＝4.8Hz，2H)，2.19(t，J＝4.6Hz，2H)，1.78(m，J＝4.7Hz，2H)，1.82(t，J＝4.5Hz，2H)，1.46(d，J＝5.2Hz，3H)。
Embodiment 24.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-yl] preparation of ethylamino propionic acid (5Bb)
According to the operation of embodiment 19, get 196mg (99%) title compound from 212mg (0.5mmol) 4Bb, be colorless solid.Mp 233-235℃，ESI-MS(m/e)411[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝10.74(s，1H)，8.70(s，1H)，7.34(d，J＝7.5Hz，1H)，7.30(d，J＝7.5Hz，1H)，7.22(t，J＝7.5Hz，1H)，7.12(t，J＝7.5Hz，1H)，4.63(d，J＝4.7Hz，1H)，4.46(m，J＝6.0Hz，1H)，4.27(m，J＝5.6Hz，1H)，4.18(m，J＝5.7Hz，1H)，3.94(m，J＝4.8Hz，2H)，3.24(m，J＝4.7Hz，1H)，3.18(dd，J＝15.2Hz，J＝10.3Hz，2H)，2.22(d，J＝4.8Hz，2H)，2.17(t，J＝4.6Hz，2H)，1.87(m，J＝4.7Hz，2H)，1.65(t，J＝4.5Hz，2H)，1.45(d，J＝5.2Hz，3H)。
Embodiment 25.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 4-methylvaleric acid (5Ca)
According to the operation of embodiment 19, from 241mg (0.5mmol) 4Ca) get 224mg (99%) title compound, be colorless solid.Mp 189-191℃，ESI-MS(m/e)453[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.22(s，1H)，8.65(s，1H)，7.47(d，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.24(t，J＝7.5Hz，1H)，7.13(t，J＝7.5Hz，1H)，4.98(t，J＝6.4Hz，1H)，4.64(t，J＝4.8Hz，1H)，4.26(m，J＝5.5Hz，1H)，4.15(m，J＝5.6Hz，1H)，3.92(m，J＝4.6Hz，2H)，3.22(m，J＝4.7Hz，1H)，3.16(dd，J＝15.6Hz，J＝11.0Hz，2H)，2.22(d，J＝4.9Hz，2H)，2.20(t，J＝4.5Hz，2H)，1.91(m，J＝4.6Hz，2H)，1.73(m，J＝4.2Hz，1H)，1.69(t，J＝4.5Hz，2H)，1.65(m，J＝4.6Hz，2H)，1.63(d，J＝4.3Hz，3H)，1.60(t，J＝4.4Hz，3H)。
Embodiment 26.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 4-methylvaleric acid (5Cb)
According to the operation of embodiment 19, from 241mg (0.5mmol) 4Ca) get 223mg (99%) title compound, be colorless solid.Mp 128-130℃，ESI-MS(m/e)453[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝10.90(s，1H)，8.62(s，1H)，7.52(d，J＝7.6Hz，1H)，7.33(d，J＝7.6Hz，1H)，7.26(t，J＝7.7Hz，1H)，7.15(t，J＝7.7Hz，1H)，4.96(t，J＝5.5Hz，1H)，4.58(d，J＝5.7Hz，1H)，4.45(dd，J＝8.0Hz，J＝4.5Hz，1H)，4.39(t，J＝6.2Hz，1H)，3.97(m，J＝5.5Hz，1H)，3.95(dd，J＝14.2Hz，J＝4.4Hz，1H)，3.52(dd，J＝15.2Hz，J＝11.3Hz，2H)，3.24(m，J＝4.7Hz，2H)，3.17(m，J＝6.1Hz，1H)，2.25(t，J＝4.7Hz，2H)，1.85(m，J＝4.5Hz，2H)，1.72(m，J＝4.8Hz，2H)，1.69(m，J＝4.3Hz，1H)，1.66(m，J＝4.6Hz，2H)，1.44(d，J＝4.3Hz，3H)，1.40(t，J＝4.4Hz，3H)。
Embodiment 27.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 "; 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-and pyrido-[3,4-b]-indoles-12-base ethylamino]-1, the preparation of 4-Succinic Acid (5Da)
According to the operation of embodiment 19, from 241mg (0.5mmol) 4Da) get 224mg (99%) title compound, be colorless solid.Mp 228-230℃，ESI-MS(m/e)469[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.92(s，1H)，11.46(s，1H)，8.75(s，1H)，7.52(d，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.26(t，J＝7.6Hz，1H)，7.16(t，J＝7.5Hz，1H)，4.95(d，J＝5.5Hz，1H)，4.48(d，J＝5.9Hz，1H)，4.44(dd，J＝8.1Hz，J＝4.4Hz，1H)，4.36(t，J＝6.2Hz，1H)，3.92(m，J＝5.5Hz，1H)，3.90(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.52(dd，J＝15.8Hz，J＝11.7Hz，2H)，3.24(m，J＝4.8Hz，2H)，3.16(m，J＝6.1Hz，1H)，2.36(d，J＝5.1Hz，2H)，2.27(t，J＝4.6Hz，2H)，1.90(m，J＝4.5Hz，2H)，1.85(m，J＝4.8Hz，2H)。
Embodiment 28.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 "; 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-and pyrido-[3,4-b]-indoles-12-base ethylamino]-1, the preparation of 4-Succinic Acid (5Db)
According to the operation of embodiment 19, get 226mg (99%) title compound from 241mg (0.5mmol) 4Db, be colorless solid.Mp 220-222℃，ESI-MS(m/e)469[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.40(s，1H)，11.25(s，1H)，8.59(s，1H)，7.58(d，J＝7.5Hz，1H)，7.39(d，J＝7.5Hz，1H)，7.26(t，J＝7.6Hz，1H)，7.17(t，J＝7.5Hz，1H)，4.98(d，J＝5.5Hz，1H)，4.54(d，J＝5.9Hz，1H)，4.45(dd，J＝8.1Hz，J＝4.4Hz，1H)，4.39(t，J＝6.2Hz，1H)，3.92(m，J＝5.5Hz，1H)，3.90(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.56(dd，J＝15.0Hz，J＝11.1Hz，2H)，3.24(m，J＝4.8Hz，2H)，3.17(m，J＝6.1Hz，1H)，2.36(d，J＝5.1Hz，2H)，2.27(t，J＝4.6Hz，2H)，1.93(m，J＝4.5Hz，2H)，1.90(m，J＝4.8Hz，2H)。
Embodiment 29.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-phenylpropionic acid (5Ea)
According to the operation of embodiment 19, get 240mg (98%) title compound from 235mg (0.5mmol) 4Ea, be colorless solid.Mp 181-183℃，ESI-MS(m/e)487[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.06(s，1H)，8.45(s，1H)，7.47(d，J＝7.5Hz，1H)，7.42(d，J＝7.5Hz，1H)，7.37(d，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，7.24(d，J＝7.5Hz，2H)，7.13(t，J＝7.5Hz，1H)，6.96(t，J＝7.5Hz，2H)，4.98(t，J＝6.1Hz，1H)，4.66(d，J＝4.6Hz，1H)，4.25(m，J＝5.5Hz，1H)，4.16(m，J＝5.6Hz，1H)，3.92(m，J＝4.6Hz，2H)，3.25(m，J＝4.8Hz，1H)，3.24(s，2H)，3.16(dd，J＝15.5Hz，J＝11.1Hz，2H)，2.24(d，J＝4.8Hz，2H)，2.20(t，J＝4.5Hz，2H)，1.90(m，J＝4.8Hz，2H)，1.88(t，J＝4.6Hz，2H)。
Embodiment 30.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-phenylpropionic acid (5Eb)
According to the operation of embodiment 19, get 242mg (98%) title compound from 235mg (0.5mmol) 4Eb, be colorless solid.Mp 187-189℃，ESI-MS(m/e)487[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.02(s，1H)，8.57(s，1H)，7.63(d，J＝7.5Hz，1H)，7.58(d，J＝7.5Hz，1H)，7.49(d，J＝7.5Hz，1H)，7.36(t，J＝7.5Hz，1H)，7.25(t，J＝7.5Hz，1H)，7.21(d，J＝7.5Hz，2H)，6.95(t，J＝7.5Hz，2H)，4.94(d，J＝5.6Hz，1H)，4.54(d，J＝5.7Hz，1H)，4.45(dd，J＝8.1Hz，J＝4.6Hz，1H)，4.37(t，J＝6.1Hz，1H)，3.94(m，J＝5.5Hz，1H)，3.92(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.52(dd，J＝15.1Hz，J＝11.2Hz，2H)，3.24(m，J＝4.5Hz，2H)，3.17(s，2H)，3.15(m，J＝6.1Hz，1H)，2.24(t，J＝4.5Hz，2H)，1.92(m，J＝4.5Hz，2H)，1.90(m，J＝4.7Hz，2H)。
Embodiment 31.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-hydroxy-propionic acid (5Fa)
According to the operation of embodiment 19, get 242mg (98%) title compound from 235mg (0.5mmol) 4Fa, be colorless solid.Mp 228-230℃，ESI-MS(m/e)427[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.78(s，1H)，8.65(s，1H)，7.48(d，J＝7.5Hz，1H)，7.42(d，J＝7.5Hz，1H)，7.30(t，J＝7.5Hz，1H)，7.12(t，J＝7.5Hz，1H)，4.96(t，J＝6.1Hz，1H)，4.64(d，J＝4.9Hz，1H)，4.25(m，J＝5.6Hz，1H)，4.14(m，J＝5.7Hz，1H)，4.04(s，1H)，3.96(m，J＝4.7Hz，2H)，3.79(d，J＝5.6Hz，2H)，3.25(m，J＝4.7Hz，1H)，3.18(dd，J＝15.7Hz，J＝11.0Hz，2H)，2.25(d，J＝4.8Hz，2H)，2.23(t，J＝4.5Hz，2H)，1.94(m，J＝4.8Hz，2H)，1.88(t，J＝4.4Hz，2H)。
Embodiment 32.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-hydroxy-propionic acid (5Fb)
According to the operation of embodiment 19, get 244mg (98%) title compound from 235mg (0.5mmol) 4Fb, be colorless solid.Mp 233-235℃，ESI-MS(m/e)427[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.82(s，1H)，8.57(s，1H)，7.55(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.26(t，J＝7.5Hz，1H)，7.12(t，J＝7.5Hz，1H)，4.95(d，J＝5.5Hz，1H)，4.55(d，J＝5.7Hz，1H)，4.46(dd，J＝8.2Hz，J＝4.6Hz，1H)，4.37(t，J＝6.1Hz，1H)，4.07(s，1H)，3.96(m，J＝5.5Hz，1H)，3.92(dd，J＝14.0Hz，J＝4.6Hz，1H)，3.77(d，J＝5.6Hz，2H)，3.55(dd，J＝15.6Hz，J＝11.7Hz，2H)，3.24(m，J＝4.6Hz，2H)，3.16(m，J＝6.1Hz，1H)，2.28(t，J＝4.7Hz，2H)，1.92(m，J＝4.6Hz，2H)，1.87(m，J＝4.8Hz，2H)。
Embodiment 33.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-(indol-3-yl-) propionic acid (5Ga)
According to the operation of embodiment 19, get 258mg (98%) title compound from 270mg (0.5mmol) 4Ga, be colorless solid.Mp 150-152℃，ESI-MS(m/e)526[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.03(s，1H)，8.77(s，1H)，8.65(s，1H)，7.54(d，J＝7.5Hz，1H)，7.51(d，J＝7.5Hz，1H)，7.46(d，J＝7.5Hz，1H)，7.42(d，J＝7.5Hz，1H)，7.37(t，J＝7.5Hz，1H)，7.34(t，J＝7.5Hz，1H)，7.24(t，J＝7.5Hz，1H)，7.18(t，J＝7.5Hz，1H)，6.91(s，1H)，4.97(t，J＝6.1Hz，1H)，4.65(d，J＝4.9Hz，1H)，4.25(m，J＝5.7Hz，1H)，4.16(m，J＝5.6Hz，1H)，3.96(m，J＝4.8Hz，2H)，3.75(d，J＝5.1Hz，2H)，3.24(m，J＝4.6Hz，1H)，3.15(dd，J＝15.1Hz，J＝10.9Hz，2H)，2.27(d，J＝4.8Hz，2H)，2.24(t，J＝4.5Hz，2H)，1.92(m，J＝4.8Hz，2H)，1.87(t，J＝4.7Hz，2H)。
Embodiment 34.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 3-(indol-3-yl-) propionic acid (5Gb)
According to the operation of embodiment 19, get 259mg (98%) title compound from 270mg (0.5mmol) 4Gb, be colorless solid.Mp 233-235℃，ESI-MS(m/e)526[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl3，300MHz)δ＝11.06(s，1H)，8.54(s，1H)，8.41(s，1H)，7.68(d，J＝7.5Hz，1H)，7.54(d，J＝7.5Hz，1H)，7.40(d，J＝7.5Hz，1H)，7.37(d，J＝7.5Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.26(t，J＝7.5Hz，1H)，7.23(t，J＝7.5Hz，1H)，7.20(t，J＝7.5Hz，1H)，6.91(s，1H)，4.98(d，J＝5.4Hz，1H)，4.55(d，J＝5.7Hz，1H)，4.46(dd，J＝8.1Hz，J＝4.3Hz，1H)，4.36(t，J＝6.1Hz，1H)，3.95(m，J＝5.5Hz，1H)，3.92(dd，J＝14.0Hz，J＝4.3Hz，1H)，3.84(d，J＝5.7Hz，2H)，3.53(dd，J＝15.7Hz，J＝11.6Hz，2H)，3.24(m，J＝4.7Hz，2H)，3.17(m，J＝6.1Hz，1H)，2.23(t，J＝4.7Hz，2H)，1.92(m，J＝4.5Hz，2H)，1.87(m，J＝4.7Hz，2H)。
Embodiment 35.2-[2-(5aS, 12R, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 2-(the amino butyl of 4--1-yl) acetate (5Ha)
According to the operation of embodiment 19, get 229mg (98%) title compound from 241mg (0.5mmol) 4Ha, be colorless solid.Mp 186-188℃，ESI-MS(m/e)468[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.52(s，1H)，8.78(s，1H)，7.56(d，J＝7.5Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.27(t，J＝7.5Hz，1H)，7.16(t，J＝7.4Hz，1H)，4.76(t，J＝6.0Hz，1H)，4.65(d，J＝4.8Hz，1H)，4.25(m，J＝5.5Hz，1H)，4.16(m，J＝5.8Hz，1H)，3.94(m，J＝4.9Hz，2H)，3.25(t，J＝4.9Hz，2H)，3.16(dd，J＝15.9Hz，J＝11.3Hz，2H)，2.79(s，1H)，2.28(d，J＝4.9Hz，2H)，2.25(t，J＝4.4Hz，2H)，1.96(m，J＝4.9Hz，2H)，1.93(m，J＝4.7Hz，2H)，1.87(t，J＝4.5Hz，2H)，1.78(m，J＝4.7Hz，2H)，1.68(m，J＝5.2Hz，2H)，1.65(m，J＝5.2Hz，2H)。
Embodiment 36.2-[2-(5aS, 12S, 14aS)-5,14-dioxy-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, the 14H-pyrrolo--[1 ", 2 ": 4 ', 5 ']-pyrazine is also-[1 ', 2 ': 1,6]-pyrido-[3,4-b]-indoles-12-base ethylamino]-preparation of 2-(the amino butyl of 4--1-yl) acetate (5Hb)
According to the operation of embodiment 19, get 231mg (98%) title compound from 241mg (0.5mmol) 4Hb, be colorless solid.Mp 216-218℃，ESI-MS(m/e)468[M+H]
+.
(c＝0.35，CHCl
3/CH
3OH，1∶1，v/v).
1H-NMR(CDCl
3，300MHz)δ＝11.18(s，1H)，8.74(s，1H)，7.52(d，J＝7.5Hz，1H)，7.41(d，J＝7.5Hz，1H)，7.21(t，J＝7.5Hz，1H)，7.11(t，J＝7.4Hz，1H)，4.67(d，J＝4.8Hz，1H)，4.55(t，J＝6.0Hz，1H)，4.24(m，J＝5.5Hz，1H)，4.18(m，J＝5.8Hz，1H)，3.95(m，J＝4.9Hz，2H)，3.27(t，J＝4.9Hz，2H)，3.16(dd，J＝15.6Hz，J＝11.1Hz，2H)，2.78(s，1H)，2.26(d，J＝4.9Hz，2H)，2.23(t，J＝4.4Hz，2H)，1.94(m，J＝4.9Hz，2H)，1.95(m，J＝4.7Hz，2H)，1.88(t，J＝4.5Hz，2H)，1.76(m，J＝4.7Hz，2H)，1.69(m，J＝5.2Hz，2H)，1.65(m，J＝5.2Hz，2H)。
The anti-tumor activity test of test example 1 The compounds of this invention
One, test materials
1, for test agent: the sample that the embodiment of the invention is prepared, use the RPMI-1640 that contains 10% foetal calf serum to be mixed with the detected solution of desired concn
2, reagent: four tetrazolium bromides (MTT) are dissolved in that to make concentration among the PBS be 5mg/mL, filtration sterilization, and 4 ℃ keep in Dark Place.SRB is made into 0.4% solution with 1% acetic acid, and 4 ℃ keep in Dark Place.Contain 8.2gNaCl in every liter of PBS solution, 0.20g KCl, 1.56g Na
2HPO
4H
2O and 0.2g KH
2PO
4, pH7.4.The RPMI-1640 substratum is prepared routinely.
3, cell: Bel-7402, Kb and Hela (from Department Of Medicine, Peking University's preclinical medicine institute pharmacology department)
Two, test method and result
Growth conditions is good, concentration is 1 * 10
4Individual/mL, as to be in logarithmic phase Bel-7402, Kb and Hela cell inoculation be in 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the incubator.Abandon old liquid, renew nutrient solution, add sterilising treatment compound solution of the present invention, cultivated 48 hours again.Discarding nutrient solution, every hole adds RPMI-1640 (containing 10% calf serum) nutrient solution (5mg/ml) that 20ml contains four tetrazolium bromides, cultivates 4 hours, the centrifugal 20min of 2500rpm, sucking-off supernatant liquor, room temperature again and dry.Add a certain amount of dmso solution in the residue, purple solution is measured absorption value with microplate reader in 570nm, and the antitumour activity of compound sees Table 1-3 with the absorption value of measuring (A) by cell inhibitory rate=(1-treatment group A/ control group A) * 100% calculation result.
Table 1 compound of the present invention is to the restraining effect (inhibiting rate %) of Hela tumour cell
| Comp. | Concentration is the inhibiting rate (%) when 10,1,0.1 μ mol/l respectively | ||
| 10μmol/l | 1μmol/l | 0.1μmol/l | |
| 5Aa | 82.98 | 75.45 | 52.16 |
| 5Ab | 84.56 | 78.45 | 50.81 |
| 5Ba | 68.23 | 43.51 | 29.55 |
| 5Bb | 69.12 | 45.00 | 28.43 |
| 5Ca | 43.15 | 27.41 | 9.36 |
| 5Cb | 41.12 | 30.10 | 28.55 |
| 5Da | 45.13 | 29.34 | 15.41 |
| 5Db | 43.22 | 31.10 | 25.14 |
| 5Ea | 91.44 | 77.22 | 46.15 |
| 5Eb | 89.70 | 68.15 | 44.23 |
| 5Fa | 78.54 | 54.33 | 35.66 |
| 5Fb | 80.37 | 56.71 | 40.11 |
| 5Ga | 28.11 | 15.32 | -12.23 |
| 5Gb | 26.51 | 14.35 | -12.11 |
| 5Ha | 79.58 | 61.41 | 43.65 |
| 5Hb | 81.22 | 60.15 | 44.23 |
Table 2 compound of the present invention is to the restraining effect (inhibiting rate %) of HepG2 tumour cell
| Comp. | Concentration is the inhibiting rate (%) when 10,1,0.1 μ mol/l respectively | ||
| 10μmol/l | 1μmol/l | 0.1μmol/l | |
| 5Aa | 80.22 | 69.81 | 41.02 |
| 5Ab | 82.31 | 68.00 | 43.31 |
| 5Ba | 60.24 | 38.15 | 19.07 |
| 5Bb | 65.45 | 41.36 | 25.01 |
| 5Ca | 40.01 | 25.11 | 12.32 |
| 5Cb | 32.25 | 19.00 | -9.89 |
| 5Da | 39.55 | 16.36 | -7.88 |
| 5Db | 34.42 | 18.40 | 9.65 |
| 5Ea | 87.98 | 73.22 | 40.14 |
| 5Eb | 85.35 | 60.11 | 39.17 |
| 5Fa | 75.61 | 52.07 | 33.86 |
| 5Fb | 72.89 | 50.11 | 34.55 |
| 5Ga | 29.33 | 13.44 | -10.66 |
| 5Gb | 22.87 | 10.10 | -10.11 |
| 5Ha | 75.19 | 54.21 | 37.41 |
| 5Hb | 74.51 | 55.33 | 34.99 |
Table 3 compound of the present invention is to the restraining effect (inhibiting rate %) of MCF-7 tumour cell
| Comp. | Concentration is the inhibiting rate (%) when 10,1,0.1 μ mol/l respectively | ||
| 10μmol/l | 1μmol/l | 0.1μmol/l | |
| 5Aa | 79.36 | 68.25 | 44.12 |
| 5Ab | 77.33 | 65.21 | 43.55 |
| 5Ba | 62.32 | 38.99 | 25.88 |
| 5Bb | 64.48 | 40.59 | 20.28 |
| 5Ca | 39.87 | 23.98 | -13.58 |
| 5Cb | 37.86 | 19.89 | 11.22 |
| 5Da | 41.36 | 25.96 | -9.96 |
| 5Db | 37.88 | 22.30 | 12.28 |
| 5Ea | 86.67 | 60.10 | 42.12 |
| 5Eb | 82.51 | 55.00 | 38.99 |
| 5Fa | 70.99 | 45.35 | 29.94 |
| 5Fb | 75.11 | 52.63 | 38.65 |
| 5Ga | 29.96 | 19.99 | -10.67 |
| 5Gb | 22.62 | 7.85 | -13.38 |
| 5Ha | 72.46 | 53.60 | 38.78 |
| 5Hb | 76.79 | 50.19 | 33.33 |
Test-results shows that The compounds of this invention has stronger anti-tumor activity.
Claims (10)
1, a kind of Aspergillus fumigatus dardarin C analogue has the structure of following general formula I and I ' compound:
Wherein R is amino acid whose side chain of L-or hydrogen, R
1Be OH or OCH
3
2, according to the Aspergillus fumigatus dardarin C analogue of claim 1, it is characterized in that: described L-amino acid side chain is-CH
3,-CH
2CH (CH
3)
2,-CH
2COOH ,-CH
2C
6H
5,-CH
2OH, indol-3-yl-CH
2Or-(CH
2)
3NH
2.
3, a kind of pharmaceutical composition with anti-tumor activity contains the compound of Formula I and the pharmaceutically acceptable carrier of the described structure of claim 1.
4, a kind of intermediate of compound of Formula I is characterized in that having the structure of following general formula I I and II '
General formula I I and II ', wherein R=CH (OCH
3)
2Or CHO.
5, the preparation method of general formula I and I ' compound may further comprise the steps:
1) with the activated state of Fmoc-Pro-OH under base catalysis will (1S/R, 3S)-(2, the 2-dimethoxy-ethyl)-1,2,3,2 acidylates of 4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester, the product after the acidylate taken off Fmoc under base catalysis in intramolecular cyclization,
2) the product heating hydrolysis under acid catalysis with gained after the step 1) cyclisation goes acetalation,
3) with step 2) go the product of acetalation gained and amino acid methyl ester hydrochloride under base catalysis dehydrating condensation after reductive agent it is reduced,
4) saponification is promptly under base catalysis with the reduzate of step 3) gained.
6, according to the described preparation method of claim 5, it is characterized in that: the activation form of Fmoc-Pro-OH can be an acyl chlorides in the step 1), acid anhydrides or active ester; Described acylation reaction is carried out under organic base catalytic; Take off the used reagent of Fmoc and be the general reagent of polypeptide in synthetic.
7, according to the described preparation method of claim 6, it is characterized in that: the activation form of Fmoc-Pro-OH is an acyl chlorides in the step 1); Described acylation reaction is to carry out under diisopropyl ethyl amine catalysis; Taking off the used reagent of Fmoc reaction is diethylamine.
8, according to the described preparation method of claim 5, it is characterized in that: the catalysis alkali of the dehydration condensation in the step 3) is organic bases; Dewatering is azeotropic dehydration or dewaters with dewatering agent; Dewatered product reduces through reductive agent, and used reductive agent is common reductive agent.
9, according to the described preparation method of claim 8, it is characterized in that: the catalysis alkali of the dehydration condensation in the step 3) is triethylamine; Dewatering is an anhydrous sodium sulfate dehydration; Dewatered product reduces through reductive agent, and reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride.
10, general formula I and the I ' compound purposes in the preparation antitumor drug:
General formula I and I ', wherein R is amino acid whose side chain of L-or hydrogen, R
1Be OH or OCH
3
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100742027A CN100494199C (en) | 2004-09-03 | 2004-09-03 | Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100742027A CN100494199C (en) | 2004-09-03 | 2004-09-03 | Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1743330A true CN1743330A (en) | 2006-03-08 |
| CN100494199C CN100494199C (en) | 2009-06-03 |
Family
ID=36138877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100742027A Expired - Fee Related CN100494199C (en) | 2004-09-03 | 2004-09-03 | Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100494199C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250202A (en) * | 2010-05-19 | 2011-11-23 | 首都医科大学 | 1-paranitrophenyl-beta-carboline-3-formyl amine acid carbamates and synthesis method and use thereof |
| CN102260259A (en) * | 2010-05-27 | 2011-11-30 | 首都医科大学 | Pyrrolidine-pymetrozine-[1-(N-ethyl amino acid)-tetrahydro-beta-carboline] and its synthetic method and application |
| CN102276608A (en) * | 2011-06-27 | 2011-12-14 | 陕西科技大学 | Method for synthesizing tetrahydro-beta-carboline diketopiperazine compound |
| CN102127079B (en) * | 2010-01-15 | 2012-09-19 | 首都医科大学 | Pyrrolo-pyrazin-carboline diketone compounds and preparation method and applications thereof |
| CN105273049A (en) * | 2014-07-03 | 2016-01-27 | 首都医科大学 | CIPPCT, preparation method thereof, nanostructure thereof, activity thereof and application thereof |
-
2004
- 2004-09-03 CN CNB2004100742027A patent/CN100494199C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127079B (en) * | 2010-01-15 | 2012-09-19 | 首都医科大学 | Pyrrolo-pyrazin-carboline diketone compounds and preparation method and applications thereof |
| CN102250202A (en) * | 2010-05-19 | 2011-11-23 | 首都医科大学 | 1-paranitrophenyl-beta-carboline-3-formyl amine acid carbamates and synthesis method and use thereof |
| CN102250202B (en) * | 2010-05-19 | 2013-08-28 | 首都医科大学 | 1-paranitrophenyl-beta-carboline-3-formyl amine acid carbamates and synthesis method and use thereof |
| CN102260259A (en) * | 2010-05-27 | 2011-11-30 | 首都医科大学 | Pyrrolidine-pymetrozine-[1-(N-ethyl amino acid)-tetrahydro-beta-carboline] and its synthetic method and application |
| CN102276608A (en) * | 2011-06-27 | 2011-12-14 | 陕西科技大学 | Method for synthesizing tetrahydro-beta-carboline diketopiperazine compound |
| CN102276608B (en) * | 2011-06-27 | 2012-12-19 | 陕西科技大学 | Method for synthesizing tetrahydro-beta-carboline diketopiperazine compound |
| CN105273049A (en) * | 2014-07-03 | 2016-01-27 | 首都医科大学 | CIPPCT, preparation method thereof, nanostructure thereof, activity thereof and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100494199C (en) | 2009-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1199959C (en) | Percyquinnin, Process for its production and its use pharmaceutical | |
| CN1095835C (en) | Derivatives of tricyclo-substituted isohydroxyloxime acid | |
| CN1066445C (en) | Aroyl-piperidine derivatives | |
| JP5021711B2 (en) | Hepatitis C inhibitor tripeptide | |
| CN1708495A (en) | Heterocyclic compounds and antitumor drugs containing the same as the active ingredient | |
| CN1712399A (en) | Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer | |
| CN1743330A (en) | Aspergillus fumigatus dardarin C analogue, and its synthesizing method and use | |
| CN1184209C (en) | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof | |
| CN1736986A (en) | Polyhydroxy stilbenes compound preparation and uses as drugs for suppressing SARS | |
| Brockmeyer et al. | Two sequential multicomponent reactions: synthesis of thiazolidin-4-yl-1, 3, 4-oxadiazoles under mild conditions | |
| CN1199045A (en) | Substituted 6- and 7-aminotetrahydroisoquinolinecarboxylic acids | |
| CN102378751A (en) | Improved method for preparing dipeptidyl peptidase-iv inhibitor and intermediate | |
| CN111393459B (en) | SHP2 inhibitor and application thereof | |
| CN1313766A (en) | DNA-cleaving antitumor agents | |
| CN1743327A (en) | Indole alkaloid derivative, and its preparing method and use | |
| CN102532080A (en) | Novel sialic acid derivant, preparation method thereof, drug composite comprising the same and application thereof | |
| CN106905193A (en) | Aroyl guanidine radicals Oseltamivir carboxylic acid derivates and its preparation method and application | |
| CN1255121A (en) | Selective epoxidation process for preparing pharmaceutical compounds | |
| CN1712408A (en) | Dicycloalcohol glucoside compound its production and use | |
| Lin et al. | Improved synthesis of rupintrivir | |
| CN1155590C (en) | Chromone compounds with antineoplastic activity and its open-loop products and preparing process | |
| CN1636997A (en) | Substituted tricyclocoumarin compound and its prepn and anti-HIV application | |
| CN100510098C (en) | Optically active, heteroaromatic beta-hydroxy esters, processes for their preparation from beta-keto esters and processes for the preparation of these beta-keto esters | |
| CN101077866A (en) | Substituted benzoxazoles antifungal compounds and preparation method thereof | |
| CN101062925A (en) | Paclitaxel derivatives, preparation method and medicinal composition and usage thereof |
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 |
Granted publication date: 20090603 Termination date: 20140903 |
|
| EXPY | Termination of patent right or utility model |