CN103483414B - A kind of 4-aza sterides purine nucleoside analogs and preparation thereof, application - Google Patents
A kind of 4-aza sterides purine nucleoside analogs and preparation thereof, application Download PDFInfo
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- CN103483414B CN103483414B CN201310387010.0A CN201310387010A CN103483414B CN 103483414 B CN103483414 B CN 103483414B CN 201310387010 A CN201310387010 A CN 201310387010A CN 103483414 B CN103483414 B CN 103483414B
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Abstract
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of nucleoside analog, be specifically related to a kind of 4-aza sterides purine nucleoside analogs and preparation thereof, application. This 4-aza sterides purine nucleoside analogs has following general formula:
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of nucleoside analog, be specifically related to a kind of 4-aza sterides purine nucleoside analogs and preparation thereof, application.
Background technology
Nucleoside analog be a class important there is anticancer and compound antiviral activity, comprise the derivative of various purine and pyrimidine nucleoside. Nucleoside analog is mainly a class antimetabolite, thereby plays the effect of inhibition tumor cell and viral growth by interference cell DNA or rna replicon, the synthetic relevant enzyme of inhibition nucleic acid etc. Treatment from first nucleoside medicine iodoxuridine for bleb, to the application of the acyclic nucleosides such as ACV, has promoted the exploitation of uncleosides as antiviral agents. From early stage floxuridine to the novel anti-cancer chemotherapeutic agents gemcitabine of developing in recent years, nucleoside compound has been brought into play important function in antitumor field. Along with the development of the related disciplines such as chemistry, biology, pharmacology, by the structure of modification to nucleoside analog, being constantly developed of new nucleoside compound.
The structure of modification of nucleosides can be set about from sugar ring and base two parts as basis taking the molecular structure of natural nucleus glycoside. Compared with the transformation result of base, more to the transformation site of sugared loop section, and obtained the activated derivative of a lot of tools. By the transformation to glycosyl, can filter out drug effect, the pharmacological properties of more highly active medicine and improvement known drug, and reduce toxic and side effect. The nucleoside medicine of most of clinical practice is all the derivative of glycosyl transformation, if the hematologic cancers medicinal applications such as fludarabine and conduct treatment of carat Qu Bin chronic lymphatic hemophilia are in clinical.
The nucleoside compound of glycosyl part transformation, because having good antitumor, antiviral activity, has caused that medicine scholar pays close attention to widely, and the nucleoside analog of various novel structures is reported in succession. But the nucleoside analog research using steroidal as glycosyl donor is few. Recently, we have reported a kind of novel steroidal purine nucleoside analogs, and in its molecule, 4-aza sterides D ring is transformed into the pyranoid ring (BioorgMedChemLett, 2011,21:6203 – 6205) of similar pyranose structure. Preliminary evaluated biological activity discovery, it is active that this series compound has good inhibition to reproductive system cancer cell. But the steroidal nucleoside analog quantity directly obtaining by the method very little, is not enough to it to carry out further structure activity study.
Summary of the invention
The object of the present invention is to provide a kind of 4-aza sterides purine nucleoside analogs, preparation method and the application of this 4-aza sterides purine nucleoside analogs are provided simultaneously.
The present invention is by the following technical solutions:
A kind of 4-aza sterides purine nucleoside analogs, has following general formula:
The piperazinyl replacing is mainly the piperazinyl that N-replaces, and can be also the piperazinyl of other positions replacements.
Preparing the method for 4-aza sterides purine nucleoside analogs, is that chlorine atom, 2-position are R by purine 6-position1Steroidal nucleosides precursor be placed in alcoholic solvent, add triethylamine and corresponding ring-type secondary amine, back flow reaction 5-30min, post processing can obtain 4-aza sterides purine nucleoside analogs.
The mol ratio of secondary amine and steroidal nucleosides precursor is 1.0-1.2:1; The mol ratio of triethylamine and steroidal nucleosides precursor is 1.0-1.2:1; The amount of the steroidal nucleosides precursor alcoholic solvent used of 1mmol is 10-20mL.
Alcoholic solvent used is methyl alcohol, ethanol, isopropyl alcohol, the tert-butyl alcohol or n-butanol; Ring-type secondary amine used is the piperazine of pyrrolidines, piperidines, morpholine, piperazine and replacement.
Last handling process is that decompression distillation, carrene dissolve, washing, dry, concentrated.
4-aza sterides purine nucleoside analogs is in the application of preparing on antineoplastic.
Steroidal nucleosides precursor is:。
Synthetic route is as follows:
4-aza sterides purine nucleoside analogs of the present invention has obvious inhibitory action to the cell line such as prostate cancer, cervical carcinoma, can be used in and prepare antineoplastic, there is potential medicinal application and be worth, for a kind new medicine of developing one's own intellectual property is had laid a good foundation.
4-aza sterides purine nucleoside analogs of the present invention by its steroidal nucleosides precursor (a-c) make by 6 chlorine atoms of ring-type secondary amine substituted purin, preparation method is simple, mild condition, and yield is high.
Detailed description of the invention
Enumerate the compound in table 1:
Embodiment 1:Prepare shown in general formula R in table 11For hydrogen atom, R2For the compound 1 of piperazinyl
Get compounda(0.2mmol) be dissolved in methyl alcohol (3mL), add triethylamine (0.24mmol) and piperazine (0.24mmol), be warming up to backflow, about 5min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 1, yield 91%.
mp272-273℃;1HNMR(400MHz,CDCl3):δ8.34(s,1H,2′-H),7.96(s,1H,8′-H),6.13(m,2H,4N-Hand17β-H),4.37(s,4H,protonsofpiperazine),3.07(dd,J=12.2,3.3Hz,1H,5α-H),3.03–2.91(m,4H,protonsofpiperazine),0.89(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.18,153.88,152.33,150.03,136.08,119.76,77.64,76.12,60.31,50.64,48.93,46.30,39.18,36.06,35.76,33.51,33.19,28.52,28.25,27.10,21.87,21.51,16.46,11.30.HRMS(ESI):m/zcacldforC27H40N7O2(M+H)+,494.3243;found,494.3241.
Embodiment 2:Prepare shown in general formula R in table 11For chlorine atom, R2For the compound 8 of N-isopropyl piperazinyl
Get compoundb(0.2mmol) be dissolved in ethanol (3mL), add triethylamine (0.24mmol) and N-isopropyl piperazine (0.24mmol), be warming up to backflow, about 10min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 8, yield 95%.
mp254-255℃;1HNMR(400MHz,CDCl3):δ7.91(s,1H,8′-H),6.17(brs,1H,4N-H),6.04(dd,J=11.2,2.5Hz,1H,17β-H),4.20(brs,4H,protonsofpiperazine),3.06(dd,J=12.1,2.7Hz,1H,5α-H),2.84–2.67(m,1H,-NCH(CH3)2),2.67–2.56(m,4H,protonsofpiperazine),1.07(d,J=6.5Hz,6H,-NCH(CH 3)2),0.89(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.18,153.82,153.72,151.18,136.38,118.54,77.72,76.34,60.30,54.60,50.68,48.97,48.73,39.20,36.06,35.76,33.66,33.20,28.50,28.24,27.08,21.85,21.37,18.38,16.53,11.29.HRMS(ESI):m/zcacldforC30H45ClN7O2(M+H)+,570.3323;found,570.3322.
Embodiment 3:Prepare shown in general formula R in table 11For chlorine atom, R2For the compound 11 of N-benzyl piperazine base
Get compoundb(0.2mmol) be dissolved in methyl alcohol or (3mL) in, add triethylamine (0.24mmol) and N-benzyl piperazine (0.24mmol), be warming up to backflow, about 10min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 11, yield 92%.
mp183-187℃;1HNMR(400MHz,CDCl3):δ7.91(s,1H,8′-H),7.35(m,5H,Ar-H),6.05(dd,J=11.2,2.4Hz,1H,17β-H),5.91(m,1H,4N-H),4.21(brs,4H,protonsofpiperazine),3.57(s,2H,ArCH 2N-),3.08(dd,J=12.3,3.4Hz,1H,5α-H),2.61–2.54(m,4H,protonsofpiperazine),0.90(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.07,153.80,151.19,137.61,136.38,129.21,128.32,128.24,127.25,118.58,77.72,76.35,63.04,60.32,53.09,50.68,48.98,39.21,36.07,35.81,33.67,33.22,28.53,28.26,27.16,21.87,21.38,16.54,11.30.HRMS(ESI):m/zcacldforC34H45ClN7O2(M+H)+,618.3323;found,618.3325.
Embodiment 4:Prepare shown in general formula R in table 11For hydrogen atom, R2For the compound 16 of N-Phenylpiperazinyl
Get compounda(0.2mmol) be dissolved in ethanol (3mL), add triethylamine (0.24mmol) and N-phenylpiperazine (0.24mmol), be warming up to backflow, about 5min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 16, yield 92%.
mp239-240℃;1HNMR(400MHz,CDCl3):δ8.37(s,1H,2′-H),7.98(s,1H,8′-H),7.29(t,J=8.0Hz,2H,Ar-H),6.98(d,J=8.0Hz,2H,Ar-H),6.90(t,J=7.3Hz,1H,Ar-H),6.12(dd,J=11.3,2.6Hz,1H,17β-H),5.85(s,1H,4N-H),4.46(s,4H,protonsofpiperazine),3.36–3.24(m,4H,protonsofpiperazine),3.07(dd,J=12.3,3.7Hz,1H,5α-H),0.89(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.07,153.76,152.36,151.24,150.10,136.33,129.23,120.29,119.88,116.52,77.68,76.19,60.32,50.64,49.62,48.94,39.19,36.08,35.81,33.53,33.21,28.54,28.26,27.18,21.88,21.52,16.47,11.31.HRMS(ESI):m/zcacldforC33H44N7O2(M+H)+,570.3556;found,570.3553
Embodiment 5:Prepare shown in general formula R in table 11For chlorine atom, R2For the compound 26 of N-(2-pyrimidine radicals) piperazinyl
Get compoundb(0.2mmol) be dissolved in isopropyl alcohol (3mL), add triethylamine (0.24mmol) and N-(2-pyrimidine radicals) piperazine (0.24mmol), be warming up to backflow, about 15min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 26, yield 95%.
mp256-257℃;1HNMR(400MHz,CDCl3):δ8.35(d,J=4.6Hz,2H,protonsofpyrimidine),7.96(s,1H,8′-H),6.55(t,J=4.6Hz,1H,protonofpyrimidine),6.30(s,1H,4N-H),6.05(d,J=11.0Hz,1H,17β-H),4.37(brs,4H,protonsofpiperazine),3.97(s,4H,protonsofpiperazine),3.07(d,J=10.0Hz,1H,5α-H),0.89(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.24,161.62,157.76,153.99,153.80,151.31,136.67,118.72,110.35,77.75,76.42,60.32,50.70,48.98,43.73,39.22,36.07,35.75,33.65,33.20,28.52,28.26,27.04,21.86,21.37,16.53,11.29.HRMS(ESI):m/zcacldforC31H41ClN9O2(M+H)+,606.3072;found,606.3073.
Embodiment 6:Prepare shown in general formula R in table 11For hydrogen atom, R2For the compound 31 of piperidyl
Get compounda(0.2mmol) be dissolved in n-butanol (3mL), add triethylamine (0.24mmol) and piperidines (0.24mmol), be warming up to backflow, about 20min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 31, yield 90%.
mp266-267℃;1HNMR(400MHz,CDCl3):δ8.31(s,1H,2′-H),7.93(s,1H,8′-H),6.21–5.99(m,2H,4N-Hand17β-H),4.22(s,4H,protonsofpiperidine),3.04(dd,J=12.3,3.4Hz,1H,5α-H),0.87(s,3H,19-H).13CNMR(100MHz,CDCl3):δ172.17,153.82,152.42,149.90,135.73,119.65,77.58,76.06,60.31,50.65,48.94,46.39,39.19,36.07,35.76,33.51,33.21,28.53,28.25,27.11,26.15,24.84,21.87,21.53,16.47,11.30.HRMS(ESI):m/zcacldforC28H41N6O2(M+H)+,493.3291;found,493.3289.
Embodiment 7:Prepare shown in general formula R in table 11For fluorine atom, R2For the compound 36 of morpholinyl
Get compoundc(0.2mmol) be dissolved in the tert-butyl alcohol (3mL), add triethylamine (0.24mmol) and morpholine (0.24mmol), be warming up to backflow, about 10min reaction is complete; Solvent evaporated, carrene for product (10mL) dissolves, and then uses distilled water (1mL × 2) washing, anhydrous Na2SO4Dry, solvent evaporated obtains white solid compound 36, yield 91%.
mp188-190℃;1HNMR(400MHz,CDCl3):δ7.92(s,1H,8′-H),6.03(m,2H,4N-Hand17β-H),4.20(s,2H,protonsofmorpholine),3.92–3.70(m,6H,protonsofmorpholine),3.08(dd,J=12.4,3.8Hz,1H,5α-H),0.89(d,J=12.3Hz,3H).13CNMR(100MHz,CDCl3):δ172.13,157.95,154.69,151.86,136.57,117.93,77.78,76.39,66.95,60.31,50.65,48.91,44.94,39.17,36.05,35.78,33.41,33.20,28.53,28.25,27.11,21.87,21.41,16.46,11.31.HRMS(ESI):m/zcacldforC27H38FN6O3(M+H)+,513.2989;found,513.3019.
When other compou nd synthesis, identical with the synthetic method of compound in embodiment in table 1, difference is to adopt that (compound a, compound b, compound are c) corresponding to the ring-type secondary amine of structural formula and corresponding precursor.
Compound a in above embodiment is:，
Compound b is，
Compound c is。
Activity test:The test of part of compounds Anticancer Activity in vitro
Adopt mtt assay to carry out In Vitro Anti cervical cancer cell (Hela), prostate gland cancer cell (PC-3), breast cancer cell (MCF-7) test to the part 4-aza sterides purine nucleoside analogs described in table 1 of the present invention. Above-mentioned cell is inoculated in to 96 hole sterile culture plates, is placed in CO2In moist incubator, cultivate, then add the compounds of this invention of variable concentrations, carry out 3 parallel tests simultaneously, cultivate after 72h, add MTT, measure absorbance on ELIASA, the compound concentration when calculating respectively inhibition cancer cell and growing into 50%, with IC50Represent, result is as shown in table 2:
As can be seen from Table 2, the compound of surveying PC-3 is had to certain inhibition activity; Part of compounds has activity to three kinds of cells, and individual compound is remarkable to PC-3 cyto-inhibition.
Claims (6)
1. a 4-aza sterides purine nucleoside analogs, is characterized in that having following general formula:
Wherein, described R1Hydrogen atom, chlorine atom and fluorine atom; Described R2Be the piperazinyl of pyrrolidinyl, piperidyl, morpholinyl, piperazinyl or replacement, the piperazinyl of replacement is 、、、、、Or。
2. the method for preparation 4-aza sterides purine nucleoside analogs claimed in claim 1, is characterized in that, is that chlorine atom, 2-position are R by purine 6-position1Steroidal nucleosides precursor be placed in alcoholic solvent, add triethylamine and corresponding ring-type secondary amine, back flow reaction 5-30min, post processing can obtain 4-aza sterides purine nucleoside analogs; Corresponding ring-type secondary amine is the piperazine of pyrrolidines, piperidines, morpholine, piperazine and replacement.
3. the method for preparing 4-aza sterides purine nucleoside analogs as claimed in claim 2, is characterized in that, the mol ratio of secondary amine and steroidal nucleosides precursor is 1.0-1.2:1; The mol ratio of triethylamine and steroidal nucleosides precursor is 1.0-1.2:1; The amount of the steroidal nucleosides precursor alcoholic solvent used of 1mmol is 10-20mL.
4. the method for preparing as claimed in claim 2 or claim 3 4-aza sterides purine nucleoside analogs, is characterized in that, alcoholic solvent used is methyl alcohol, ethanol, isopropyl alcohol, the tert-butyl alcohol or n-butanol.
5. the method for preparing 4-aza sterides purine nucleoside analogs as claimed in claim 4, is characterized in that, last handling process is decompression distillation, dissolving, washing, dry, concentrated.
6. 4-aza sterides purine nucleoside analogs claimed in claim 1 is in the application of preparing on antineoplastic.
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| CN109293727A (en) * | 2018-10-22 | 2019-02-01 | 郑州大学 | 1- methyl purine -4- methylenandrosta-triazole derivatives, its synthetic method and application |
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