CN1876672A - Steroid imidazole salt compound and its preparing process - Google Patents
Steroid imidazole salt compound and its preparing process Download PDFInfo
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- CN1876672A CN1876672A CN 200610011025 CN200610011025A CN1876672A CN 1876672 A CN1876672 A CN 1876672A CN 200610011025 CN200610011025 CN 200610011025 CN 200610011025 A CN200610011025 A CN 200610011025A CN 1876672 A CN1876672 A CN 1876672A
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Abstract
The invention relates the novel style steroid imidazole salt compound. The invention comprises the following steps: using 3- delta5- hydroxyl steroid (cholesterin, stigmasterol, diosgenin, saponin, gestation ketenes and dehydroepiandrosterone), triethylamine, methanesulfonyl chloride, imidazole or polysubstitution imidazole as raw material, getting 1- steroid imidazole compound, then reacting with halogenating benzyl, and getting steroid imidazole salt compound. The compound has good anticancer active.
Description
Technical field: the present invention relates to novel steroid imidazole salt compound, its preparation method is the application of the pharmaceutical composition of activeconstituents at anticancer aspect with this compound.
Background technology: cancer is a class disease of serious threat human health.The main means that are used for the treatment of cancer at present are chemotherapy.The chemotherapeutics overwhelming majority of clinical application makes toxic side effect such as the patient feels sick, vomiting, leukopenia, bone marrow depression.Therefore, searching high reactivity, nontoxic or hypotoxic anticancer compound become an important topic of new drug research.
Imidazoles extensively is present in the natural product molecule as the important five member ring heterocyclic compound of a class.Imidazole ring also is present in the molecule of synthetic mycocide, weedkiller, plant-growth regulator and medicine as the important structure unit of physiologically active.Synthetic imidazole salt compound on the imidazo ring systems basis is subjected to domestic and international organic synthesis and pharmaceutical chemistry research worker's attention owing to having multiple biological activity.Up to now, studies show that imidazole salt compound has anti-tumor activity, antibacterium and antimycotic activity, anti-inflammatory activity, anti-arrhythmia activity, the synthetic enzyme inhibition activity of thrombocyte, and as oral hypoglycemia agent.With the steroidal be raw material synthetic steroid imidazole salt compound and preparation method thereof up to now document do not appear in the newspapers.
Summary of the invention:
The invention provides a series of steroid imidazole salt compounds and preparation method thereof.With 3-hydroxyl-Δ
5-steroidal; as cholesterol, Stigmasterol, diosgenin, Hecogenin, gravidity pregnenolone, dehydroepiandros-sterone etc. is raw material; after methylsulfonylization; with imidazoles reflux in dry toluene; form 1-steroid imidazole compounds, synthesized 1-steroidal-3-benzyl imidazole salt compounds with halogenation benzyl reflux in toluene on this basis.The present invention has synthesized a series of steroid imidazole salt compounds, through external antitumour activity screening and structure activity study, find the imidazole salt compound of 1-position diosgenin, gravidity pregnenolone, with commercial cancer therapy drug---cis-platinum (DDP) is compared, and has extraordinary external anticancer physiologically active.
Steroid imidazole salt compound provided by the invention is represented with following general structural formula (I) with (II):
The R=benzyl
R
1, R
2=H, aryl, alkyl
R
3=H, alkyl, carbonyl, alkoxyl group, hydroxyl, amido, alkylamino radical, aryl amine, sulfydryl, aryl
X＝Cl，Br，I，OH
A kind of preparation method with general structure (I) and compound (II), this method may further comprise the steps:
Synthesizing of A, 1-steroid imidazole compound:
1. with 3-hydroxyl-Δ
5-steroidal (as cholesterol, Stigmasterol, diosgenin, Hecogenin, gravidity pregnenolone, dehydroepiandros-sterone etc.), triethylamine, methylsulfonyl chloride are raw material, earlier synthetic 3-methanesulfonates steroidal in dichloromethane solvent.3-hydroxy steroid and triethylamine are dissolved in the dichloromethane solvent, slowly are added dropwise to methylsulfonyl chloride under ice bath (0 ℃), after dropwising, reaction is 1-4 hour under room temperature, makes 3-methanesulfonates steroidal.Each compound amount (mole ratio mol) is: 3-hydroxy steroid/triethylamine/methylsulfonyl chloride=1/2.0～2.5/1.0～1.5, the consumption of methylene dichloride are 50～200ml/g 3-hydroxy steroid.
2. be raw material with 3-methanesulfonates steroidal, imidazoles, synthetic 1-steroid imidazole compound in the dry toluene solvent.3-methanesulfonates steroidal, imidazoles are dissolved in dry toluene or 1, and 4-dioxane or tetraethoxysilane or tetrahydrofuran (THF) or 1 in the 2-ethylene dichloride solvent, stirring and refluxing 48-72 hour, make 1-steroid imidazole compound.Each compound amount (mole ratio mol) is: 3-methanesulfonates steroidal/imidazoles=1/2, and solvent is preferentially selected dry toluene for use, and its consumption is 50～200ml/g 3-methanesulfonates steroidal.
R
1, R
2,=H, aryl, alkyl
R
3=H, alkyl, carbonyl, alkoxyl group, hydroxyl, amido, alkylamino radical, aryl amine, sulfydryl, aryl
A) MsCl, Et
3N, CH
2Cl
2, 0 ℃ of b) and imidazoles, the dry toluene equal solvent refluxes
Synthesizing of B, 1-steroidal-3-benzyl imidazole salt compounds:
With 1-steroid imidazole compound and halogenation benzyl is raw material, synthetic 1-steroidal-3-benzyl imidazole salt compounds in toluene solvant.1-steroid imidazole compound is dissolved in toluene or dimethylbenzene or 1, and 4-dioxane or tetraethoxy-silicane alkane solvents stir adding halogenation benzyl down, and stirring and refluxing is spent the night, and makes 1-steroidal-3-benzyl imidazole salt compounds.Each compound amount (mole ratio mol) is: 1-steroid imidazole/halogenation benzyl=1.0/2.0～2.5, and solvent is preferentially selected toluene for use, and its consumption is 50～200ml/g 1-steroid imidazole.
The R=benzyl
R
1, R
2=H, aryl, alkyl
R
3=H, alkyl, carbonyl, alkoxyl group, hydroxyl, amido, alkylamino radical, aryl amine, sulfydryl, aryl
X＝Cl，Br，I，OH
C) PhCH
3, reflux
Above-mentioned have the medicine that general structure (I) and compound (II) and at least a pharmaceutically acceptable excipient, diluent or carrier make and can be used for treating cancer.
Embodiment: enumerate typical compound of the present invention below in conjunction with example.
Embodiment 1 1-(3 β-diosgenin)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 β-diosgenin) imidazolium compounds:
With diosgenin (4.00g, 10mmol) (3.4ml 24mmol) is dissolved in the dichloromethane solvent (400ml) with triethylamine, stir, under ice bath (0 ℃), slowly be added dropwise to methylsulfonyl chloride (1.37mg, 12mmol), after dropwising, reaction is 3 hours under room temperature.After reaction finishes, add entry (50ml), with the dilute hydrochloric acid neutralization, separate organic phase, water merges organic phase with dichloromethane extraction 3 times (20ml/ time), uses saturated NaHCO successively
3Solution behind the saturated NaCl solution washing, adds anhydrous sodium sulfate drying, removes by filter siccative, and underpressure distillation obtains crude product after removing and desolvating.
With above-mentioned crude product (5mmol), imidazoles (680mg 10mmol) is dissolved in the dry toluene solvent (200ml), stirring and refluxing 72 hours, underpressure distillation removes and desolvates, and through column chromatography for separation, obtains 1-(3 β-diosgenin) imidazolium compounds, yield 4.4%.
The preparation of (2.1-3 β-diosgenin)-3-benzyl-imidazoles bromine salt:
1-(3 β-diosgenin) imidazoles (0.2mmol) are dissolved in toluene (10ml), and adding cylite under stirring (69mg, 0.4mmol), stirring and refluxing, reacted about 72 hours, and obtained solid chemical compound, filter, for several times with toluene wash, drying gets white amorphous powder compound 1, yield 82.3%.
mp.218-220℃；IR(KBr)v
maxcm
-1：3424，3058，2950，2904，1630，1559，1455，1377，1242，1159，1053，983，899，711；
ESI-MS(m/e，％)：556([M+1-Br]
+，43)，555([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.98(s，1H)，7.55-7.52(m，2H)，7.40-7.38(m，3H)，7.27(S，2H)，5.69(s，2H，PhCH
2)，5.48-5.47(d，1H，J＝3Hz，H-6)，4.46-4.38(dd，1H，J＝9，15Hz)，4.28-4.20(m，1H，H-3)，3.50-3.32(m，2H)，2.78-2.70(t，1H，J＝12Hz)，2.57-2.53(d，1H，J＝12Hz)，1.11(s，3H)，0.99(d，3H)，0.80-0.79(d，6H)；
13C?NMR(75MHz，CDCl
3)：δ138.0，137.0，133.3，129.7，129.6，129.4，124.5，121.6，119.7，109.5，80.9，67.0，62.3，61.0，56.5，53.6，50.0，42.3，41.8，39.8，39.6，37.6，36.9，32.1，32.0，31.6，31.5，30.5，29.5，29.0，21.0，19.6，17.3，16.4，14.7。
Embodiment 2 1-(3 α-diosgenin)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α-diosgenin) imidazolium compounds:
The preparation method obtains 1-(3 α-diosgenin) imidazolium compounds, yield 11.5% with compound 1.
The preparation of (2.1-3 α-diosgenin)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 2, yield 94.9% with compound 1.
mp.236-238℃；IR(KBr)v
max?cm
-1：3435，3063，2950，2873，1631，1558，1455，1377，1242，1134，1052，968，899，712；
ESI-MS(m/e，％)：556([M+1-Br]
+，43)，555([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.18(S，1H)，7.54-7.51(d，4H)，7.38-7.36(t，3H)，5.73-5.68(d，2H，PhCH
2)，5.64(S，1H，H-6)，4.86(S，1H，H-3)，4.45-4.38(dd，1H，J＝6，15Hz)，3.49-3.34(m，2H)，2.95-2.90(d，1H，J＝15Hz)，2.68-2.63(d，1H，J＝15Hz)，1.06(S，3H)，0.96-0.93(d，3H)，0.80-0.87(d，6H)；
13C?NMR(75MHz，CDCl
3)：δ137.1，136.8，133.5，129.4，129.3，125.5，121.7，121.5，109.4，80.8，66.9，62.1，56.5，53.3，50.0，41.7，40.3，39.6，37.1，34.9，32.3，32.0，31.8，31.4，31.1，30.3，28.8，27.6，20.5，19.3，17.2，16.3，14.5。
Embodiment 3 1-(3 α, 5 α-ring-6 β-diosgenins)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α, 5 α-ring-6 β-diosgenins) imidazolium compounds:
The preparation method obtains 1-(3 α, 5 α-ring-6 β-diosgenins) imidazolium compounds, yield 37.9% with compound 1.
The preparation of (2.1-3 α, 5 α-ring-6 β-diosgenins)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 3, yield 80.2% with compound 1.
IR(KBr)v
max?cm
-1：3432，3056，2951，2850，1631，1558，1454，1381，1217，1053，968，899，712；
ESI-MS(m/e，％)：556([M+1-Br]
+，41)，555([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.92(S，1H)，7.54-7.51(m，4H)，7.38-7.36(m，3H)，5.70(s，2H，PhCH
2)，4.48-4.40(dd，1H，J＝9，15Hz)，3.56(s，1H，H-6)，3.50-3.45(dd，1H，J＝3，12Hz)，3.41-3.34(t，1H，J＝12Hz)，2.39-2.35(d，1H，J＝12Hz)，2.18-2.01(m，1H)，0.98-0.96(d，3H)，0.80-078(d，3H)，0.75(s，3H)，0.72(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ136.4，134.1，129.1，128.7，125.8，128.4，117.8，109.1，80.5，66.8，62.2，58.6，55.7，53.5，48.0，43.1，41.5，40.6，39.8，35.1，34.6，33.4，31.5，31.3，30.3，30.2，28.7，24.4，24.2，22.2，19.6，17.1，16.5，14.5，14.3。
Embodiment 4 1-(3 β-gravidity pregnenolone)-3-benzyl-imidazoles bromine salt
The preparation of (1.1-3 β-gravidity pregnenolone) imidazolium compounds:
(2.8ml 20mmol) is dissolved in the dichloromethane solvent (180ml), stirs, and (1.14mg, 10mmol), after dropwising, reaction is 1 hour under room temperature slowly to be added dropwise to methylsulfonyl chloride under ice bath (0 ℃) with triethylamine with gravidity pregnenolone (10mmol).After reaction finishes, add entry (50ml), with the dilute hydrochloric acid neutralization, separate organic phase, water merges organic phase with dichloromethane extraction 3 times (20ml/ time), uses saturated NaHCO successively
3Solution behind the saturated NaCl solution washing, adds anhydrous sodium sulfate drying, removes by filter siccative, and underpressure distillation obtains crude product after removing and desolvating.
(680mg 10mmol) is dissolved in 1, in the 4-dioxane solvent (90ml) with above-mentioned crude product (5mmol), imidazoles, stirring and refluxing 48 hours, underpressure distillation removes and desolvates, through column chromatography for separation, obtain 1-(3 β-gravidity pregnenolone) imidazolium compounds, yield 1.9%.
The preparation of (2.1-3 β-gravidity pregnenolone)-3-benzyl-imidazoles bromine salt:
1-(3 β-gravidity pregnenolone) imidazoles (0.2mmol) are dissolved in dimethylbenzene (4ml), stir and add cylite (69mg down, 0.4mmol), stirring and refluxing, reaction needs 48 hours approximately, obtain solid chemical compound, filter, with toluene wash for several times, drying, get white amorphous powder compound 4, yield 99.0%.
mp.224-226℃；IR(KBr)v
maxcm
-1：3432，3380，3086，2944，2847，1700，1628，1557，1457，1356，1226，1093，767，714；
ESI-MS(m/e，％)：458([M+1-Br]
+，45)，457([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.11(S，1H)，7.49-7.46(m，4H)，7.35-7.33(m，3H)，5.69-5.61(t，2H，PhCH
2)，5.58-5.57(d，1H，H-6，J＝3Hz)，4.82(S，1H，H-3)，2.92-2.87(d，1H，J＝15Hz)，2.64-2.59(d，1H，J＝15Hz)，2.51-2.45(t，1H，J＝9Hz)，2.08(S，3H)，1.01(S，3H)，0.58(S，3H)；
13C?NMR(75MHz，CDCl
3)：δ209.7，137.3，137.0，133.8，129.8，129.6，125.8，122.0，121.8，63.9，57.1，56.8，53.7，50.2，44.2，39.0，37.4，35.3，32.7，32.1，31.9，27.8，24.7，23.3，21.0，19.6，13.6。
Embodiment 5 1-(3 α-gravidity pregnenolone)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α-gravidity pregnenolone) imidazolium compounds:
The preparation method obtains 1-(3 α-gravidity pregnenolone) imidazolium compounds, yield 10.6% with compound 4.
The preparation of (2.1-3 α-gravidity pregnenolone)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 5, yield 95.4% with compound 4.
mp.＞300℃；IR(KBr)v
maxcm
-1：3413，3058，2943，2849，1700，1621，1559，1432，1357，1164，760，714；
ESI-MS(m/e，％)：458([M+1-Br]
+，45)，457([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.92(s，1H)，7.55-7.53(m，2H)，7.40-7.38(m，3H)，7.32-7.28(m，2H)，5.68(s，2H，PhCH
2)，5.49(s，1H，H-6)，4.34-4.23(m，1H，H-3)，2.79-2.71(t，1H，J＝12Hz)，2.13(s，3H，H-21)，1.09(s，3H)，0.63(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ209.5，137.9，136.8，133.2，129.6，129.5，129.4，124.4，121.7，119.7，63.7，60.9，56.9，53.5，49.9，44.0，39.5，38.8，37.5，36.7，31.8，31.8，31.6，29.5，24.6，23.0，21.1，19.5，13.3。
Embodiment 6 1-(3 β-cholesterol)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 β-cholesterol) imidazolium compounds:
The preparation method obtains 1-(3 α-cholesterol) imidazolium compounds, yield 6.3% with compound 1.
The preparation of (2.1-3 β-cholesterol)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 6, yield 85.3% with compound 1.
mp.234-236℃；IR(KBr)v
maxcm
-1：3439，3078，2950，2930，2905，2851，1633，1558，1444，1379，1132，817，710；
ESI-MS(m/e，％)：528([M+1-Br]
+，42)，527([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.03(s，1H)，7.62-7.47(m，4H)，7.38-7.34(m，3H)，5.72-5.64(t，2H，PhCH
2)，5.60-5.59(d，1H，H-6，J＝3Hz)，4.85(s，1H，H-3)，2.94-2.89(d，1H，J＝15Hz)，2.67-2.62(d，1H，J＝15Hz)，1.03(s，3H)，0.92(s，3H)，0.88-0.87(d，3H)，0.86-0.85(d，3H)，0.66(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ137.3，136.7，133.9，129.7，129.6，126.1，122.2，121.9，56.9，56.7，56.5，53.5，50.3，42.6，39.8，37.3，36.5，36.1，35.2，32.6，32.2，31.9，28.6，28.4，27.9，24.5，24.3，23.2，22.9，20.9，19.6，19.1，12.2。
Embodiment 7 1-(3 α-cholesterol)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α-cholesterol) imidazolium compounds:
The preparation method obtains 1-(3 α-cholesterol) imidazolium compounds, yield 15.1% with compound 1.
The preparation of (2.1-3 α-cholesterol)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 7, yield 92.9% with compound 1.
mp.284-286℃；IR(KBr)v
maxcm
-1：3417，3052，2951，2932，2850，1631，1561，1485，1457，1380，1162，760，710；
ESI-MS(m/e，％)：528([M+1-Br]
+，45)，527([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.69(s，1H)，7.57-7.47(m，4H)，7.36-7.31(m，3H)，5.66(s，2H，PhCH
2)，5.45(s，1H，H-6)，4.26-4.18(m，1H，H-3)，2.79-2.71(t，1H，J＝12Hz)，2.56-2.52(d，1H，J＝12Hz)，1.07(s，3H)，0.93-0.91(d，3H)，0.88(s，3H)，0.85(s，3H)，0.67(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ138.4，136.2，133.8，129.7，129.6，124.7，122.4，120.8，61.1，57.0，56.5，53.5，50.2，42.7，40.0，39.9，39.8，37.8，36.9，36.6，36.2，32.2，32.0，29.8，28.6，28.4，24.6，24.2，23.2，23.0，21.3，19.8，19.1，12.2。
Embodiment 8 1-(3 beta-stigmasterol)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 beta-stigmasterol) imidazolium compounds:
The preparation method obtains 1-(3 α-Stigmasterol) imidazolium compounds, yield 6.3% with compound 1.
The preparation of (2.1-3 beta-stigmasterol)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 8, yield 85.3% with compound 1.
mp.216-218℃；IR(KBr)v
maxcm
-1：3419，3052，2957，2938，2869，1630，1561，1456，1380，1181，972，709；
ESI-MS(m/e，％)：554([M+1-Br]
+，42)，553([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.69(s，1H)，7.58-7.48(m，4H)，7.36-7.31(m，3H)，5.67(s，2H，PhCH
2)，5.46(s，1H，H-6)，5.20-5.12(dd，1H，J＝9，15Hz)，5.06-4.98(dd，1H，J＝9，15Hz)，4.26-4.18(m，1H，H-3)，2.80-2.72(t，1H，J＝12Hz)，2.56-2.52(d，1H，J＝12Hz)，1.08(s，3H)，1.04-1.03(d，3H)，0.86(s，3H)，0.84(s，3H)，0.81(s，3H)，0.70(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ138.3，138.0，135.8，133.4，129.4，129.3，124.3，122.1，120.5，60.8，56.7，55.9，53.1，51.3，49.9，42.2，40.5，39.5，39.4，37.4，36.6，31.9，31.8，31.7，29.4，28.9，25.4，24.3，21.2，21.1，21.0，19.4，19.0，12.3，12.1。
Embodiment 9 1-(3 α-Stigmasterol)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α-Stigmasterol) imidazolium compounds:
The preparation method obtains 1-(3 α-Stigmasterol) imidazolium compounds, yield 15.1% with compound 1.
The preparation of (2.1-3 α-Stigmasterol)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 9, yield 92.9% with compound 1.
mp.234-236℃；IR(KBr)v
maxcm
-1：3483，3412，3089，2955，2826，1634，1559，1457，1380，1136，972，709；
ESI-MS(m/e，％)：554([M+1-Br]
+，42)，553([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.16(s，1H)，7.56-7.52(m，4H)，7.38-7.36(m，3H)，5.73-5.64(t，2H，PhCH
2)，5.62-5.60(d，1H，H-6，J＝6Hz)，5.20-5.12(dd，1H，J＝9，15Hz)，5.06-4.98(dd，1H，J＝9，15Hz)，4.86(s，1H，H-3)，2.95-2.90(d，1H，J＝15Hz)，2.67-2.62(d，1H，J＝15Hz)，1.04(s，3H)，1.03-1.01(d，3H)，0.86(s，3H)，0.84-0.83(d，3H)，0.81(s，3H)，0.69(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ138.6，137.4，136.9，133.8，130.0，129.6，126.1，122.1，121.9，57.1，56.8，56.3，53.6，51.6，50.4，42.5，40.9，39.8，37.4，35.3，32.6，32.3，32.3，31.9，29.3，27.9，25.8，24.6，21.6，21.5，21.0，19.6，19.4，12.6，12.4。
Embodiment 10 1-(3 β-dehydroepiandros-sterone)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 β-dehydroepiandros-sterone) imidazolium compounds:
The preparation method obtains 1-(3 α-dehydroepiandros-sterone) imidazolium compounds, yield 3.0% with compound 1.
The preparation of (2.1-3 β-dehydroepiandros-sterone)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 10, yield 88.6% with compound 1.
mp.240-242℃；IR(KBr)v
maxcm
-1：3434，3078，2947，2835，1735，1632，1559，1443，1130，810，711；
ESI-MS(m/e，％)：430([M+1-Br]
+，33)，429([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.21(s，1H)，7.50-7.47(m，4H)，7.41-7.32(m，3H)，5.69-5.56(m，3H，PhCH
2，H-6)，4.83(s，1H，H-3)，2.95-2.90(d，2H)，2.72-2.67(d，2H)，1.04(s，3H)，0.84(s，3H)；
13C?NMR(75MHZ，CDCl
3)：δ220.7，137.1，136.9，133.5，129.4，129.3，125.2，121.7，121.4，56.5，53.3，51.7，50.1，47.5，37.2，35.8，34.9，32.3，31.4，31.2，30.8，27.5，21.8，20.0，19.3，13.6。
Embodiment 11 1-(3 α-dehydroepiandros-sterone)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
The preparation of (1.1-3 α-dehydroepiandros-sterone) imidazolium compounds:
The preparation method obtains 1-(3 α-dehydroepiandros-sterone) imidazolium compounds, yield 14.3% with compound 1.
The preparation of (2.1-3 α-dehydroepiandros-sterone)-3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 11, yield 82.9% with compound 1.
mp.292-294℃；IR(KBr)v
maxcm
-1：3417，3057，2945，2856，1741，1620，1558，1469，1371，1163，1030，759，714；
ESI-MS(m/e，％)：430([M+1-Br]
+，33)，429([M-Br]
+，100)；
1H?NMR(300MHz，CDCl
3)：δ10.66(s，1H)，7.43-7.41(m，2H)，7.29-7.23(m，5H)，5.54(s，2H，PhCH
2)，5.38-5.37(d，1H，H-6，J＝3Hz)，4.18-4.07(m，1H，H-3)，2.71-2.63(t，1H，J＝12Hz)，2.48-2.44(d，1H，J＝12Hz)，2.39-2.29(m，1H)，0.99(s，3H)，0.75(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ220.8，138.3，136.4，133.3，129.6，129.5，129.4，123.8，121.9，120.2，60.8，53.4，51.7，50.1，47.6，39.4，37.4，36.8，35.9，31.4，31.4，30.8，29.4，21.9，20.4，19.5，13.7。
Embodiment 12 1-(3 α, 5 α-ring-6 α-steroidals)-3-benzyl-2,4,5-triphenyl imidazoles villaumite
Preparation process is as follows:
(1.1-3 α, 5 α-ring-6 α-steroidals)-2,4, the preparation of 5-triphenyl imidazolium compounds:
(3.5ml 25mmol) is dissolved in the dichloromethane solvent (800ml), stirs, and (1.71mg, 15mmol), after dropwising, reaction is 4 hours under room temperature slowly to be added dropwise to methylsulfonyl chloride under ice bath (0 ℃) with triethylamine with 3-hydroxy steroid (10mmol).After reaction finishes, add entry (50ml), with the dilute hydrochloric acid neutralization, separate organic phase, water merges organic phase with dichloromethane extraction 3 times (20ml/ time), uses saturated NaHCO successively
3Solution behind the saturated NaCl solution washing, adds anhydrous sodium sulfate drying, removes by filter siccative, and underpressure distillation obtains crude product after removing and desolvating.
With above-mentioned crude product (5mmol), 2,4, (680mg 10mmol) is dissolved in the dry toluene solvent (200ml) 5-triphenyl imidazoles, stirring and refluxing 72 hours, underpressure distillation removes and desolvates, and through column chromatography for separation, obtains 1-(3 α, 5 α-ring-6 α-steroidals)-2,4,5-triphenyl imidazolium compounds, yield 8.4%.
(2.1-3 α, 5 α-ring-6 α-steroidals)-3-benzyl-2,4, the preparation of 5-triphenyl imidazoles villaumite:
1-(3 α, 5 α-ring-6 α-steroidals)-2,4,5-triphenyl imidazoles (0.2mmol) is dissolved in toluene (20ml), and adding Benzyl Chloride under stirring (86mg, 0.5mmol), stirring and refluxing, reacted about 72 hours, and obtained solid chemical compound, filter, with toluene wash for several times, drying gets white amorphous powder compound 12, yield 75.3%.
Embodiment 13 1-(3 α, 5 α-ring-6 α-17-hydroxyl-steroidal)-3-benzyl-2,4,5-tri-methylimidazolium villaumite
Preparation process is as follows:
(1.1-3 α, 5 α-ring-6 α-17-hydroxyl-steroidal)-2,4, the preparation of 5-tri-methylimidazolium compound:
The preparation method is with compound 12, and the substrate steroidal is 3-hydroxyl-17-hydroxyl-steroidal, and the substrate imidazoles is 2,4, and the 5-tri-methylimidazolium obtains 1-(3 α, 5 α-ring-6 α-17-hydroxyl-steroidal)-2,4,5-tri-methylimidazolium compound, yield 6.8%.
(2.1-3 α, 5 α-ring-6 α-17-hydroxyl-steroidal)-3-benzyl-2,4, the preparation of 5-tri-methylimidazolium villaumite:
The preparation method gets white amorphous powder compound 13, yield 78.5% with compound 12.
Embodiment 14 1-(3 β-Δ
5-17-amido-steroidal)-3-benzyl-iodonium imidazolide salts
Preparation process is as follows:
1.1-(3 β-Δ
5-17-amido-steroidal) preparation of imidazolium compounds:
The preparation method is with compound 1, and the substrate steroidal is 3-hydroxyl-Δ
5-17-amido-steroidal obtains 1-(3 β-Δ
5-17-amido-steroidal) imidazolium compounds, yield 5.2%.
2.1-(3 β-Δ
5-17-amido-steroidal)-preparation of 3-benzyl-iodonium imidazolide salts:
The preparation method is with compound 1, and the halogenation benzyl is the iodate benzyl, gets white amorphous powder compound 14, yield 86.1%.
Embodiment 15 1-(3 β-Δ
5-17-methylamino-steroidal)-3-benzyl-iodonium imidazolide salts
Preparation process is as follows:
1.1-(3 β-Δ
5-17-methylamino-steroidal) preparation of imidazolium compounds:
The preparation method is with compound 1, and the substrate steroidal is 3-hydroxyl-Δ
5-17-methylamino-steroidal obtains 1-(3 β-Δ
5-17-methylamino-steroidal) imidazolium compounds, yield 4.7%.
2.1-(3 β-Δ
5-17-methylamino-steroidal)-preparation of 3-benzyl-iodonium imidazolide salts:
The preparation method is with compound 1, and the halogenation benzyl is the iodate benzyl, gets white amorphous powder compound 15, yield 87.2%.
Embodiment 16 1-(3 β-17-anilino-steroidal)-3-benzyl-imidazoles alkali salt
Preparation process is as follows:
1.1-(3 β-Δ
5-17-anilino-steroidal) preparation of imidazolium compounds:
The preparation method is with compound 1, and the substrate steroidal is 3-hydroxyl-Δ
5-17-anilino-steroidal obtains 1-(3 β-Δ
5-17-anilino-steroidal) imidazolium compounds, yield 2.1%.
2.1-(3 β-Δ
5-17-anilino-steroidal)-preparation of 3-benzyl-imidazoles alkali salt:
The preparation method is with compound 1, and the imidazoles bromine salt that obtains again through ammonia treatment, gets white amorphous powder compound 16, yield 80.1%.
Embodiment 17 1-(3 β-Δ
5-17-phenyl-steroidal)-3-benzyl-imidazoles alkali salt
Preparation process is as follows:
1.1-(3 β-Δ
5-17-phenyl-steroidal) preparation of imidazolium compounds:
The preparation method is with compound 1, and the substrate steroidal is 3-hydroxyl-Δ
5-17-phenyl-steroidal obtains 1-(3 β-Δ
5-17-phenyl-steroidal) imidazolium compounds, yield 1.7%.
2.1-(3 β-Δ
5-17-phenyl-steroidal)-preparation of 3-benzyl-imidazoles alkali salt:
The preparation method gets white amorphous powder compound 17, yield 80.7% with compound 16.
Embodiment 18 1-(3 β-Δ
5-17-sulfydryl-steroidal)-3-benzyl-imidazoles bromine salt
Preparation process is as follows:
1.1-(3 β-Δ
5-17-sulfydryl-steroidal) preparation of imidazolium compounds:
The preparation method is with compound 1, and the substrate steroidal is 3-hydroxyl-Δ
5-17-sulfydryl-steroidal obtains 1-(3 β-Δ
5-17-sulfydryl-steroidal) imidazolium compounds, yield 1.5%.
2.1-(3 β-Δ
5-17-sulfydryl-steroidal)-preparation of 3-benzyl-imidazoles bromine salt:
The preparation method gets white amorphous powder compound 18, yield 75.6% with compound 1.
The antitumour activity experiment of compound 1,2,3
Compound 1,2,3 has carried out the cytotoxic activity screening of leukemia, liver cancer, laryngocarcinoma and lung cancer according to the MTT method, and its mld measurement result is with commercial cancer therapy drug---cis-platinum (DDP) is compared in the following table.
Above data show that compound 1,2,3 has extraordinary external antitumour activity.
Claims (7)
1, have following general structural formula (I) and steroid imidazole salt compound (II):
The R=benzyl
R
1, R
2=H, aryl, alkyl
R
3=H, alkyl, carbonyl, alkoxyl group, hydroxyl, amido, alkylamino radical, aryl amine, sulfydryl, aryl
X＝Cl，Br，I，OH。
2, compound according to claim 1 is characterized in that: contain polysubstituted imidazole structure unit, imidazoles 1-position connects steroidal, and the 3-position forms benzyl halogeno salt or benzyl alkali salt.
3, a kind of preparation method of compound as claimed in claim 1, this method may further comprise the steps:
Synthesizing of A, 1-steroid imidazole compound:
1. with 3-hydroxyl-Δ
5-steroidal, triethylamine, methylsulfonyl chloride are raw material, in dichloromethane solvent, synthesize 3-methanesulfonates steroidal earlier: 3-hydroxy steroid and triethylamine are dissolved in the dichloromethane solvent, under 0 ℃, slowly be added dropwise to methylsulfonyl chloride, consumption by mole ratio is: 3-hydroxy steroid/triethylamine/methylsulfonyl chloride=1/2.0～2.5/1.0～1.5, the consumption of methylene dichloride is 50～200ml/g 3-hydroxy steroid, after dropwising, reaction is 1-4 hour under room temperature, makes 3-methanesulfonates steroidal;
2. be raw material with 3-methanesulfonates steroidal, imidazoles or polysubstituted imidazoles, in dry toluene or 1,4-dioxane or tetraethoxysilane or tetrahydrofuran (THF) or 1, synthetic 1-steroid imidazole compound in the 2-ethylene dichloride solvent: 3-methanesulfonates steroidal, imidazoles are dissolved in the dry toluene solvent, consumption by mole ratio is: 3-methanesulfonates steroidal/imidazoles=1/2, solvent load is 50～200ml/g 3-methanesulfonates steroidal, and reaction stirring and refluxing 48-72 hour makes 1-steroid imidazole compound;
Synthesizing of B, 1-steroidal-3-benzyl imidazole salt compounds:
With 1-steroid imidazole compound and halogenation benzyl is raw material, in toluene or dimethylbenzene or 1, synthetic 1-steroidal-3-benzyl imidazole salt compounds in 4-dioxane or the tetraethoxy-silicane alkane solvents: 1-steroid imidazole compound is dissolved in toluene or dimethylbenzene or 1, the 4-dioxane, stir and add the halogenation benzyl down, consumption by mole ratio is: 1-steroid imidazole/halogenation benzyl=1.0/2.0～2.5, solvent load is 50～200ml/g 1-steroid imidazole, reaction stirring and refluxing 48-72 hour makes 1-steroidal-3-benzyl imidazole salt compounds.
4, the preparation method of compound according to claim 3, when it is characterized in that synthesizing 1-steroid imidazole compound, the sequencing that each reactant adds adopts: 3-hydroxy steroid and triethylamine are dissolved in the dichloromethane solvent, under 0 ℃, slowly be added dropwise to methylsulfonyl chloride, after dropwising, reaction is 1-4 hour under room temperature, makes 3-methanesulfonates steroidal, and the consumption of methylene chloride adopts 150ml/g 3-hydroxy steroid; Again 3-methanesulfonates steroidal, imidazoles are dissolved in the dry toluene solvent, stirring and refluxing 48-72 hour, make 1-steroid imidazole compound, the consumption of solvent dry toluene adopts 100ml/g 3-methanesulfonates steroidal.
5, the preparation method of compound according to claim 3, when it is characterized in that synthetic 1-steroidal-3-benzyl imidazole salt compounds, each compound amount adopts 1-steroid imidazole/3-halogenation benzyl=1.2/1.0 by mole ratio, and solvent load adopts 100ml/g 1-steroid imidazole.
6, the preparation method of compound according to claim 3, it is characterized in that with 3-hydroxy steroid, triethylamine, methylsulfonyl chloride, imidazoles be raw material, prepare 1-steroid imidazole compound earlier, with the reaction of halogenation benzyl, prepare steroid imidazole salt compound again.
7, has the application that medicine that general structure (I) and compound (II) and at least a pharmaceutically acceptable excipient, diluent or carrier make is used for the treatment of cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103343013A (en) * | 2013-07-05 | 2013-10-09 | 东北大学 | Ionic liquid crystal compound containing imidazole and cholesteric ester groups and preparation method thereof |
| CN108383892A (en) * | 2018-03-12 | 2018-08-10 | 西南民族大学 | A kind of diosgenin quaternary ammonium salt derivative and preparation method and application |
| CN109053847A (en) * | 2018-07-18 | 2018-12-21 | 云南大学 | One kind 17 β-imidazolidinyl bromide-remove hydrogen meter androstane derivatives and its preparation method and application |
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| DE3926365A1 (en) * | 1989-08-04 | 1991-02-07 | Schering Ag | CYCLOALKYLENAZOLES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS THAT CONTAIN THEY AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| US6878731B2 (en) * | 2002-08-14 | 2005-04-12 | Pure World Botanicals, Inc. | Imidazole alkaloids from Lepidium meyenii and methods of usage |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103343013A (en) * | 2013-07-05 | 2013-10-09 | 东北大学 | Ionic liquid crystal compound containing imidazole and cholesteric ester groups and preparation method thereof |
| CN103343013B (en) * | 2013-07-05 | 2014-12-10 | 东北大学 | Ionic liquid crystal compound containing imidazole and cholesteric ester groups and preparation method thereof |
| CN108383892A (en) * | 2018-03-12 | 2018-08-10 | 西南民族大学 | A kind of diosgenin quaternary ammonium salt derivative and preparation method and application |
| CN109053847A (en) * | 2018-07-18 | 2018-12-21 | 云南大学 | One kind 17 β-imidazolidinyl bromide-remove hydrogen meter androstane derivatives and its preparation method and application |
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