CN104031047B - A kind of chlorethylnitrosourea and synthetic method thereof with antitumour activity - Google Patents
A kind of chlorethylnitrosourea and synthetic method thereof with antitumour activity Download PDFInfo
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Abstract
The present invention relates to a kind of novel chlorethylnitrosourea with antitumour activity and synthetic method thereof, described chlorethylnitrosourea is the compound with logical formula I structure, wherein: n is the integer of 2-6.Chlorethylnitrosourea provided by the invention, glioma brain tumour, colorectal carcinoma and leukemia can be treated, and than existing nitrosoureas cancer therapy drug, there is lower resistance and better chemotherapy effect, its preparation method is simple to operate, reaction yield is high, toxicity is little, cost is low, be applicable to suitability for industrialized production, there is vast potential for future development, have good using value.
Description
Technical field
The present invention relates to novel chlorethylnitrosourea and synthetic method thereof, be specifically related to N-(2-the chloroethyl)-N '-2-(O with antitumour activity
6-benzyl-9-guanine base) alkyl-N-nitrosourea and synthetic method thereof.
Background technology
The essential therapeutic arsenals of noumenal tumour has radiotherapy, surgical operation therapy, chemotherapy and biotherapy etc., and cancer therapy drug has become a fast-developing forward position in recent years.Nitrosourea all shows good antitumour activity in experimentation on animals and clinical application, is therefore widely used in the treatment of brain tumor, malignant lymphoma, leukemia, neurospongioma and melanoma etc.Research shows, the major target class of nitrosourea and biomacromolecule effect is DNA base, N and the O position in DNA base can be made to produce and modify, and then cause list/double-strand break equivalent damage, or induction sister chromatid exchang and chromosome aberration etc.
The anticancer alkylating agent of nitrosoureas applied clinically mostly at present is bifunctional alkylating agent chlorethylnitrosourea, as carmustine (BCNU), nimustine (ACNU), lomustine (CCNU) and semustine (Me-CCNU) etc., be widely used in the treatment of brain tumor, Hokdkin disease, malignant melanoma and various solid tumor.Such cancer therapy drug can decompose produce chloroethyl carbonium ion and with guanine O
6there is electrophilic substitution reaction and generate O in position
6-chloroethyl guanine, between the N1 of guanine and the N3 of cytosine(Cyt), cross-linking products 1-between stock [N-(2 '-deoxidation born of the same parents base)]-2-[N-(2 '-deoxidation bird base)] ethane (dG-dC is cross-linked) is connected to form after further rearrangement reaction, thus hinder the normal replication transcription of DNA, cause mitotic division normally can not carry out or DNA double chain is ruptured, final inducing apoptosis of tumour cell.But, study discovery further, O
6-alkylguanine-DNA-alkyl-transferase (AGT) is cause tumour cell to the important factor of the anti-medicine of alkylating agent class medicine to the reparation that DNA of tumor cell damages.Its concrete repair mechanism is that AGT is by alkylated product O
6chloroethyl on-chloroethyl guanine is transferred on AGT the 145th cysteine residues, thus blocks O
6-chloroethyl guanine reacts with cytosine(Cyt) further and forms dG-dC and be cross-linked, and causes tumour cell to strengthen the tolerance of chlorethylnitrosourea, affects chemotherapy effect.
In order to suppress AGT active thus improve tumour cell to the susceptibility of chloroethylnitrosoureas alkylating agent, people start to explore new chemotherapy regimen: first, use the inhibitor of AGT enzyme effectively to be consumed by the AGT in tumour cell; And then treat with chlorethylnitrosourea, likely obtain better result for the treatment of.
The people such as Pegg (Biochemistry, 1993,32,11998-12006) have synthesized a kind of strong effective people AGT inhibitor---O
6-benzyl guanine, this compound can be combined by the AGT effectively in tumour cell, reduces the activity of AGT, thus improves the cytotoxicity of cancer therapy drug.Research shows, O
6the benzyl group of self can be transferred on the cysteine residues of AGT reactive site by-benzyl guanine, makes Benzylation AGT lose the function of DNA plerosis damage, the O of 0.2 μM
6-benzyl guanine acts on cell 30min can make AGT activity decrease 50%.The result of study of the people such as Wan Yongling (the Chinese Journal of Clinical Pharmacology, 1999,15:52-57) shows, lotus knurl athymic mouse is through O
6-benzyl guanine experimental therapy, finds to give O in advance
6chlorethylnitrosourea treatment is given again after-benzyl guanine process 2h, can the growth of obvious Tumor suppression, significantly enhance the chemotherapy effect of chlorethylnitrosourea.The people such as Schold (CancerResearch, 1996,56:2076-2081) have synthesized O
6the ribodesose homologue O of-benzyl guanine
6-benzyl pancreatic desoxyribonuclease, and study its therapeutic action to tumor-bearing mice, result shows O
6-benzyl pancreatic desoxyribonuclease and chlorethylnitrosourea drug combination can make the survival rate of tumor-bearing mice increase by 65%, and along with O
6the raising of-benzyl pancreatic desoxyribonuclease dosage, chlorethylnitrosourea strengthens the restraining effect of tumor growth.
At present, O
6the drug combination of-benzyl guanine and chlorethylnitrosourea has become the study hotspot of chemotherapy, becomes the important channel of improving chlorethylnitrosourea chemotherapy effect by the activity of inhibition tumor cell AGT with the reparation reducing cancer cells DNA damage.But research finds, due to O
6the restraining effect of-benzyl guanine to AGT does not have targeting, with the drug combination of chlorethylnitrosourea, and O
6-benzyl guanine optionally can not play its effect suppressing AGT for tumour cell; But simultaneously non-target tropism act on normal cell, cause the AGT in normal cell suppressed, thus destroy the repair mechanism of normal cell to DNA damage, add the risk of normal cell DNA damage, finally cause the raising of toxic and side.
In order to more effectively anticancer to the resistance of chlorethylnitrosourea, improve medicine antitumour activity, the present invention synthesize a kind of can cause between DNA stock crosslinked again simultaneously can in targeting ground anticancer AGT to the novel chlorethylnitrosourea of crosslinked reparation.This compounds can reduce the resistance of chlorethylnitrosourea thus improve its antitumour activity, and simplifies combined clinical medication process.Such compou nd synthesis has no bibliographical information.
Summary of the invention
The present invention is directed to chlorethylnitrosourea in prior art easily to produce resistance and then cause antitumour activity to reduce and chlorethylnitrosourea and O
6the deficiency that-benzyl guanine drug combination is larger to normal cytotoxic effect, provides a kind of compound N-(2-chloroethyl)-N '-2-(O had compared with high anti-cancer activity
6-benzyl-9-guanine base) alkyl-N-nitrosourea (I) and synthetic method thereof.
The invention provides a kind of compound with antitumour activity of logical formula I structure:
Wherein: n is the integer of 2-6.
The chemical name of this compound is: N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) alkyl-N-nitrosourea.
Preferably, n is 2,3 or 4, and its chemical name is:
N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) ethyl-N-nitrosourea (compound 1),
N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) propyl group-N-nitrosourea (compound 2) or
N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) butyl-N-nitroso urea (compound 3).
Present invention also offers one and prepare N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) method of alkyl-N-nitrosourea, the reaction formula of the method is as follows:
Invention provide the concrete synthesis step of compound as follows:
1) by O
6-benzyl guanine a is dissolved in acetone, adds Anhydrous potassium carbonate wherein and drips dibromoalkane hydrocarbon Br-(CH
2)
n-Br, with O
6there is the substitution reaction of N9 position in-benzyl guanine, heat and stir and make its reacting generating compound b, tlc monitoring extent of reaction, to filtering without after raw material point, collect filtrate, after underpressure distillation is spin-dried for solvent, the yellow oil obtained is dissolved in methyl alcohol, use silica gel column chromatography separation and purification, obtain compound b;
2) by step 1) the compound b that obtains is dissolved in N ' dinethylformamide, and add potassium phthalimide, heated and stirred reacts to obtain compound c, the thick product of compound c is obtained after underpressure distillation, gained compound c crude product is dissolved in ethanol, adds hydrazine hydrate, heated and stirred refluxes, make it that hydrazinolysis occur, tlc monitoring extent of reaction, extremely without underpressure distillation after raw material point, residuum is dissolved in methylene dichloride, suction filtration removing insolubles, distills to obtain compound d by filtrate decompression;
3) by step 2) the compound d that obtains is dissolved in methylene dichloride, add 2-chloroethyl isocyanate, adularescent precipitation produces, and heated and stirred, generates Verbindung after completion of the reaction, underpressure distillation obtains Verbindung crude product, add a small amount of deionized water wherein, stir evenly, suction filtration, washing, 60 DEG C of vacuum-dryings obtain Verbindung;
4) by step 3) e that obtains is dissolved in formic acid, and add the sodium nitrite in aqueous solution of new preparation, through nitrosation reaction salify, use dehydrated alcohol recrystallization, filtration drying, precipitating 2 times with cold water and washing with acetone respectively must compound f.
In aforesaid method:
Described step 1) in:
Described O
6-benzyl guanine, Anhydrous potassium carbonate and dibromoalkane hydrocarbon Br-(CH
2)
nthe mol ratio of-Br is 1:1-4:2-10, preferred 1:2-3:4-6;
Solvent acetone is mainly used in solubilizing reaction thing a, makes a be in solution, and easy and other materials react, and its consumption is the 15-25 times amount volume (mL) of reactant a molar weight (mmol);
Temperature of reaction controls at 30-70 DEG C, preferred 40-60 DEG C.
Reaction times is 12-80h, preferred 40-72h;
During underpressure distillation, temperature controls at 25-60 DEG C, preferred 30-40 DEG C;
Silica gel column chromatography eluent used is sherwood oil and ethyl acetate, and adopt gradient elution, petrol ether/ethyl acetate volume ratio is increased to 5:1 gradually from 2:1.
Described step 2) in:
The mol ratio of described compound b and potassium phthalimide is 1:1-4, preferred 1:2-2.1.
The consumption of solvent N ' dinethylformamide is mainly used in dissolved compound b, makes compound b be in solution, and easy and other materials react, and its consumption is the 5-10 times amount volume (mL) of compound b molar weight (mmol);
The temperature of reaction of described compound b and potassium phthalimide controls at 50-90 DEG C, preferred 65-80 DEG C; Reaction times is 4-12h, preferred 6-8h;
After reactant b and potassium phthalimide react, vacuum distillation temperature controls at 40-80 DEG C, preferred 60-75 DEG C;
Compound c is 2-6 (mmol): 1 (mL) with the materials ratio of hydrazine hydrate, and preferred 4-4.5 (mmol): 1 (mL), the concentration of hydrazine hydrate is 70%.
The consumption of etoh solvent is mainly used in dissolved compound c, makes c be in solution, and easy and other materials react, and its consumption is the 6-8 times amount volume (mL) of compound c molar weight (mmol);
The stirring and refluxing temperature of compound c and hydrazine hydrate controls at 50-90 DEG C, preferred 60-80 DEG C; Time is 1-8h, preferred 3-5h;
During twice underpressure distillation after hydrazinolysis, temperature all controls at 30-70 DEG C, preferred 30-50 DEG C;
Step 3) in:
The mol ratio of compound d and 2-chloroethyl isocyanate is 1:1-4, preferred 1:2-2.4.
The consumption of methylene chloride is mainly used in solubilizing reaction thing d, makes d be in solution, and easy and other materials react, and its consumption is the 8-10 times amount volume (mL) of reactant d molar weight (mmol);
Temperature during reaction controls at 30-50 DEG C, preferred 35-45 DEG C; Time is 2-10h, preferred 6-8h;
Vacuum distillation temperature can be controlled in 20-40 DEG C, preferred 30-40 DEG C.
Step 4) in:
The mass percent concentration of described sodium nitrite in aqueous solution is 20%-50%, preferred 25%-35%;
The amount ratio of Verbindung, formic acid and Sodium Nitrite is 1 (mmol): 8-10 (mL): 2-8 (mmol), is preferably 1 (mmol): 10 (mL): 3.0-4.2 (mmol);
The described nitrosation reaction time is 1-5h, preferred 2-3h;
Described nitrosation reaction temperature controls at 0-10 DEG C, preferred 0-5 DEG C.
Present invention also offers the preparation containing above-claimed cpd, described preparation is made up of compound and pharmaceutically acceptable carrier.
Described preparation is tablet, capsule, pill, powder, injection liquid or injection freeze-dried powder.
Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, is selected from one or more in weighting agent, tackiness agent, disintegrating agent, lubricant, solubilizing agent, suspending agent, wetting agent, pigment, essence, solvent, tensio-active agent or correctives.
Described weighting agent is selected from starch, pregelatinized Starch, dextrin, glucose, sucrose, lactose, Saccharum lactis, Microcrystalline Cellulose, N.F,USP MANNITOL, sorbyl alcohol or Xylitol, preferred sorbyl alcohol, Microcrystalline Cellulose, lactose or pregelatinized Starch;
Described disintegrating agent is selected from croscarmellose sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or starch, preferred polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose or sodium starch glycolate;
Described lubricant is selected from Magnesium Stearate, talcum powder, micropowder silica gel, PEG4000, PEG6000, sodium laurylsulfate, preferred Magnesium Stearate, talcum powder;
Described tackiness agent is selected from Xylo-Mucine, HPMC, ethyl cellulose, polyvidone, starch slurry, sucrose, Icing Sugar, rubber cement, gelatin, polyoxyethylene glycol, preferred HPMC, polyvidone;
Described solubilizing agent is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, meglumine, 1B, L-arginine, preferred sodium hydroxide, meglumine;
Described suspending agent is selected from micropowder silica gel, beeswax, Mierocrystalline cellulose, solid polyethylene glycol;
Described wetting agent is selected from glycerine, tween-80, ethoxy aluminium Viscotrol C or Yelkin TTS;
Described solvent selected from ethanol, liquid polyethylene glycol, Virahol, tween-80, glycerine, propylene glycol or vegetables oil, described vegetables oil is selected from soybean oil, Viscotrol C, peanut oil, mediation wet goods;
Described tensio-active agent is selected from smooth or polysorbate (tween) of Sodium dodecylbenzene sulfonate, stearic acid, Pluronic F68, lipid acid sorb etc.;
Described correctives is selected from aspartame, Sucralose, essence, Steviosin, acesulfame potassium, citric acid or soluble saccharin.
Present invention also offers above-claimed cpd or the application in antitumor drug prepared by preparation, described tumour is glioma brain tumour, colorectal carcinoma, leukemia.
New compound provided by the invention has the following advantages:
1, the present invention retains (2-the chloroethyl)-1-nitrosourea part in two (2-the chloroethyl)-1-nitrosourea structure of prior art 1,3-, by 1, and another chloroethyl O of two (2-the chloroethyl)-1-nitrosourea of 3-
6-benzyl-9-alkylguanine replaces, and obtains a kind of chloroethylnitrosoureas compound of novel texture.This compound has than existing nitrosoureas cancer therapy drug the advantage that resistance is lower, antitumour activity is higher; Optionally can act on cancer cells, reduce the toxic side effect of drug combination, improve the targeting of medicine.
2, the shortcoming of chlorethylnitrosourea mainly easily produces resistance.O
6-benzyl guanine is as the drug combination of chlorethylnitrosourea, and its side effect mainly targeting is not strong, can not work for tumour cell specifically.
Novel chlorethylnitrosourea provided by the invention to can be used for improving in clinical treatment high AGT active cells for the resistance of chlorethylnitrosourea, and it decomposes the O produced
6the expression of-benzyl guanine analogue middle AGT capable of inhibiting cell, thus the dG-dC crosslinking rate improved in mdr cell and cytotoxicity, improve chemotherapy effect.
3, effect experimental result: N-provided by the invention (2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) alkyl-N-nitrosourea, glioma brain tumour, colorectal carcinoma and leukemia can be treated, and than existing nitrosoureas cancer therapy drug, there is lower resistance and better chemotherapy effect, its preparation method is simple to operate, reaction yield is high, toxicity is little, cost is low, be applicable to suitability for industrialized production, there is vast potential for future development, have good using value.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1:N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) synthesis of ethyl-N-nitrosourea (compound 1)
1) N9-bromotrifluoromethane-O
6the synthesis of-benzyl guanine
Take O
6-benzyl guanine (0.96g, 4mmol), Anhydrous potassium carbonate (1.66g, 12mmol) join in there-necked flask, add 100mL acetone, slowly be warming up to 50 DEG C, drip 1, 2-ethylene dibromide (3.10g, 16mmol), drip after finishing and continue reaction 48h, degree is carried out in tlc monitoring reaction, to filtering without after raw material point, collect filtrate, after 40 DEG C of underpressure distillation are spin-dried for solvent, the yellow oil obtained is dissolved in 2mL methyl alcohol, use silica gel column chromatography separation and purification, eluent is sherwood oil and ethyl acetate, adopt gradient elution, the volume ratio of petrol ether/ethyl acetate is increased to 5:1 gradually from 2:1, 60 DEG C of vacuum-dryings obtain white solid N9-bromotrifluoromethane-O
6-benzyl guanine (0.92g, 2.6mmol), productive rate 65%.
UVλ：250,284nm。
IR (KBr compressing tablet) v/cm
-1: 3468.6 (N-(CH
2)
2-); 3319.9 (N-H); 2961.9 (-CH
2-); 1638.1 (C=C); 1262.4 (C-O-C); 1064.3 (C-N); 704.9 (C-Br).
1HNMR(400MHz,CDCl
3)δ：3.71-3.74(t,2H,CH
2)；4.45-4.52(t,2H,CH
2)；4.98(s,2H,NH
2)；5.57(s,2H,CH
2)；7.32-7.52(m,5H,C
6H
5)；7.68(s,1H,CH)。
ESI-MS：m/z348(M+H)
+。
2) N9-(2-amido) ethyl-O
6the synthesis of-benzyl guanine
By gained solid N9-bromotrifluoromethane-O
6-benzyl guanine (0.92g, 2.6mmol) be dissolved in 20mL anhydrous N ' dinethylformamide solution, add potassium phthalimide solid (0.96g, 5.2mmol), temperature control is in 70 DEG C of stirring reaction 8h, solvent is removed in 65 DEG C of underpressure distillation, obtains N9-[2-(N phlhalimide base) ethyl]-O
6-benzyl guanine crude product.Crude product (1.1g, 2.6mmol) is dissolved in 20mL ethanol, and adds 0.6mL hydrazine hydrate, temperature control, in 70 DEG C of stirring and refluxing reaction 4h, makes it that hydrazinolysis occur.Tlc monitoring extent of reaction, to being spin-dried for solvent without 40 DEG C of underpressure distillation after raw material point, residuum is dissolved in 20mL methylene dichloride, and suction filtration removing insolubles, 35 DEG C of underpressure distillation filtrates, 60 DEG C of vacuum-dryings obtain N9-(2-amido) ethyl-O
6-benzyl guanine sterling (0.64g, 2.2mmol), productive rate 85%.
UVλ：249,283nm。
IR (KBr compressing tablet) v/cm
-1: 3438.2 (N-(CH
2)
2-); 3320.4 (N-H); 2958.1 (-CH
2-); 1642.3 (C=C); 1244.7 (C-O-C); 1070.2 (C-N).
1HNMR(400MHz,CDCl
3)δ：2.87-2.94(d,2H,NH
2)；3.08-3.10(t,2H,CH
2)；4.45-4.52(t,2H,CH
2)；5.03(s,2H,NH
2)；5.55(s,2H,CH
2)；7.29-7.50(m,5H,C
6H
5)；7.65(s,1H,CH)。
ESI-MS：m/z285(M+H)
+。
3) N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) synthesis of ethyl carbamide
By N9-(2-amido) ethyl-O
6-benzyl guanine (0.64g, 2.2mmol) be dissolved in 20mL methylene dichloride, drip 2-chloroethyl isocyanate (0.4mL, 4.8mmol), adularescent precipitation produces, 35 DEG C are continued heated and stirred 8h, and 30 DEG C of underpressure distillation are spin-dried for solvent after completion of the reaction, obtain N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) ethyl carbamide crude product, in crude product, add a small amount of deionized water, stir evenly, suction filtration, washing, 60 DEG C of vacuum-dryings obtain N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) ethyl carbamide sterling (0.54g, 1.4mmol), yield 64%.
UVλ：251,283nm。
IR (KBr compressing tablet) v/cm
-1: 3326.9 (N-H); 2960.2 (-CH
2-); 1727.2 (C=O); 1664.9 (C=C); 1285.4 (C-O-C); 1128.4 (C-N); 744.9 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：3.08-3.10(t,2H,CH
2)；3.52-3.55(t,2H,CH
2)；4.09-4.11(d,2H,NH
2)；4.17-4.22(t,2H,CH
2)；4.30-4.33(t,2H,CH
2)；4.80(s,1H,N-H)；5.32(s,1H,N-H)；5.49(s,2H,CH
2)；7.34-7.53(m,5H,C
6H
5)；7.83(s,1H,CH)。
ESI-MS：m/z390(M+H)
+。
4) N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) synthesis of ethyl-N-nitrosourea
By N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) ethyl carbamide (0.54g, 1.4mmol) be dissolved in 14mL formic acid, the mass percent concentration adding new preparation is the sodium nitrite in aqueous solution 1mL (4.3mmol) of 30%, through nitrosation reaction salify, 4 DEG C of stirring reaction 2h, use dehydrated alcohol recrystallization, filtration drying, use cold water (4 DEG C) and washing with acetone to precipitate 2 times respectively, obtain N-(2-chloroethyl)-N '-2-(O
6-benzyl-9-guanine base) ethyl-N-nitrosourea sterling (0.30g, 0.7mmol), yield 50%.
UVλ：249,283nm。
IR (KBr compressing tablet) v/cm
-1: 3326.6 (N-H); 2959.7 (-CH
2-); 1726.1 (C=O); 1663.5 (C=C); 1563.6 (N=O); 1280.3 (C-O-C); 1128.1 (C-N); 1073.4 (N-N); 744.8 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：3.15-3.20(t,2H,CH
2)；3.62-3.66(t,2H,CH
2)；4.13-4.17(d,2H,NH
2)；4.22-4.41(t,2H,CH
2)；4.35-4.38(t,2H,CH
2)；5.25(s,1H,N-H)；5.62(s,2H,CH
2)；7.37-7.57(m,5H,C
6H
5)；7.87(s,1H,CH)。
ESI-MS：m/z419(M+H)
+。
Embodiment 2:N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) synthesis of propyl group-N-nitrosourea (compound 2)
1) N9-bromopropyl-O
6the synthesis of-benzyl guanine
Take O
6-benzyl guanine (0.48g, 2mmol), Anhydrous potassium carbonate (0.55g, 4mmol) joins in there-necked flask, add 50mL acetone, be slowly warming up to 40 DEG C, drip 1,3-dibromopropane (1.62g, 8mmol), drips after finishing and continues reaction 72h.Tlc monitoring reaction carries out degree, to filtering without after raw material point.Collect filtrate, after 35 DEG C of decompressions are spin-dried for solvent, the yellow oil obtained is dissolved in 1mL methyl alcohol, use silica gel column chromatography separation and purification, eluent is sherwood oil and ethyl acetate, and adopt gradient elution, petrol ether/ethyl acetate volume ratio is increased to 5:1 gradually from 2:1.60 DEG C of vacuum-dryings obtain white solid N9-bromopropyl-O
6-benzyl guanine (0.51g, 1.4mmol), productive rate 70%.
UVλ：250,284nm。
IR (KBr compressing tablet) v/cm
-1: 3452.4 (N-(CH
2)
3-); 3312.6 (N-H); 2947.9 (-CH
2-); 1634.7 (C=C); 1258.9 (C-O-C); 1052.7 (C-N); 733.9 (C-Br).
1HNMR(400MHz,CDCl
3)δ：2.73-2.78(m,2H,CH
2)；3.53-3.58(t,2H,CH
2)；4.26-4.32(t,2H,CH
2)；4.57(s,2H,NH
2)；5.39(s,2H,CH
2)；7.24-7.32(m,5H,C
6H
5)；7.68(s,1H,CH)。
ESI-MS：m/z362(M+H)
+。
2) N9-(3-amido) propyl group-O
6the synthesis of-benzyl guanine
By gained solid N9-bromopropyl-O
6-benzyl guanine (0.51g, 1.4mmol) be dissolved in 10mL anhydrous N ' dinethylformamide solution, add potassium phthalimide solid (0.56g, 3mmol), temperature control is in 75 DEG C of stirring reaction 6h, and 70 DEG C of underpressure distillation are removed solvent and obtained N9-[3-(N phlhalimide base)-propyl group]-O
6-benzyl guanine crude product.Crude product (0.6g, 1.4mmol) is dissolved in 10mL ethanol, and adds 0.3mL hydrazine hydrate, temperature control, in 75 DEG C of stirring and refluxing reaction 3h, makes it that hydrazinolysis occur.Tlc monitoring extent of reaction, to being spin-dried for solvent without 40 DEG C of underpressure distillation after raw material point, residuum is dissolved in 10mL methylene dichloride, and suction filtration removing insolubles, 30 DEG C of underpressure distillation filtrates, 60 DEG C of vacuum-dryings obtain N9-(3-amido) propyl group-O
6-benzyl guanine sterling (0.30g, 1.0mmol), productive rate 71%.
UVλ：249,284nm。
IR (KBr compressing tablet) v/cm
-1: 3440.6 (N-(CH
2)
3-); 3319.4 (N-H); 2960.2 (-CH
2-); 1652.8 (C=C); 1236.5 (C-O-C); 1069.7 (C-N).
1HNMR(400MHz,CDCl
3)δ：2.56-2.61(m,2H,CH
2)；3.24(s,2H,NH
2)；3.82-3.87(t,2H,CH
2)；4.40-4.45(t,2H,CH
2)；5.03(s,2H,NH
2)；5.53(s,2H,CH
2)；7.25-7.46(m,5H,C
6H
5)；7.69(s,1H,CH)。
ESI-MS：m/z299(M+H)
+。
3) N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) synthesis of propyl group urea
By N9-(3-amido) propyl group-O
6-benzyl guanine (0.30g, 1.0mmol) be dissolved in 10mL methylene dichloride, drip 2-chloroethyl isocyanate (0.2mL, 2.4mmol), adularescent precipitation produces, 40 DEG C are continued heated and stirred 6h, and 35 DEG C of underpressure distillation are spin-dried for solvent after completion of the reaction, obtain N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) propyl group urea crude product, in crude product, add a small amount of deionized water, stir evenly, suction filtration, washing, 60 DEG C of vacuum-dryings obtain N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) propyl group urea sterling (0.24g, 0.6mmol), yield 60%.
UVλ：251,283nm。
IR (KBr compressing tablet) v/cm
-1: 3335.2 (N-H); 2961.9 (-CH
2-); 1730.5 (C=O); 1662.5 (C=C); 1292.4 (C-O-C); 1126.7 (C-N); 735.6 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：2.73-2.78(m,2H,CH
2)；3.53-3.58(t,2H,CH
2)；4.26-4.32(t,2H,CH
2)；4.57(s,2H,NH
2)；5.39(s,2H,CH
2)；7.24-7.32(m,5H,C
6H
5)；7.88(s,1H,CH)。
ESI-MS：m/z404(M+H)
+。
4) N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) synthesis of propyl group-N-nitrosourea
By N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) propyl group urea (0.24g, 0.6mmol) be dissolved in 6mL formic acid, the mass percent concentration adding new preparation is the sodium nitrite in aqueous solution 0.6mL (2.6mmol) of 30%, through nitrosation reaction salify, 0 DEG C of stirring reaction 3h, uses dehydrated alcohol recrystallization, filtration drying, use cold water (4 DEG C) and washing with acetone to precipitate 2 times respectively, obtain N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) propyl group-N-nitrosourea sterling (0.13g, 0.3mmol), yield 50%.
UVλ：249,283nm。
IR (KBr compressing tablet) v/cm
-1: 3325.7 (N-H); 2961.2 (-CH
2-); 1722.5 (C=O); 1661.5 (C=C); 1549.3 (N=O); 1276.8 (C-O-C); 1122.7 (C-N); 1069.5 (N-N); 742.5 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：2.55-2.60(m,2H,CH
2)；3.06-3.11(t,2H,CH
2)；3.60-3.65(t,2H,CH
2)；4.09-4.12(d,2H,NH
2)4.19-4.25(t,2H,CH
2)；4.30-4.34(t,2H,CH
2)；5.23(s,1H,NH)；5.58(s,2H,CH
2)；7.32-7.53(m,5H,C
6H
5)；7.85(s,1H,CH)。
ESI-MS：m/z433(M+H)
+。
Embodiment 3:N-(2-chloroethyl)-N '-3-(O
6-benzyl-9-guanine base) synthesis of ethyl-N-nitrosourea (compound 3)
1) N9-brombutyl-O
6the synthesis of-benzyl guanine
Take O
6-benzyl guanine (1.93g, 8mmol), Anhydrous potassium carbonate (2.21g, 16mmol) joins in there-necked flask, add 150mL acetone, slowly be warming up to 60 DEG C, drip Isosorbide-5-Nitrae-dibromobutane (6.91g, 32mmol), drip after finishing and continue reaction 40h, tlc monitoring reaction carries out degree, to filtering without after raw material point.Collect filtrate, after 40 DEG C of decompressions are spin-dried for solvent, the yellow oil obtained is dissolved in 4mL methyl alcohol, with silica gel column chromatogram separating purification, eluent is sherwood oil and ethyl acetate, adopt gradient elution, petrol ether/ethyl acetate volume ratio is increased to 5:1 gradually from 2:1, and 60 DEG C of vacuum-dryings obtain white solid N9-brombutyl-O
6-benzyl guanine (1.35g, 5.0mmol), productive rate 63%.
UVλ：250,284nm。
IR (KBr compressing tablet) v/cm
-1: 3436.8 (N-(CH
2)
4-); 3309.5 (N-H); 2942.0 (-CH
2-); 1638.2 (C=C); 1256.2 (C-O-C); 1063.2 (C-N); 729.3 (C-Br).
1HNMR(400MHz,CDCl
3)δ：2.26-2.30(m,2H,CH
2)；2.53-2.58(m,2H,CH
2)；3.46-3.48(t,2H,CH
2)；4.15-4.18(t,2H,CH
2)；4.47(s,2H,NH
2)；5.32(s,2H,CH
2)；7.18-7.27(m,5H,C
6H
5)；7.72(s,1H,CH)。
ESI-MS：m/z376(M+H)
+。
2) N9-(4-amido) butyl-O
6the synthesis of-benzyl guanine
By gained solid N9-brombutyl-O
6-benzyl guanine (1.35g, 5.0mmol) be dissolved in 30mL anhydrous N ' dinethylformamide solution, add potassium phthalimide solid (1.85g, 10mmol), temperature control is in 80 DEG C of stirring reaction 6h, and 75 DEG C of underpressure distillation are removed solvent and obtained N9-[4-(N phlhalimide base)-butyl]-O
6-benzyl guanine crude product.Crude product (2.1g, 5.0mmol) is dissolved in 30mL ethanol, and adds 1.2mL hydrazine hydrate, temperature control, in 70 DEG C of stirring and refluxing reaction 5h, makes it that hydrazinolysis occur.Tlc monitoring extent of reaction, extremely without after raw material point, 35 DEG C of underpressure distillation are spin-dried for solvent, and residuum is dissolved in 20mL methylene dichloride, and suction filtration removing insolubles, 40 DEG C of underpressure distillation filtrates, 60 DEG C of vacuum-dryings obtain N9-(4-amido) butyl-O
6-benzyl guanine sterling (1.10g, 3.5mmol), productive rate 70%.
UVλ：249,283nm。
IR (KBr compressing tablet) v/cm
-1: 3438.6 (N-(CH
2)
4-); 3320.5 (N-H); 2973.8 (-CH
2-); 1660.3 (C=C); 1231.7 (C-O-C); 1062.8 (C-N).
1HNMR(400MHz,CDCl
3)δ：2.23-2.28(m,2H,CH
2)；2.53-2.58(m,2H,CH
2)；3.22(s,2H,NH
2)；3.79-3.82(t,2H,CH
2)；4.35-4.39(t,2H,CH
2)；5.07(s,2H,NH
2)；5.50(s,2H,CH
2)；7.23-7.39(m,5H,C
6H
5)；7.75(s,1H,CH)。
ESI-MS：m/z313(M+H)
+。
3) N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) synthesis of N-Butylurea
By N9-(4-amido) butyl-O
6-benzyl guanine (1.10g, 3.5mmol) be dissolved in 30mL methylene dichloride, drip 2-chloroethyl isocyanate (0.6mL, 7.0mmol), adularescent precipitation produces, 45 DEG C are continued heated and stirred 7h, and 40 DEG C of underpressure distillation are spin-dried for solvent after completion of the reaction, obtain N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) N-Butylurea crude product, in crude product, add a small amount of deionized water, stir evenly, suction filtration, washing, 60 DEG C of vacuum-dryings obtain N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) N-Butylurea sterling (0.89g, 2.1mmol), yield 60%.
UVλ：251,283nm。
IR (KBr compressing tablet) v/cm
-1: 3329.2 (N-H); 2963.7 (-CH
2-); 1727.0 (C=O); 1660.4 (C=C); 1296.4 (C-O-C); 1131.2 (C-N); 741.8 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：2.27-2.33(m,2H,CH
2)；2.58-2.63(m,2H,CH
2)；3.55-3.59(t,2H,CH
2)；4.27-4.33(t,2H,CH
2)；4.59(s,2H,NH
2)；5.43(s,2H,CH
2)；7.26-7.35(m,5H,C
6H
5)；7.86(s,1H,CH)。
ESI-MS：m/z418(M+H)
+。
4) N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) synthesis of butyl-N-nitroso urea
By N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) N-Butylurea (0.89g, 2.1mmol) be dissolved in 21mL formic acid, the mass percent concentration adding new preparation is the sodium nitrite in aqueous solution 2mL (8.7mmol) of 30%, through nitrosation reaction salify, 5 DEG C of stirring reaction 3h, use dehydrated alcohol recrystallization, filtration drying, use cold water (4 DEG C) and washing with acetone to precipitate 2 times respectively, obtain N-(2-chloroethyl)-N '-4-(O
6-benzyl-9-guanine base) butyl-N-nitroso urea sterling (0.49g, 1.1mmol), yield 52%.
UVλ：249,283nm。
IR (KBr compressing tablet) v/cm
-1: 3320.6 (N-H); 2963.3 (-CH
2-); 1719.3 (C=O); 1663.7 (C=C); 1545.0 (N=O); 1282.4 (C-O-C); 1120.5 (C-N); 1072.9 (N-N); 738.9 (C-Cl).
1HNMR(400MHz,CDCl
3)δ：2.20-2.27(m,2H,CH
2)；2.53-2.58(m,2H,CH
2)；3.02-3.06(t,2H,CH
2)；3.55-3.59(t,2H,CH
2)；4.03-4.07(d,2H,NH
2)；4.17-4.23(t,2H,CH
2)；4.26-4.30(t,2H,CH
2)；5.21(s,1H,NH)；5.53(s,2H,CH
2)；7.30-7.51(m,5H,C
6H
5)；7.82(s,1H,CH)。
ESI-MS：m/z447(M+H)
+。
The antitumor activity evaluation of the novel chlorethylnitrosourea compound that the present invention obtains is as follows:
Experimental example 1: the evaluation of anti-tumor activity
1, experiment material and instrument
Test compound: compound 1,2 and 3 obtained in above-mentioned preparation embodiment;
Clone: mouse leukemia cell L1210, human brain neuroglial cytoma SF763, SF767, SF126, SF188 and human colon cancer cell HT29.
2, experimental technique
Six kinds of tumour cells inoculate 96 orifice plates with 1000/ hole respectively, at 37 DEG C, and 5%CO
2cultivate after 24 hours, change with the carmustine (positive controls) of series concentration (1 μM, 5 μMs, 10 μMs, 50 μMs, 100 μMs, 200 μMs, 400 μMs and 1000 μMs), BCNU+20 μM O
6-benzyl guanine (drug combination group), compound 1, compound 2 and compound 3, and negative control group (20 μMs of O are set
6-benzyl guanine), often organize 5 multiple holes, act on 48 hours.Then, in every hole, add 10 μ LCCK-8 solution, act on 4 hours.Finally, be determined at the absorbance at 450nm place, calculate cytoactive as follows, and calculate half inhibiting rate IC by regression analysis
50.
Cell mortality (%)=(control group OD
450– drug treating group OD
450)/control group OD
450× 100
3, experimental result: in table 1
Table 1: the half inhibiting rate (IC of tumour cell
50, μM)
| Compound | L1210 | SF763 | SF767 | SF126 | SF188 | HT29 |
| Positive controls | 35±4 | 186±8 | 65±4 | 55±5 | 192±6 | 247±12 |
| Drug combination group | 28±2 | 97±8 | 43±4 | 33±4 | 123±9 | 149±9 |
| 1 | 18±1 | 67±4 | 32±2 | 19±2 | 77±4 | 95±8 |
| 2 | 22±1 | 71±6 | 37±3 | 21±3 | 75±5 | 92±7 |
| 3 | 20±3 | 75±7 | 38±4 | 21±4 | 80±9 | 101±10 |
Table 1 result shows:
Compared with positive controls (BCNU group), the IC of compound 1,2 and 3 to 6 kinds of tumour cells
50be worth lower, show that compound 1,2 and 3 is all significantly improved than BCNU to the restraining effect of 6 kinds of tumour cells.
With drug combination group (BCNU+20 μM of O
6-benzyl guanine) to compare, compound 1,2 and 3 pairs of tumor inhibitory effect are higher.
Negative control group (O
6-benzyl guanine group) to 6 kinds of tumour cells all without obvious restraining effect.
Experimental result shows, compound provided by the invention is than existing chlorethylnitrosourea and and O thereof
6the drug combination of-benzyl guanine has higher tumors inhibition activity, can be used for antitumor.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (13)
1. the compound with antitumour activity of a logical formula I structure:
Wherein: n is the integer of 2-6.
2. compound according to claim 1, it is characterized in that, n is 2,3 or 4.
3. prepare a method for compound described in claim 1 or 2, the reaction formula of the method is as follows:
Specifically comprise the following steps:
1) by O
6-benzyl guanine a is dissolved in acetone, adds Anhydrous potassium carbonate wherein and drips dibromoalkane hydrocarbon Br-(CH
2)
n-Br, with O
6there is the substitution reaction of N9 position in-benzyl guanine, heat and stir and make its reacting generating compound b, tlc monitoring extent of reaction, to filtering without after raw material point, collect filtrate, after underpressure distillation is spin-dried for solvent, the yellow oil obtained is dissolved in methyl alcohol, use silica gel column chromatography separation and purification, obtain compound b;
2) by step 1) the compound b that obtains is dissolved in N ' dinethylformamide, and add potassium phthalimide, heated and stirred reacts to obtain compound c, the thick product of compound c is obtained after underpressure distillation, gained compound c crude product is dissolved in ethanol, adds hydrazine hydrate, heated and stirred refluxes, make it that hydrazinolysis occur, tlc monitoring extent of reaction, extremely without underpressure distillation after raw material point, residuum is dissolved in methylene dichloride, suction filtration removing insolubles, distills to obtain compound d by filtrate decompression;
3) by step 2) the compound d that obtains is dissolved in methylene dichloride, add 2-chloroethyl isocyanate, adularescent precipitation produces, and heated and stirred, generates Verbindung after completion of the reaction, underpressure distillation obtains Verbindung crude product, add a small amount of deionized water wherein, stir evenly, suction filtration, washing, 60 DEG C of vacuum-dryings obtain Verbindung;
4) by step 3) e that obtains is dissolved in formic acid, and add the sodium nitrite in aqueous solution of new preparation, through nitrosation reaction salify, use dehydrated alcohol recrystallization, filtration drying, precipitating 2 times with cold water and washing with acetone respectively must compound f.
4. method according to claim 3, is characterized in that, described step 1) in:
Described O
6-benzyl guanine, Anhydrous potassium carbonate and dibromoalkane hydrocarbon Br-(CH
2)
nthe mol ratio of-Br is 1:1-4:2-10;
Temperature of reaction controls at 30-70 DEG C;
Reaction times is 12-80h;
During underpressure distillation, temperature controls at 25-60 DEG C;
Silica gel column chromatography eluent used is sherwood oil and ethyl acetate, and adopt gradient elution, petrol ether/ethyl acetate volume ratio is increased to 5:1 gradually from 2:1.
5. method according to claim 4, is characterized in that, described step 1) in:
Described O
6-benzyl guanine, Anhydrous potassium carbonate and dibromoalkane hydrocarbon Br-(CH
2)
nthe mol ratio of-Br is 1:2-3:4-6;
Temperature of reaction controls at 40-60 DEG C;
Reaction times is 40-72h;
During underpressure distillation, temperature controls at 30-40 DEG C;
Silica gel column chromatography eluent used is sherwood oil and ethyl acetate, and adopt gradient elution, petrol ether/ethyl acetate volume ratio is increased to 5:1 gradually from 2:1.
6. method according to claim 3, is characterized in that, described step 2) in:
The mol ratio of described compound b and potassium phthalimide is 1:1-4;
The temperature of reaction of described compound b and potassium phthalimide controls at 50-90 DEG C; Reaction times is 4-12h;
After reactant b and potassium phthalimide react, vacuum distillation temperature controls at 40-80 DEG C;
Compound c is 2-6mmol:1mL with the materials ratio of hydrazine hydrate;
The stirring and refluxing temperature of compound c and hydrazine hydrate controls at 50-90 DEG C; Time is 1-8h;
During twice underpressure distillation after hydrazinolysis, temperature all controls at 30-70 DEG C.
7. method according to claim 6, is characterized in that, described step 2) in:
The mol ratio of described compound b and potassium phthalimide is 1:2-2.1;
The temperature of reaction of described compound b and potassium phthalimide controls at 65-80 DEG C; Reaction times is 6-8h;
After reactant b and potassium phthalimide react, vacuum distillation temperature controls at 60-75 DEG C;
Compound c is 4-4.5mmol:1mL with the materials ratio of hydrazine hydrate, and the concentration of hydrazine hydrate is 70%;
The stirring and refluxing temperature of compound c and hydrazine hydrate controls at 60-80 DEG C; Time is 3-5h;
During twice underpressure distillation after hydrazinolysis, temperature all controls at 30-50 DEG C.
8. method according to claim 3, is characterized in that, described step 3) in:
The mol ratio of compound d and 2-chloroethyl isocyanate is 1:1-4;
Temperature during reaction controls at 30-50 DEG C; Time is 2-10h;
Vacuum distillation temperature controls at 20-40 DEG C.
9. method according to claim 8, is characterized in that, described step 3) in:
The mol ratio of compound d and 2-chloroethyl isocyanate is 1:2-2.4;
Temperature during reaction controls at 35-45 DEG C; Time is 6-8h;
Vacuum distillation temperature controls at 30-40 DEG C.
10. method according to claim 3, is characterized in that, described step 4) in:
The mass percent concentration of described sodium nitrite in aqueous solution is 20%-50%;
The amount ratio of Verbindung, formic acid and Sodium Nitrite is 1mmol:8-10mL:2-8mmol;
The described nitrosation reaction time is 1-5h; Temperature of reaction controls at 0-10 DEG C.
11. methods according to claim 10, is characterized in that, described step 4) in:
The mass percent concentration of described sodium nitrite in aqueous solution is 25%-35%;
The amount ratio of Verbindung, formic acid and Sodium Nitrite is 1mmol:10mL:3-4.2mmol;
The described nitrosation reaction time is 2-3h; Temperature of reaction controls at 0-5 DEG C.
12., containing the preparation of compound described in claim 1 or 2, is characterized in that, are made up of compound and pharmaceutically acceptable carrier.
The application in antitumor drug prepared by compound described in 13. claims 1 or 2 or preparation according to claim 12, and described tumour is glioma brain tumour, colorectal carcinoma or leukemia.
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