CN107722010A - A kind of hypoxemia activation chlorethylnitrosourea containing nitroimidazole group and its preparation method and application - Google Patents

A kind of hypoxemia activation chlorethylnitrosourea containing nitroimidazole group and its preparation method and application Download PDF

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CN107722010A
CN107722010A CN201711052556.5A CN201711052556A CN107722010A CN 107722010 A CN107722010 A CN 107722010A CN 201711052556 A CN201711052556 A CN 201711052556A CN 107722010 A CN107722010 A CN 107722010A
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赵丽娇
余然
葛瑶
任婷
宋秀庆
钟儒刚
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Beijing University of Technology
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Beijing University of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine

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Abstract

The present invention relates to the compound or pharmaceutically acceptable salt of formula (I) structure：

Description

A kind of hypoxemia activation chlorethylnitrosourea containing nitroimidazole group and its preparation Methods and applications
Technical field
The present invention relates to pharmaceutical field, and in particular to hypoxemia containing nitroimidazole group activation chlorethylnitrosourea and Its synthetic method.
Background technology
Chlorethylnitrosourea (CENUs) is clinically a kind of important anticancer alkylating agent, clinically applied to brain tumor, bone Myeloma, the treatment of malignant mela noma, malignant lymphoma, lung cancer, breast cancer, stomach cancer and leukaemia.CENUs can be in physiology bar Decomposed under part, caused chloroethyl carbonium ion and DNA guanines O6Alkylation reaction generation O occurs for position6- chloroethyl guanine, then By N1, O6Cytimidine of-ethano- guanine the intermediate further with complementation reacts, finally in guanine N1 positions and It is crosslinked between the N3 positions of cytimidine between formation DNA stocks.Crosslinking hinders DNA duplication in tumour cell and turned between this DNA stocks Record process, mitosis is caused to be normally carried out or so that DNA double chain is broken, final inducing apoptosis of tumour cell.So And the drug resistance that CENUs is shown in clinical practice seriously hinders the further exploitation of such medicine.O6- alkyl bird is fast The repair that purine-DNA alkyl-transferases (AGT) damage to DNA alkanisations is the main reason for causing CENUs drug resistances.AGT is A kind of important DNA repair protein, it can be by DNA guanines O6The alkyl bases such as methyl, chloroethyl, benzyl and benzyl on position Group removes, and is damaged so as to the alkanisation of DNA plerosis.Research shows that AGT passes through O caused by repairing CENUs6- chloroethyl guanine And N1, O6- ethano- guanine, handed over so as to block both alkylated products further to react to be formed between DNA stocks with cytimidine Connection, ultimately resulting in CENUs effectively can not suppress tumour cell and produce drug resistance.
At present, effective AGT inhibitor is designed and developed and by itself and CENUs drug combinations, it has also become block AGT mediations Drug resistance, the important channel for improving CENUs chemotherapy effects.Coming into the AGT inhibitor of clinical experimental stage mainly includes O6- Benzyl guanine and Lomeguatrib (PaTrin-2), both compounds are blocked by consuming the AGT enzymes in tumour cell AGT is to O caused by CENUs6- chloroethyl guanine and N1, O6The repair of-ethano- guanine, and then cause CENUs can effectively cause to be crosslinked between DNA stocks, the final death rate for improving tumour cell.However, both AGT inhibitor are deposited Serious problems be not have tumour cell targeting, with being used in combination of CENUs during, these non-target tropisms AGT inhibitor also inhibits the activity of AGT in normal cell while tumour cell AGT activity is suppressed so that normal cell The DNA as caused by CENUs can not be repaired in time to damage, so as to cause CENUs toxic side effect to significantly increase.Therefore, design tool Novel C ENUs or the AGT inhibitor for having tumor-targeting is the key point to solve the above problems.
Hypoxemia microenvironment is the key character that most solid tumors are different from normal structure, and it is new to explore treatment using tumor hypoxia Strategy is as one of focus of neoplasm targeted therapy.Hypoxemia activation prodrug (HAPs) is based on tumor hypoxia and designs conjunction Into a kind of new compound, their normal tissues are nontoxic or toxicity is relatively low, and releasably have in tumor hypoxia region thin The pharmacophore of cellular toxicity, so as to realize the targeted therapy of tumour.Hypoxemia activation prodrug mainly includes nitro-heteroaromatic chemical combination Thing, N- oxides, quinones, transition metal complex and the compound containing azo group.Nitro glyoxaline compound belongs to nitre Base-aromatic heterocyclic compounds, the medicine of group is activated using nitroimidazole as hypoxemia, under low oxygen conditions, through single electron also The effect of protoenzyme, release pharmacophore is decomposed after electron rearrangement occurs.Therefore it is contemplated that utilizing the above-mentioned of nitro glyoxaline compound Property prepares anticancer compound.
The content of the invention
There is the characteristic of hypoxemia microenvironment using tumor tissues in the present invention, design has synthesized one kind and contained nitroimidazole group New hypoxemia activation joint CENUs prodrugs, the compound can specifically hypoxic tumors region release it is active AGT inhibitor, sensitiveness of the low oxygen area tumour cell to chemotherapeutics is improved to targeting, and then strengthen CENUs pharmacophores Anticancer effect.The compound or the structure of pharmaceutically acceptable salt are such as shown in (I)：
R1For H, Br, CH3, CH2CH3, CH (CH3)2In one kind；
R2For H, NH2, CH3, CH2NH2, CH2One kind in OH；
R3=R4=H, or R3=H, R4=CH3, or R3=R4=CH3；
N is 2-6 integer.
Preferably, R is worked as1For CH3When, the compound or its salt has preferable antitumor activity and selectivity.
It is further preferred that work as R1For CH3, R2For H when, the compound or its salt has more preferably antitumor activity and choosing Selecting property；
Still further preferably, R is worked as1For CH3, R2For H, R3=R4During=H, the antitumor activity of the compound or its salt and Selectivity further improves.
The present invention most preferably, works as R1For CH3, R2For H, R3=R4=H, and when n is 2, i.e., there is following knot respectively During structure formula, the antitumor activity and selectivity of compound or its salt are optimal.
Preferably, the pharmaceutically acceptable salt is hydrochloride, hydrobromate, hydriodate, sulfate, hydrogen sulfate Salt, phosphate, acetate, propionate, butyrate, lactate, mesylate, tosilate, maleate, benzoic acid One or more in salt, succinate, tartrate, citrate, fumarate, taurate, gluconate.
Using this area conventional technology, can equally have into the compound after salt by any of the above-described compound into salt Have and non-salt-forming compound identical pharmacological activity.
Second object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition includes therapeutically effective amount Formula (I) structural compounds or pharmaceutically acceptable salt, and at least one pharmaceutical carrier.
The pharmaceutical carrier is material commonly used in the art, such as disintegrant, dispersant, lubricant, emulsifying agent, stabilizer. Described pharmaceutical composition can use this area conventional meanses to be prepared into pharmaceutically conventional formulation, such as tablet, injection, capsule Agent etc..
Experiments verify that any one above-mentioned compound or its pharmaceutically acceptable salt or pharmaceutical composition can Active AGT inhibitor is specifically discharged in hypoxic tumors region, improves to targeting low oxygen area tumour cell pair The sensitiveness of chemotherapeutics, and then strengthen the anticancer effect of CENUs pharmacophores.
Third object of the present invention is to protect compound of the present invention or the preparation method of pharmaceutically acceptable salt, Its reaction mechanism mechanism of reaction is as follows：
(1) compound a obtains compound b with saturated dihalide hydrocarbon reaction；
(2) compound b reacts to obtain compound c with phthalimide；
(3) compound c first reacts to obtain compound d with triphosgene, and compound d reacts to obtain compound e with nitroimidazole alcohol again；
(4) compound e generations hydrazinolysis reacts to obtain compound f；
(5) compound f reacts to obtain compound g with 2- chloroethyl isocyanates；
(6) compound g reacts to obtain compound h with tetrafluoro boric acid nitrous.
The preferred steps of methods described are：
(1) compound a and alkylene dihalide are according to 1：The mol ratio of (1-6), under the catalytic action of alkali, in 40-60 DEG C Reaction, obtains compound b；
(2) compound b and phthalimide are according to 1：The mol ratio of (1-4), in 40-75 DEG C of reaction, obtain compound c；
(3) it is 2 according to the mol ratio of compound c, triphosgene, nitroimidazole alcohol：(1-5)：(1-4), compound c elder generations and three Phosgene reacts under the conditions of 0-10 DEG C, obtains compound d；Compound d reacts with nitroimidazole alcohol under the conditions of 10-40 DEG C, must change Compound e；
(4) compound e reacts with hydrazine hydrate under the conditions of 25-50 DEG C, obtains compound f；
(5) compound f and 2- chloroethyl isocyanates are according to 1：The mol ratio of (1-6), in 0-10 DEG C of reaction, obtain compound g；
(6) compound g and nitrous tetrafluoroborate are according to 1：The mol ratio of (1-4), reacted at 0-10 DEG C, obtain chemical combination Thing h.
Wherein, in step (1), the alkylene dihalide may be selected from dibromoalkane hydrocarbon or dichloro- alkane, further preferably For dibromoalkane hydrocarbon, dibromoalkane hydrocarbon has higher reactivity, can ensure that reaction is smoothed out, and obtains higher yield Purer product.
In above-mentioned reaction, the concrete operations of step (1)：Compound a is dissolved, catalyst inorganic alkali is added thereto and drips Add the bromic ethers of 1,2- bis-, then reacted under the conditions of 40-60 DEG C, produce compound b；
Wherein, compound a, inorganic base, the mol ratio of the bromic ethers of 1,2- bis- are preferably 1： (1-6)：(1-7)；The nothing Machine alkali is preferably Anhydrous potassium carbonate；Dissolved compound a solvent is preferably acetone or DMF；Step (1) is also The step of including being purified to compound b, specially concentration of reaction solution, separation is carried out to concentrate using column chromatography and carried Pure, preferably the stationary phase of column chromatography is silica gel, and mobile phase is petroleum ether and ethyl acetate, further preferably according to petroleum ether/second Acetoacetic ester (v/v) 1:2 gradually become 1:4 ratio carries out gradient elution and compound b is purified.
The concrete operations of step (2) are：Compound b is with potassium phthalimide according to 1：The mol ratio of (1-4), in 40-75 DEG C of reaction, obtains compound c.
Wherein, reaction dissolvent used in step (2) is preferably acetonitrile or DMF；Step (2) is also wrapped The step of being purified to compound c is included, ethyl acetate and water (v are added specially into reaction solution：V=1:1) extracted, Organic phase is collected, is washed using saturated sodium-chloride water solution, dries, solvent is distilled off and produces.
The concrete operations of step (3) are：Mol ratio according to compound c, triphosgene, nitroimidazole alcohol is 2：(1-5)： (1-4), compound c first react with triphosgene, obtain compound d, and compound d reacts with nitroimidazole alcohol under the conditions of 0-10 DEG C, Obtain compound e.
The concrete operations of step (3) are preferably：Compound c is dissolved, acid binding agent is added, in 0- under inert gas shielding 10 DEG C of solution that dissolving triphosgene is added dropwise, after being added dropwise, in 10-40 DEG C of reaction, generation compound d；Dissolved compound c's is molten Agent is preferably dichloromethane or toluene；Acid binding agent is preferably pyridine or triethylamine.Nitroimidazole alcohol is added into reaction solution again, in 10-40 DEG C of reaction, obtains compound e.
The step of being purified to compound e, specially concentration of reaction solution, concentrate is separated using column chromatography Purification, the preferably stationary phase of column chromatography are silica gel, and mobile phase is petroleum ether and ethyl acetate, further preferably according to petroleum ether/ Ethyl acetate (v/v) 1:1 gradually becomes 1:4 ratio carries out gradient elution and compound e is purified.
The concrete operations of step (4) are：Compound e reacts with hydrazine hydrate under the conditions of 25-50 DEG C, obtains compound f, preferably The molal volume of compound e and 70% hydrazine hydrate ratio is (1-7)： 1(mmol：mL).
Wherein, again with being hydrated hydrazine reaction after compound e is dissolved first, preferably dissolved compound e solvent is DMF or first Alcohol；The step of step (4) also includes purifying compound f, dichloromethane and water (v are added specially into reaction solution：v =1:1) extracted, collect organic phase, washed using saturated sodium-chloride water solution, dried, solvent is distilled off and produces.
The concrete operations of step (5) are：Compound f is with 2- chloroethyl isocyanates according to 1：The mol ratio of (1-6), 0-10 DEG C of reaction, obtains compound g.Wherein, reaction dissolving is preferably dichloromethane, and solvent is distilled off after reaction completely, is added Deionized water washing precipitation, filtration drying produce.
The concrete operations of step (6) are：Compound g, glacial acetic acid and nitrous tetrafluoroborate are according to 1：(1-4)：(1- 4) mol ratio, react under condition of ice bath, obtain compound h.
Wherein, the reaction dissolvent of step (6) is preferably acetonitrile or acetone.Step (6) also includes purifying compound h The step of, after specially reaction terminates, ethyl acetate and water (v are added into reaction solution：V=1:1) extracted, washing is organic Phase, concentration is dried, concentrate is separated using column chromatography, the column chromatography is preferably that stationary phase is silica gel, and mobile phase is Petroleum ether and ethyl acetate, it is 1 further preferably according to petrol ether/ethyl acetate (v/v):1 gradually becomes 1:5 gradient is entered Row elution, is produced.
Compound h of the present invention is the compound described in formula (I).
Above-mentioned preparation method mainly includes the preparation process of the compound described in formula (I), if need to be into salt, after can also carrying out Continuous salt-forming reaction.
Final object of the present invention is protection compound of the present invention or pharmaceutically acceptable salt and medicine Application of the compositions in antineoplastic is prepared.
Preferably, the tumour is brain tumor, myeloma, malignant mela noma, lymph cancer, lung cancer, breast cancer, stomach cancer, knot One or more in intestinal cancer, tumor of prostate, leukaemia；
One or more more preferably in brain tumor, leukaemia, lung cancer, colon cancer, lymph cancer.
Compound or pharmaceutically acceptable salt in the logical formula (I) of the present invention, have anti-drug resistance and tumour for new Cell targeted joint chlorethylnitrosourea, the compound in mutual-through type (I) of the present invention have carried out extracorporeal anti-tumor screening Experiment.As a result show, the compound led under low oxygen conditions in formula (I) is to L1210 mouse leukemia cells, HT29 human colon carcinomas The kinds of tumors such as cell, A549 human pneumonocytes, HUT102 human T lymphoma cells, human glioma cell SF763, SF126 Cell line has an obvious inhibitory action, and suppression of the compound led under aerobic conditions in formula (I) to above-mentioned tumour cell Act on simultaneously unobvious.Therefore, the compound led in formula (I) has good targeting and kills the ability of tumour cell, can be with As targeting tumor chemotherapeutic drug.On the one hand, it can decompose generation chloroethyl carbonium ion in vivo, cause between DNA stocks The generation of crosslinking, play suppress growth of tumour cell effect, on the other hand, nitroimidazole group can optionally in Decomposed in cancer cell under hypoxia condition, discharge O6- benzyl guanine analog pharmacophore, targeting to tumor hypoxia area The AGT in domain plays inhibitory action, reduces tolerance of the tumour cell to nitroso ureas pharmacophore.The work of compound energy selectivity For the tumour cell in anaerobic condition, the toxic side effect of drug combination is reduced, improves the targeting of medicine, it is and existing Nitrosoureas cancer therapy drug, which is compared, has the advantages of drug resistance is lower, active anticancer is higher.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.It is related in following examples Medicine without specified otherwise, commercially available acquisition；The operation being related to, no specified otherwise, it is the conventional operation in this area.
The compound 1 that is related in following examples, the structural formula of compound 2 are as follows：
Embodiment 1：N- (2- bromoethyls)-N ' -3- (O6- benzyl-N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl) 9- Guanyl-) ethyl-N-nitrosourea (compound 1) synthesis
1) N9- bromoethyls-O6The synthesis of-benzyl guanine
Weigh O6- benzyl guanine (1.96g, 8.13mmol), Anhydrous potassium carbonate (3.32g, 24.06mmol) are added to In 100mL round-bottomed flasks, 50mL acetone is added, is to slowly warm up to 52 DEG C, 1,2- Bromofumes (2.8mL, 32mmol) are added dropwise, Drop continues to react 72h after finishing, and filtering reacting liquid, filtrate is collected, after 40 DEG C of vacuum distillations are spin-dried for solvent, with silica gel column chromatography point From purifying, eluant, eluent is petroleum ether and ethyl acetate, and using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 is gradual Increase to 1:4,40 DEG C of vacuum drying obtain white solid N9- bromoethyls-O6- benzyl guanine (1.94g, 5.6mmol), production Rate 69%.
UVλ:248,283nm；
IR (KBr tablettings) υ/cm-1:3467.1(-(CH2)2-N-H)；2957.3(-CH2-)；1633.6 (C=C)； 1249.9(C-O-C)；1065.7(C-N)；687.8(C-Br)；
1H NMR(400MHz,CDCl3)δ:3.78(t,2H,CH2)；4.23(t,2H,CH2)； 5.16(s,2H,CH2)； 6.99(s,2H,NH2)；7.38-7.47(m,5H,C6H5)；8.05 (s,1H,CH)；
ESI-MS:m/z348(M+H)+。
2) N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine
By gained solid N9- bromoethyls-O6- benzyl guanine (1.94g, 5.6mmol), add the anhydrous N of 15mL, N- diformazans Base formyl amine solvent, potassium phthalimide solid (3.36g, 18.2mmol) is added, is heated to 65 DEG C, stirring reaction 6h, extracted with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying mistake Night, 35 DEG C of vacuum drying obtain white solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (1.99g, 4.8mmol), yield 85%.
UVλ:228,284nm；
IR (KBr tablettings) υ/cm-1:3492.4(-(CH2)2-N-H)；2955.9(-CH2-)；1723.9 (C=O)； 1621.9 (C=C)；1256.9(C-O-C)；1069.1(C-N)；
1H NMR(400MHz,CDCl3)δ:4.13(t,2H,CH2)；4.64(t,2H,CH2)； 5.13(s,2H,CH2)； 6.97(s,2H,NH2)；7.39-7.45(m,5H,C6H5)；7.81-7.88 (m,4H,C6H4)；8.09(s,1H,CH)；
ESI-MS:m/z415(M+H)+。
3)N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) ethyl) - O6The synthesis of-benzyl guanine
By gained solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (1.99g, 4.8mmol), add the dissolving of 10mL anhydrous methylene chlorides, add 6mL anhydrous pyridines and be sufficiently stirred, weigh triphosgene (0.89g, 3mmol) it is added in there-necked flask, adds the dissolving of 15mL dichloromethane, by N9- (2- (N- under conditions of ice bath, nitrogen protection Phthalimide-based) ethyl)-O6- benzyl guanine solution is added drop-wise in triphosgene solution, after being added dropwise, ice bath 4h, The dichloromethane solution that 10mL contains 3- methyl -2- nitroimidazole -4- methanol (1.57g, 10mmol) is added, slowly heating To 25 DEG C of reaction 5h, 30 DEG C are evaporated under reduced pressure removing solvent, are isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and acetic acid Ethyl ester, using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 progressively increases to 1:4,30 DEG C of vacuum drying obtain White solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) ethyl)-O6- Benzyl guanine (2.2g, 3.7mmol), yield 77%.
UVλ:225,270nm；
IR (KBr tablettings) υ/cm-1:3489.4(-(CH2)2-N-H)；3327.9(N-H)；3174.9 (C-H)；1797.4 (C=O)；1645.1 (C=C)；1382.4(N-O)；1265.5(C-O-C)； 1086.7(C-N)；
1H NMR(400MHz,CDCl3)δ:3.76(s,3H,CH3)；4.17(t,2H,CH2)； 4.62(t,2H,CH2)； 5.11(s,2H,CH2)；5.48(s,2H,CH2)；7.45(s,1H,CH)； 7.35-7.43(m,5H,C6H5)；7.81-7.86(m, 4H,C6H4)；8.12(s,1H,CH)；9.13 (s,1H,NH)；
ESI-MS:m/z598(M+H)+。
4)N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- amidos) ethyl-O6The synthesis of-benzyl guanine
By gained solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) Ethyl)-O6- benzyl guanine (2.2g, 3.7mmol) is dissolved in 10mLDMF (DMF), and adds 1.2mL water Hydrazine is closed, 32 DEG C of reaction 4h, brings it about hydrazinolysis reaction.Extracted with dichloromethane and deionized water, organic phase saturation chlorine Change sodium water solution washing, anhydrous sodium sulfate drying is overnight, and 30 DEG C are dried in vacuo to obtain N2- (((3- methyl -2- nitroimidazoles) oxygen) Carbonyl)-N9- (2- amidos) ethyl-O6- benzyl guanine (1.5g, 3.2mmol), yield 87%.
UVλ:223,272nm；
IR (KBr tablettings) υ/cm-1:3457.3(N-(CH2)2-)；3327.9(N-H)；3174.9 (C-H)；1789.5(C =O)；1692.6 (C=C)；1426.4(N-O)；1288.7(C-O-C)；1097.4(C-N)；
1H NMR(400MHz,CDCl3)δ:3.13(t,2H,CH2)；3.77(s,3H,CH3)； 4.52(t,2H,CH2)； 5.16(s,2H,NH2)；5.17(s,2H,CH2)；5.42(s,2H,CH2)； 7.41(s,1H,CH)；7.41-7.43(m,5H, C6H5)；8.07(s,1H,CH)；9.11 (s,1H,NH)；
ESI-MS:m/z468(M+H)+。
5) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9- birds are fast Purine base) ethyl carbamide synthesis
By gained solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- amidos) ethyl-O6- benzyl bird Purine (1.5g, 3.2mmol) is dissolved in 10mL dichloromethane, and the 4mL of chloroethyl isocyanate containing 2- (0.68mL, 8mmol) is added dropwise Dichloromethane solution, 0 DEG C of reaction 6h, 30 DEG C are evaporated under reduced pressure to N- (2- chloroethyls)-N ' -2- (N2- (((3- first after completion of the reaction Base -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl carbamide (1.26g, 2.2mmol), yield 69%.
UVλ:224,266nm；
IR (KBr tablettings) υ/cm-1:3345.7(N-H)；3096.2(C-H)；1762.1 (C=O)；1657.9 (C=C)； 1365.4(N-O)；1234.5(C-O-C)；1120.2(C-N)；749.7 (C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.42(t,2H,CH2)；3.61(t,2H,CH2)； 3.62(t,2H,CH2)； 3.73(s,3H,CH3)；4.57(t,2H,CH2)；5.12(s,2H,CH2)； 5.41(s,2H,CH2)；6.1(t,1H,NH)；6.2 (t,1H,NH)；7.43(s,1H,CH)； 7.41-7.49(m,5H,C6H5)；8.04(s,1H,CH)；9.17(s,1H,NH)；
ESI-MS:m/z573(M+H)+。
6) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9- birds are fast Purine base) ethyl-N-nitrosourea synthesis
By gained solid N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl Base -9-guanine base) ethyl carbamide (1.26g, 2.2mmol) is dissolved in 8mL acetonitriles, adds containing glacial acetic acid (224 μ L, 4mmol) 3mL acetonitriles, under condition of ice bath, nitrous tetrafluoroborate (0.48g, 4.1mmol) is added, reacts 5h under condition of ice bath, instead Extracted after answering with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate It is dried overnight, is evaporated under reduced pressure and removes solvent, isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and ethyl acetate, is adopted With gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 progressively increase to 1:4,30 DEG C are dried in vacuo to obtain N- (2- chloroethenes Base)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl-N-nitrosourea (0.78g, 1.3mmol), yield 59%.
UVλ:223,270nm；
IR (KBr tablettings) υ/cm-1:3365.6(N-H)；3024.5(C-H)；1745.1 (C=O)；1685.8 (C=C)； 1574.5 (N=O)；1372.6(N-O)；1293.4(C-O-C)；1132.1 (C-N)；1065.7(N-N)；752.8(C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.42(t,2H,CH2)；3.65(t,2H,CH2)； 3.66(t,2H,CH2)； 3.77(s,3H,CH3)；4.59(t,2H,CH2)；5.18(s,2H,CH2)； 5.45(s,2H,CH2)；6.2(t,1H,NH)；7.47 (s,1H,CH)；7.42-7.49(m,5H,C6H5)； 8.07(s,1H,CH)；9.15(s,1H,NH)；
ESI-MS:m/z602(M+H)+。
Embodiment 2:N- (2- bromoethyls)-N ' -3- (O6- benzyl-N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl) 9- Guanyl-) ethyl-N-nitrosourea (compound 1) synthesis
1) N9- bromoethyls-O6The synthesis of-benzyl guanine
Weigh O6- benzyl guanine (2.22g, 9.2mmol), Anhydrous potassium carbonate (3.38g, 24.5mmol) are added to In 100mL round-bottomed flasks, 50mL acetone is added, is to slowly warm up to 58 DEG C, 1,2- Bromofumes (2.98mL, 34mmol) are added dropwise, Drop continues to react 75h after finishing, and filtering reacting liquid, filtrate is collected, after 40 DEG C of vacuum distillations are spin-dried for solvent, with silica gel column chromatography point From purifying, eluant, eluent is petroleum ether and ethyl acetate, and using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 is gradual Increase to 1:4,40 DEG C of vacuum drying obtain white solid N9- bromoethyls-O6- benzyl guanine (2.33g, 6.7mmol), production Rate 72%.
UVλ:248,283nm；
IR (KBr tablettings) υ/cm-1:3462.3(-(CH2)2-N-H)；2962.3(-CH2-)；1636.3 (C=C)； 1247.1(C-O-C)；1062.4(C-N)；686.3(C-Br)；
1H NMR(400MHz,CDCl3)δ:3.73(t,2H,CH2)；4.29(t,2H,CH2)； 5.12(s,2H,CH2)； 6.95(s,2H,NH2)；7.36-7.44(m,5H,C6H5)；8.12 (s,1H,CH)；
ESI-MS:m/z348(M+H)+。
2) N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine
By gained solid N9- bromoethyls-O6- benzyl guanine (2.33g, 6.7mmol), add 15mL anhydrous N, N- bis- NMF dissolves, and adds potassium phthalimide solid (3.42g, 18.5mmol), is heated to 70 DEG C, stirring is anti- 6h is answered, is extracted with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying Overnight, 35 DEG C of vacuum drying obtain white solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.4g, 5.8mmol), yield 86%.
UVλ:228,284nm；
IR (KBr tablettings) υ/cm-1:3495.2(-(CH2)2-N-H)；2956.4(-CH2-)；1728.1 (C=O)； 1626.5 (C=C)；1262.4(C-O-C)；1072.3(C-N)；
1H NMR(400MHz,CDCl3)δ:4.16(t,2H,CH2)；4.65(t,2H,CH2)； 5.12(s,2H,CH2)； 6.96(s,2H,NH2)；7.34-7.41(m,5H,C6H5)；7.82-7.87 (m,4H,C6H4)；8.12(s,1H,CH)；
ESI-MS:m/z415(M+H)+。
3)N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) ethyl)-O6- The synthesis of benzyl guanine
By gained solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.4g, 5.8mmol), add the dissolving of 10mL anhydrous methylene chlorides, add 5mL anhydrous pyridines and be sufficiently stirred, weigh triphosgene (0.95g, 3.2mmol) it is added in there-necked flask, adds the dissolving of 18mL dichloromethane, by N9- (2- under conditions of ice bath, nitrogen protection (N phlhalimide base) ethyl)-O6- benzyl guanine solution is added drop-wise in triphosgene solution, after being added dropwise, ice bath 5h, the dichloromethane solution that 10mL contains 3- methyl -2- nitroimidazole -4- methanol (1.66g, 10.6mmol) is added, slowly Be warming up to 25 DEG C reaction 5h, 30 DEG C be evaporated under reduced pressure remove solvents, isolated and purified with silica gel column chromatography, eluant, eluent be petroleum ether and Ethyl acetate, using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 progressively increases to 1:4,30 DEG C of vacuum drying Obtain white solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) ethyl) - O6- benzyl guanine (2.75g, 4.6mmol), yield 79%.
UVλ:225,270nm；
IR (KBr tablettings) υ/cm-1:3493.7(-(CH2)2-N-H)；3331.2(N-H)；3175.4 (C-H)；1795.1 (C=O)；1652.4 (C=C)；1386.2(N-O)；1272.4(C-O-C)； 1089.2(C-N)；
1H NMR(400MHz,CDCl3)δ:3.78(s,3H,CH3)；4.12(t,2H,CH2)； 4.65(t,2H,CH2)； 5.13(s,2H,CH2)；5.44(s,2H,CH2)；7.48(s,1H,CH)；7.34-7.41(m,5H,C6H5)；7.81-7.87(m, 4H,C6H4)；8.14(s,1H,CH)；9.17 (s,1H,NH)；
ESI-MS:m/z598(M+H)+。
4)N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- amidos) ethyl-O6The synthesis of-benzyl guanine
By gained solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- (N phlhalimide base) Ethyl)-O6- benzyl guanine (2.75g, 4.6mmol) is dissolved in 12mLDMF (DMF), and adds 1.4mL Hydrazine hydrate, 35 DEG C of reaction 5h, brings it about hydrazinolysis reaction.Extracted with dichloromethane and deionized water, organic phase saturation Sodium-chloride water solution washs, and anhydrous sodium sulfate drying is overnight, and 30 DEG C are dried in vacuo to obtain N2- (((3- methyl -2- nitroimidazoles) Oxygen) carbonyl)-N9- (2- amidos) ethyl-O6- benzyl guanine (1.92g, 4.1mmol), yield 89%.
UVλ:223,272nm；
IR (KBr tablettings) υ/cm-1:3462.4(N-(CH2)2-)；3329.4(N-H)；3168.3 (C-H)；1731.4(C =O)；1695.3 (C=C)；1429.1(N-O)；1292.1(C-O-C)；1092.1(C-N)；
1H NMR(400MHz,CDCl3)δ:3.15(t,2H,CH2)；3.74(s,3H,CH3)； 4.53(t,2H,CH2)； 5.17(s,2H,NH2)；5.19(s,2H,CH2)；5.45(s,2H,CH2)； 7.40(s,1H,CH)；7.41-7.43(m,5H, C6H5)；8.07(s,1H,CH)；9.13 (s,1H,NH)；
ESI-MS:m/z468(M+H)+。
5) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9- birds are fast Purine base) ethyl carbamide synthesis
By gained solid N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-N9- (2- amidos) ethyl-O6- benzyl bird Purine (1.92g, 4.1mmol) is dissolved in 12mL dichloromethane, and chloroethyl isocyanate containing 2- (0.73mL, 8.6mmol) is added dropwise 5mL dichloromethane solutions, 0 DEG C of reaction 6h, 30 DEG C are evaporated under reduced pressure to N- (2- chloroethyls)-N ' -2- (N2- (((3- after completion of the reaction Methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl carbamide (1.66g, 2.9mmol), yield 71%.
UVλ:224,266nm；
IR (KBr tablettings) υ/cm-1:3346.1(N-H)；3098.1(C-H)；1769.2 (C=O)；1663.4 (C=C)； 1371.4(N-O)；1235.4(C-O-C)；1126.9(C-N)；752.7 (C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.40(t,2H,CH2)；3.61(t,2H,CH2)； 3.66(t,2H,CH2)； 3.73(s,3H,CH3)；4.52(t,2H,CH2)；5.14(s,2H,CH2)； 5.46(s,2H,CH2)；6.22(t,1H,NH)； 6.26(t,1H,NH)；7.45(s,1H,CH)； 7.41-7.49(m,5H,C6H5)；8.08(s,1H,CH)；9.17(s,1H,NH)；
ESI-MS:m/z573(M+H)+。
6) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9- birds are fast Purine base) ethyl-N-nitrosourea synthesis
By gained solid N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl Base -9-guanine base) ethyl carbamide (1.66g, 2.9mmol) is dissolved in 10mL acetonitriles, adds containing glacial acetic acid (252 μ L, 4.5mmol) 4mL acetonitriles, under condition of ice bath, add nitrous tetrafluoroborate (0.51g, 4.4mmol), react under condition of ice bath 5.5h, extracted after completion of the reaction with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous Sodium sulphate is dried overnight, and is evaporated under reduced pressure and is removed solvent, is isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and acetic acid second Ester, using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 progressively increase to 1:4,30 DEG C are dried in vacuo to obtain N- (2- Chloroethyl)-N ' -2- (N2- (((3- methyl -2- nitroimidazoles) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl-N- nitrous Base urea (1.08g, 1.8mmol), yield 62%.
UVλ:223,270nm；
IR (KBr tablettings) υ/cm-1:3372.1(N-H)；3024.5(C-H)；1749.1 (C=O)；1682.4 (C=C)； 1571.6 (N=O)；1373.4(N-O)；1299.2(C-O-C)；1132.4 (C-N)；1068.1(N-N)；756.1(C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.42(t,2H,CH2)；3.65(t,2H,CH2)； 3.69(t,2H,CH2)； 3.77(s,3H,CH3)；4.50(t,2H,CH2)；5.20(s,2H,CH2)； 5.45(s,2H,CH2)；6.2(t,1H,NH)；7.47 (s,1H,CH)；7.42-7.49 (m,5H,C6H5)；8.11(s,1H,CH)；9.19(s,1H,NH)；
ESI-MS:m/z602(M+H)+。
Embodiment 3：N- (2- bromoethyls)-N ' -3- (O6- benzyl-N2- (((3- methyl-5-nitros) oxygen) carbonyl) 9- birds are fast Purine base) ethyl-N-nitrosourea (compound 2) synthesis
1) N9- bromoethyls-O6The synthesis of-benzyl guanine
Weigh O6- benzyl guanine (1.98g, 8.23mmol), Anhydrous potassium carbonate (3.33g, 24.12mmol) are added to In 100mL round-bottomed flasks, 50mL acetone is added, is to slowly warm up to 52 DEG C, 1,2- Bromofumes (2.8mL, 32mmol) are added dropwise, Drop continues to react 72h after finishing, and filtering reacting liquid, filtrate is collected, after 40 DEG C of vacuum distillations are spin-dried for solvent, with silica gel column chromatography point From purifying, eluant, eluent is petroleum ether and ethyl acetate, and using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 is gradual Increase to 1:4,40 DEG C of vacuum drying obtain white solid N9- bromoethyls-O6- benzyl guanine (1.98g, 5.7mmol), production Rate 69%.
UVλ:248,283nm；
IR (KBr tablettings) υ/cm-1:3467.1(-(CH2)2-N-H)；2957.3(-CH2-)；1633.6 (C=C)； 1249.9(C-O-C)；1065.7(C-N)；687.8(C-Br)；
1H NMR(400MHz,CDCl3)δ:3.78(t,2H,CH2)；4.23(t,2H,CH2)； 5.16(s,2H,CH2)； 6.99(s,2H,NH2)；7.38-7.47(m,5H,C6H5)；8.05 (s,1H,CH)；
ESI-MS:m/z348(M+H)+。
2) N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine
By gained solid N9- bromoethyls-O6- benzyl guanine (1.98g, 5.7mmol), add 15mL anhydrous N, N- bis- NMF dissolves, and adds potassium phthalimide solid (3.4g, 18..4mmol), is heated to 65 DEG C, stirring is anti- 6h is answered, is extracted with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying Overnight, 35 DEG C of vacuum drying obtain white solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.01g, 4.85mmol), yield 85%.
UVλ:228,284nm；
IR (KBr tablettings) υ/cm-1:3492.4(-(CH2)2-N-H)；2955.9(-CH2-)；1723.9 (C=O)； 1621.9 (C=C)；1256.9(C-O-C)；1069.1(C-N)；
1H NMR(400MHz,CDCl3)δ:4.15(t,2H,CH2)；4.69(t,2H,CH2)； 5.21(s,2H,CH2)； 6.85(s,2H,NH2)；7.33-7.48(m,5H,C6H5)；7.81-7.89 (m,4H,C6H4)；8.12(s,1H,CH)；
ESI-MS:m/z415(M+H)+。
3)N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) ethyl)-O6- benzyl The synthesis of guanine
By gained solid N9- (3- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.01g, 4.85mmol), the dissolving of 10mL anhydrous methylene chlorides is added, 4mL anhydrous pyridines is added and is sufficiently stirred, weigh triphosgene (1.37g, 4.6mmol) is added in there-necked flask, adds the dissolving of 20mL dichloromethane, will under conditions of ice bath, argon gas protection N9- (3- (N phlhalimide base) ethyl)-O6-BG solution is added drop-wise in triphosgene solution, is added dropwise Afterwards, ice bath 6h, it is molten to add the dichloromethane that 12mL contains 3- 5-nitro imidazole -4- methanol (2.29g, 14.6mmol) Liquid, 25 DEG C of reaction 6h, 30 DEG C are evaporated under reduced pressure removing solvent, are isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and second Acetoacetic ester, using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 progressively increase to 1:5,30 DEG C are dried in vacuo To white solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) ethyl)-O6- Benzyl guanine (1.91g, 3.2mmol), yield 66%.
UVλ:226,274nm；
IR (KBr tablettings) υ/cm-1:3492.5(-(CH2)2-N-H)；3362.7(N-H)；3214.2 (C-H)；1841.5 (C=O)；1652.7 (C=C)；1391.5(N-O)；1245.4(C-O-C)； 1061.6(C-N)；
1H NMR(400MHz,CDCl3)δ:3.73(s,3H,CH3)；4.12(t,2H,CH2)； 4.64(t,2H,CH2)； 5.15(s,2H,CH2)；5.43(s,2H,CH2)；7.55(s,1H,CH)； 7.35-7.44(m,5H,C6H5)；7.81-7.88(m, 4H,C6H4)；8.09(s,1H,CH)；9.16 (s,1H,NH)；
ESI-MS:m/z598(M+H)+。
4)N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl-O6The synthesis of-benzyl guanine
By gained solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) second Base)-O6- benzyl guanine (1.91g, 3.2mmol) is dissolved in 12mL DMF, and adds 1.4mL hydrazine hydrates, 35 DEG C of stirring reactions 5h, hydrazinolysis is brought it about, extracted with dichloromethane and deionized water, organic phase is washed with saturated sodium-chloride water solution, nothing Aqueous sodium persulfate is dried overnight, 35 DEG C be dried in vacuo N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl- O6- benzyl guanine (1.12g, 2.4mmol), yield 75%.
UVλ:224,277nm；
IR (KBr tablettings) υ/cm-1:3467.9(-(CH2)2-N-H)；3347.9(N-H)；3014.3 (C-H)；1802.9 (C=O)；1682.1 (C=C)；1417.8(N-O)；1259.5(C-O-C)； 1072.7(C-N)；
1H NMR(400MHz,CDCl3)δ:3.18(t,2H,CH2)；3.76(s,3H,CH3)； 4.54(t,2H,CH2)； 5.15(s,2H,NH2)；5.19(s,2H,CH2)；5.42(s,2H,CH2)； 7.53(s,1H,CH)；7.37-7.42(m,5H, C6H5)；8.07(s,1H,CH)；9.19 (s,1H,NH)；
ESI-MS:m/z468(M+H)+。
5) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) The synthesis of ethyl carbamide
By gained solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl-O6- benzyl guanine (1.12g, 2.4mmol) is dissolved in 15mL dichloromethane, and the 5mL dichloros of chloroethyl isocyanate containing 2- (0.8mL, 10mmol) are added dropwise Dichloromethane, 0 DEG C stirring 5h, after completion of the reaction 30 DEG C be evaporated under reduced pressure to N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl - 5- nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl carbamide (0.92g, 1.6mmol), yield 67%.
UVλ:223,267nm；
IR (KBr tablettings) υ/cm-1:3357.4(N-H)；2997.1(C-H)；1749.3 (C=O)；1676.5 (C=C)； 1357.6(N-O)；1268.4(C-O-C)；1146.7(C-N)；739.8 (C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.45(t,2H,CH2)；3.67(t,2H,CH2)； 3.69(t,2H,CH2)； 3.72(s,3H,CH3)；4.58(t,2H,CH2)；5.17(s,2H,CH2)； 5.42(s,2H,CH2)；6.4(t,1H,NH)；6.5 (t,1H,NH)；7.57(s,1H,CH)；7.38-7.47(m,5H,C6H5)；8.05(s,1H,CH)；9.15(s,1H,NH)；
ESI-MS:m/z573(M+H)+。
6) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) The synthesis of ethyl-N-nitrosourea
By gained solid N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9- Guanyl-) ethyl carbamide (0.92g, 1.6mmol) is dissolved in 10mL acetonitriles, add the 4mL containing glacial acetic acid (264 μ L, 4.6mmol) Acetonitrile, under condition of ice bath, nitrous tetrafluoroborate (0.54g, 4.6mmol) is added, stirring reaction 6h under condition of ice bath, instead Extracted after answering with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate Dry, be evaporated under reduced pressure and remove solvent, isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and ethyl acetate, using ladder Degree elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 progressively increases to 1:4,28 DEG C be dried in vacuo N- (2- chloroethyls)- N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl-N-nitrosourea (0.66g, 1.1mmol), yield 68%.
UVλ:225,272nm；
IR (KBr tablettings) υ/cm-1:3389.6(N-H)；3042.5(C-H)；1797.3 (C=O)；1674.5 (C=C)； 1589.3 (N=O)；1391.4(N-O)；1281.8(C-O-C)；1145.9 (C-N)；1078.6(N-N)；762.2(C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.45(t,2H,CH2)；3.66(t,2H,CH2)； 3.67(t,2H,CH2)； 3.73(s,3H,CH3)；4.57(t,2H,CH2)；5.18(s,2H,CH2)； 5.44(s,2H,CH2)；6.2(t,1H,NH)；7.58 (s,1H,CH)；7.39-7.45(m,5H,C6H5)； 8.06(s,1H,CH)；9.21(s,1H,NH)；
ESI-MS:m/z602(M+H)+。
Embodiment 4：N- (2- bromoethyls)-N ' -3- (O6- benzyl-N2- (((3- methyl-5-nitros) oxygen) carbonyl) 9- birds are fast Purine base) ethyl-N-nitrosourea (compound 2) synthesis
1) N9- bromoethyls-O6The synthesis of-benzyl guanine
Weigh O6- benzyl guanine (2.22g, 9.2mmol), Anhydrous potassium carbonate (3.38g, 24.5mmol) are added to In 100mL round-bottomed flasks, add 50mL acetone, be to slowly warm up to 58 DEG C, be added dropwise 1,2- Bromofumes (3.02mL, 34.5mmol), drop continues to react 75h after finishing, and filtering reacting liquid, collects filtrate, after 40 DEG C of vacuum distillations are spin-dried for solvent, uses silica gel Column chromatography isolates and purifies, and eluant, eluent is petroleum ether and ethyl acetate, using gradient elution, the volume of petrol ether/ethyl acetate Than from 1:2 progressively increase to 1:4,40 DEG C of vacuum drying obtain white solid N9- bromoethyls-O6- benzyl guanine (2.36g, 6.8mmol), yield 74%.
UVλ:248,283nm；
IR (KBr tablettings) υ/cm-1:3462.3(-(CH2)2-N-H)；2959.4(-CH2-)；1631.2 (C=C)； 1242.6(C-O-C)；1060.2(C-N)；681.9(C-Br)；
1H NMR(400MHz,CDCl3)δ:3.71(t,2H,CH2)；4.26(t,2H,CH2)； 5.11(s,2H,CH2)； 6.92(s,2H,NH2)；7.34-7.43(m,5H,C6H5)；8.09 (s,1H,CH)；
ESI-MS:m/z348(M+H)+。
2) N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine
By gained solid N9- bromoethyls-O6- benzyl guanine (2.36g, 6.8mmol), add 15mL anhydrous N, N- bis- NMF dissolves, and adds potassium phthalimide solid (3.42g, 18.5mmol), is heated to 70 DEG C, stirring is anti- 6h is answered, is extracted with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying Overnight, 35 DEG C of vacuum drying obtain white solid N9- (2- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.43g, 5.85mmol), yield 86%.
UVλ:228,284nm；
IR (KBr tablettings) υ/cm-1:3495.6(-(CH2)2-N-H)；2958.2(-CH2-)；1731.95 (C=O)； 1626.2 (C=C)；1263.3(C-O-C)；1075.4(C-N)；
1H NMR(400MHz,CDCl3)δ:4.15(t,2H,CH2)；4.61(t,2H,CH2)； 5.16(s,2H,CH2)； 6.92(s,2H,NH2)；7.41-7.46(m,5H,C6H5)；7.80-7.86 (m,4H,C6H4)；8.11(s,1H,CH)；
ESI-MS:m/z415(M+H)+。
3)N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) ethyl)-O6- benzyl The synthesis of guanine
By gained solid N9- (3- (N phlhalimide base) ethyl)-O6- benzyl guanine (2.43g, 5.85mmol), the dissolving of 13mL anhydrous methylene chlorides is added, 4mL anhydrous pyridines is added and is sufficiently stirred, weigh triphosgene (1.39g, 4.7mmol) is added in there-necked flask, adds the dissolving of 20mL dichloromethane, will under conditions of ice bath, argon gas protection N9- (3- (N phlhalimide base) ethyl)-O6- benzyl guanine solution is added drop-wise in triphosgene solution, is added dropwise Afterwards, ice bath 6h, it is molten to add the dichloromethane that 12mL contains 3- 5-nitro imidazole -4- methanol (2.34g, 14.9mmol) Liquid, 25 DEG C of reaction 6h, 30 DEG C are evaporated under reduced pressure removing solvent, are isolated and purified with silica gel column chromatography, eluant, eluent is petroleum ether and second Acetoacetic ester, using gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:2 progressively increase to 1:5,30 DEG C are dried in vacuo To white solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) ethyl)-O6- Benzyl guanine (2.39g, 4mmol), yield 68%.
UVλ:226,274nm；
IR (KBr tablettings) υ/cm-1:3485.2(-(CH2)2-N-H)；3368.2(N-H)；3211.3 (C-H)；1843.6 (C=O)；1658.1 (C=C)；1385.1(N-O)；1242.7(C-O-C)； 1070.2(C-N)；
1H NMR(400MHz,CDCl3)δ:3.74(s,3H,CH3)；4.16(t,2H,CH2)； 4.60(t,2H,CH2)； 5.16(s,2H,CH2)；5.48(s,2H,CH2)；7.50(s,1H,CH)； 7.41-7.49(m,5H,C6H5)；7.81-7.85(m, 4H,C6H4)；8.12(s,1H,CH)；9.18 (s,1H,NH)；
ESI-MS:m/z598(M+H)+。
4)N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl-O6The synthesis of-benzyl guanine
By gained solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- (N phlhalimide base) second Base)-O6- benzyl guanine (2.39g, 4mmol) is dissolved in 12mLDMF, and adds 1.8mL hydrazine hydrates, 40 DEG C of reaction 5h, makes it Generation hydrazinolysis, is extracted with dichloromethane and deionized water, and organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate It is dried overnight, 35 DEG C are dried in vacuo to obtain N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl-O6- benzyl bird Purine (1.42g, 3.05mmol), yield 76%.
UVλ:224,277nm；
IR (KBr tablettings) υ/cm-1:3472.3(-(CH2)2-N-H)；3349.1(N-H)；3020.4 (C-H)；1812.4 (C=O)；1685.2 (C=C)；1419.2(N-O)；1263.4(C-O-C)； 1075.1(C-N)；
1H NMR(400MHz,CDCl3)δ:3.15(t,2H,CH2)；3.79(s,3H,CH3)；4.51(t,2H,CH2)；5.18 (s,2H,NH2)；5.20(s,2H,CH2)；5.42(s,2H,CH2)； 7.54(s,1H,CH)；7.36-7.43(m,5H,C6H5)； 8.12(s,1H,CH)；9.24 (s,1H,NH)；
ESI-MS:m/z468(M+H)+。
5) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) The synthesis of ethyl carbamide
By gained solid N2- (((3- methyl-5-nitros) oxygen) carbonyl)-N9- (3- amidos) ethyl-O6- benzyl guanine (1.42g, 3.05mmol) is dissolved in 20mL dichloromethane, and the 5mL bis- of chloroethyl isocyanate containing 2- (0.96mL, 12mmol) is added dropwise Chloromethanes solution, 0 DEG C of stirring 5h, 30 DEG C are evaporated under reduced pressure to N- (2- chloroethyls)-N ' -2- (N2- (((3- first after completion of the reaction Base -5- nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl carbamide (1.18g, 2.07mmol), yield 68%.
UVλ:223,267nm；
IR (KBr tablettings) υ/cm-1:3363.2(N-H)；2991.4(C-H)；1752.4 (C=O)；1682.2 (C=C)； 1363.1(N-O)；1272.1(C-O-C)；1151.2(C-N)；743.5 (C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.42(t,2H,CH2)；3.62(t,2H,CH2)； 3.68(t,2H,CH2)； 3.76(s,3H,CH3)；4.59(t,2H,CH2)；5.18(s,2H,CH2)； 5.45(s,2H,CH2)；6.7(t,1H,NH)；6.9 (t,1H,NH)；7.51(s,1H,CH)； 7.38-7.45(m,5H,C6H5)；8.12(s,1H,CH)；9.21(s,1H,NH)；
ESI-MS:m/z573(M+H)+。
6) N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) The synthesis of ethyl-N-nitrosourea
By gained solid N- (2- chloroethyls)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9- Guanyl-) ethyl carbamide (1.18g, 2.07mmol) is dissolved in 12mL acetonitriles, adds containing glacial acetic acid (298 μ L, 4.6mmol) 5mL acetonitriles, under condition of ice bath, nitrous tetrafluoroborate (0.6g, 5.1mmol) is added, stirring reaction 6h under condition of ice bath, Extracted after completion of the reaction with ethyl acetate and deionized water, organic phase is washed with saturated sodium-chloride water solution, anhydrous slufuric acid Sodium is dried, and is evaporated under reduced pressure and is removed solvent, is isolated and purified with silica gel column chromatography, and eluant, eluent is petroleum ether and ethyl acetate, is used Gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 progressively increases to 1:4,28 DEG C are dried in vacuo to obtain N- (2- chloroethenes Base)-N ' -2- (N2- (((3- methyl-5-nitros) oxygen) carbonyl)-O6- benzyl -9-guanine base) ethyl-N-nitrosourea (0.92g, 1.53mmol), yield 74%.
UVλ:225,272nm；
IR (KBr tablettings) υ/cm-1:3395.1(N-H)；3042.5(C-H)；1791.2 (C=O)；1671.9 (C=C)； 1595.2 (N=O)；1396.1(N-O)；1289.1(C-O-C)；1153.4 (C-N)；1082.1(N-N)；769.1(C-Cl)；
1H NMR(400MHz,CDCl3)δ:3.41(t,2H,CH2)；3.63(t,2H,CH2)； 3.69(t,2H,CH2)； 3.71(s,3H,CH3)；4.55(t,2H,CH2)；5.18(s,2H,CH2)； 5.47(s,2H,CH2)；6.23(t,1H,NH)； 7.54(s,1H,CH)；7.39-7.42 (m,5H,C6H5)；8.16(s,1H,CH)；9.23(s,1H,NH)；
ESI-MS:m/z602(M+H)+。
The antitumor activity evaluation of new chlorethylnitrosourea compound produced by the present invention is as follows：
Experimental example：The evaluation of antitumor activity
1st, experiment material and instrument
Test compound：Compound 1 and 2 made from above-described embodiment preparation；
Cell line：L1210 mouse leukemia cells, HT29 human colon cancer cells, A549 human pneumonocytes, HUT102 people T leaching Bar oncocyte, human glioma cell SF763, SF126
2nd, experimental method
Six kinds of tumour cells are inoculated with 96 orifice plates, at 37 DEG C, 5%CO with 1000/ hole respectively2After culture 24 hours, change to be The BCNU (positive controls) of row concentration (1 μM, 5 μM, 10 μM, 50 μM, 100 μM, 200 μM, 400 μM and 1000 μM), change Compound 1 and compound 2, every group of 5 multiple holes, and control group is set.Above-mentioned each group is acted under aerobic and hypoxia condition respectively 48 hours.Then, to every μ L CCK-8 solution of Kong Zhongjia 10, act on 4 hours.Finally, the absorbance at 450nm is determined, Cytoactive is calculated as follows, and half inhibiting rate IC is calculated by regression analysis50。
Cell survival rate (%)=(ADosing group–ABlank group)/(AControl group–ABlank group)×100
ADosing groupFor the absorbance in the hole with cell, CCK8 solution and drug solution；
ABlank groupFor with culture medium and CCK8 solution without the absorbance in the hole of cell；
A control groups are without the absorbance in the hole of drug solution with cell, CCK8 solution.
3rd, experimental result：It is shown in Table 1
Half inhibiting rate (the IC of the tumour cell of table 150,μM)
The result of table 1 is shown：Under normal oxygen environment, compound 1,2 and positive controls (BCNU group) are thin to 6 kinds of tumours The IC of born of the same parents50Be worth close, show under the conditions of normal oxygen, the inhibiting tumour cells activity of compound 1 and 2 with BCNU difference not Greatly.
Under low-oxygen environment, the IC of 1,2 pair of 6 kinds of tumour cell of compound50Value significantly reduces than positive controls.This shows Compound 1 and 2 can discharge O under low-oxygen environment6- benzyl guanine analog is as AGT inhibitor, so as to block The tumor cell drug resistance of AGT mediations so that the antitumor activity of compound 1 and 2 significantly improves.
Contrast the IC of compound 1 and 2 under normal oxygen and low-oxygen environment50Value, it can be seen that low-oxygen environment under normal oxygen environment than changing The inhibiting tumour cells activity of compound 1 and 2 significantly improves, and shows that compound 1 and 2 has low-oxygen environment selectivity.Therefore, chemical combination Thing 1 and 2 can be selectively applied to the tumour cell being under hypoxia, and avoid to normal under normal oxygen condition Cell causes to damage, so as to reach targeting in the purpose of tumour cell.
Test result indicates that compound provided by the invention has than existing chlorethylnitrosourea under low oxygen conditions Higher tumors inhibition activity；Meanwhile such compound specific can act on tumour cell, be controlled available for cancer target Treat.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art 's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed Scope.

Claims (10)

  1. The compound or pharmaceutically acceptable salt of formula 1. (I) structure：
    R1For H, Br, CH3, CH2CH3, CH (CH3)2In one kind；
    R2For H, NH2, CH3, CH2NH2, CH2One kind in OH；
    R3=R4=H, or R3=H, R4=CH3, or R3=R4=CH3；
    N is 2-6 integer.
  2. 2. compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that R1For CH3；Preferably, R1 For CH3, R2For H；It is furthermore preferred that R1For CH3, R2For H, R3=R4=H.
  3. 3. compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that the compound is selected from such as One kind in lower structural compounds：
  4. 4. compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, it is characterised in that the medicine Acceptable salt is hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionic acid on Salt, butyrate, lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, lemon One or more in lemon hydrochlorate, fumarate, taurate, gluconate.
  5. 5. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes any institute of Claims 1 to 4 of effective dose State compound or pharmaceutically acceptable salt, and at least one pharmaceutical carrier；Described pharmaceutical composition is preferably injection, tablet Or capsule.
  6. 6. the preparation method of any one of Claims 1 to 4 compound or pharmaceutically acceptable salt, it is characterised in that bag Include at least following reaction mechanism mechanism of reaction：
    (1) compound a obtains compound b with saturated dihalide hydrocarbon reaction；
    (2) compound b reacts to obtain compound c with phthalimide；
    (3) compound c first reacts to obtain compound d with triphosgene, and compound d reacts to obtain compound e with nitroimidazole alcohol again；
    (4) compound e generations hydrazinolysis reacts to obtain compound f；
    (5) compound f reacts to obtain compound g with 2- chloroethyl isocyanates；
    (6) compound g reacts to obtain compound h with tetrafluoro boric acid nitrous.
  7. 7. preparation method according to claim 6, it is characterised in that its step is specially：
    (1) compound a and alkylene dihalide are according to 1: the mol ratio of (1-6), under the catalytic action of alkali, are reacted in 40-60 DEG C, Obtain compound b；
    (2) compound b and phthalimide are according to 1: the mol ratio of (1-4), in 40-75 DEG C of reaction, obtain compound c；
    (3) it is 2 according to the mol ratio of compound c, triphosgene, nitroimidazole alcohol: (1-5): (1-4), compound c elder generations and triphosgene Reacted under the conditions of 0-10 DEG C, obtain compound d；Compound d reacts with nitroimidazole alcohol under the conditions of 10-40 DEG C, obtains compound e；
    (4) compound e reacts with hydrazine hydrate under the conditions of 25-50 DEG C, obtains compound f；
    (5) compound f and 2- chloroethyl isocyanates are according to 1: the mol ratio of (1-6), in 0-10 DEG C of reaction, obtain compound g；
    (6) compound g and nitrous tetrafluoroborate are according to 1: the mol ratio of (1-4), are reacted at 0-10 DEG C, obtain compound h.
  8. 8. the preparation method according to claim 6 or 7, it is characterised in that in step (1), the alkylene dihalide is two Brominated alkanes or dichloro- alkane；It is preferred that dibromoalkane hydrocarbon.
  9. 9. medicine group described in the compound or pharmaceutically acceptable salt and claim 5 described in any one of Claims 1 to 4 Application of the compound in antineoplastic is prepared.
  10. 10. application according to claim 9, it is characterised in that：The tumour be brain tumor, myeloma, malignant mela noma, One or more in lymph cancer, lung cancer, breast cancer, stomach cancer, colon cancer, tumor of prostate, leukaemia；It is preferred that brain tumor, white blood One or more in disease, lung cancer, colon cancer, lymph cancer.
CN201711052556.5A 2017-10-31 2017-10-31 A kind of hypoxemia activation chlorethylnitrosourea containing nitroimidazole group and its preparation method and application Pending CN107722010A (en)

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CN109793896A (en) * 2019-03-12 2019-05-24 东华大学 A kind of preparation method of the weary oxygen bimodal contrast agent of radio therapy sensitization type based on dendrimer
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