CN109942608A - A kind of more boron phenylalanine class compounds and its preparation method and application containing nitroimidazole - Google Patents

A kind of more boron phenylalanine class compounds and its preparation method and application containing nitroimidazole Download PDF

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CN109942608A
CN109942608A CN201910121794.XA CN201910121794A CN109942608A CN 109942608 A CN109942608 A CN 109942608A CN 201910121794 A CN201910121794 A CN 201910121794A CN 109942608 A CN109942608 A CN 109942608A
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boron
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formula
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陈海燕
李瑞熙
袁振伟
何晴
王菲
万浩
张娟娟
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention discloses a kind of as led to more boron phenylalanine class compounds or its pharmaceutically acceptable salt containing nitroimidazole shown in formula (I), and its preparation method and application.Compound of the present invention can by substitution, addition, nitrification and deprotection reaction be made, have the advantage that boron that is at low cost, easily prepared, can provide high-content and to tumour cell have very high affinity, to tumor hypoxia region have specificity response, stability is good, bio-toxicity is low.The pharmaceutical composition of boron-containing compound of the present invention, in BNCT with good application prospect.

Description

A kind of more boron phenylalanine class compounds containing nitroimidazole and preparation method thereof and Using
Technical field
The invention belongs to more boron phenylalanine class compound technicals, and in particular to a kind of more boron benzene containing nitroimidazole Alanine class compound and its preparation method and application.
Background technique
Boron neutron capture therapy (Boron Neutron Capture Therapy, BNCT) is a kind of promising targeting Chemoluminescence therapy, advanced boron medicine research and development be always BNCT technology key, the continuous development of BNCT technology is to boron medicine Research and propose claimed below: (1) bio-toxicity is low；(2) cancer target specificity is high；(3) effective enrichment of boron source.Boric acid and its Derivative, enclosed borine are as first generation boron medicine, and since absorption efficiency is low, or in vivo, the residence time is short, in BNCT technology In development quickly replaced second generation boron medicine.
Currently, second generation boron medicine L- boron phenylalanine (BPA) and 11 hydrogen of sulfydryl, ten hypoboric acid sodium (BSH) have entered BNCT Clinical test.Derivative of the BPA for phenylalanine, tumor-targeting with higher, in glioma, melanoma and neck Bio distribution in portion cancer patient realizes tumor/blood (T/B) ratio by 1.1 to 3.5 or more raising, tumour/normal Tissue (T/N) ratio is 1.1-3.0.However, BPA boron content is low, therapeutic dose is big, it is low to heterogeneous strong tumour adaptability, Be unevenly distributed in tumour, biological half-life it is short.BSH is a kind of anionic boron alkane derivatives, and each molecule contains 12 boron atoms, Only needing less therapeutic dose i.e. can reach needed for effective BNCT10B level (20-35ppm).But BSH lacks active transport energy Power, tumour-specific accumulation ability is low and cytotoxicity is big, while having the tendency that being oxidized in air causing chemical stability Difference is restricted its application.
Summary of the invention
Goal of the invention: in view of the above technical problems, more boron phenylalanine classes containing nitroimidazole that the present invention provides a kind of Compound and its preparation method and application, the compound can provide high-content boron, to tumour cell have it is very high affine Power, have the response of specificity to tumor hypoxia region, stability is good, bio-toxicity is low, and there is preferable application in BNCT Prospect.
Technical solution: in order to achieve the above object of the invention, the technical solution adopted in the present invention is as follows:
It is a kind of as led to more boron phenylalanine class compounds containing nitroimidazole shown in formula (I) or its is pharmaceutically acceptable Salt:
Wherein, R1For carborane, n1=1-5；R2For the imidazoles or imdazole derivatives group of nitration, n2=1-5；With-NH2 Connected C is chiral carbon (connecting key in general formula is represented by curve), and configuration can may be S configuration for R configuration.
And the compound existence form of formula (I) can be the form of pharmaceutically acceptable salt.For example, with inorganic acid shape At salt, such as hydrochloric acid；The salt formed with organic acid, such as trifluoroacetic acid；The salt formed with metal, such as sodium salt or sylvite；Alkaline earth gold Belong to salt, such as calcium or magnesium salts.
The compound existence form of formula (I) is also possible to pharmaceutically acceptable solvate forms, such as hydrate, with And the form of non-solvent compound.
The compound existence form of formula (I) can also be pharmaceutically acceptable stereomeric mixture, as mapping is different Structure body mixture and/or non-enantiomer mixture.Further, it can be according to the compound of formula (I) pharmaceutically acceptable Single stereoisomers form, such as single enantiomter and/or diastereoisomer.May be used also according to the compound of formula (I) In the form of being pharmaceutically acceptable racemic mixture and the equimolar mixture of enantiomter.
Carborane is defined here as an at least carbon atom and is included into the compound in polyhedral boranes, can be with For natural carborane, or the carborane being transformed by isotope.It is anti-swollen to be applied to BNCT in the compound of the formula (I) When tumor, at least one boron atom is in carborane10B。
The carborane is preferably the caged carborane containing 8-11 boron atom.
Further preferably, R is constituted in formula (I)1Carborane may is that
Wherein, the expansion site of R1 is carbon atom (being connect by C atom with the parent nucleus of general formula I)；It is o-, m-, to carbon boron Alkane and its anion nido compound can be by high temperature and strong lewis bases, such as alkoxide (alkoxides), amine (amines), It is mutually converted under the action of the conditions such as fluoride (fluorides) or N- heterocycle carbine (N-heterocyclic carbenes).
It is preferred that the imidazoles or imdazole derivatives group of the nitration are selected from nitroimidazole or nitrobenzimidazole.
Further preferably, R is constituted in formula (I)2Nitration imidazoles or imdazole derivatives group may is that
Wherein,Expression is connected to n2Position in shown carbochain.
The preparation method of more boron phenylalanine class compounds, including by the position the phenyl ring 3- amido of compound III Change, is then successively reacted with compound II and VI, finally slough protecting group R4And R5To get；
Wherein, R4For the protecting group of carboxyl, R5For the protecting group of amido, " (H) " represents N atom and is connected with H atom, and Pass through singly-bound (such as N-C, N-O, N-S) and R5H atom is not present in connection, and N atom is directly and R5Connection forms imines (N=C) Or tertiary amine；R3For Cl, Br, I, OTs or OMs；N'=1-5；R6For Cl, Br, I, OTs or OMs, n=1-5.
As preferred:
The R4Selected from the blocking group that can form ester group, amide or hydrazides with carboxyl, R5It is protected selected from alkoxy carbonyl group class Base, acyl group class protecting group or alkyls protecting group.
The synthetic method of the compound II and VI is as follows:
Substitution reaction:
Wherein, X Cl, Br, I, OTs or OMs, n'=1-5；
Addition and substitution reaction:
Wherein, n=1-5.
It is further preferred: the compound of formula (I) through the following steps that preparation method realize:
(1) substitution reaction
In Formula II, X Cl, Br, I, OTs or OMs, R3Indicate Cl, Br, I, Ots or OMs；N'=1-5.
The specific method that Formula II compound is obtained by reaction are as follows: nitroimidazole is dissolved in solvent, alkalinity examination is added Agent, replaces reagent at catalytic reagent, and room temperature obtains Formula II compound to 80 DEG C of reactions.
Wherein the solvent is N,N-dimethylformamide, acetone, acetonitrile, toluene, ethyl alcohol, methanol, 1,4- dioxy six Ring, the single or mixed solvent of tetrahydrofuran；
Wherein the alkaline reagent is potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, vinegar Sour sodium, sodium ethoxide, sodium methoxide.
Wherein the catalyst is tetrabutylammonium iodide, tetrabutyl ammonium fluoride, tetrabutylammonium bromide, sodium iodide, iodate Potassium, 18- crown ether -6 and 15- crown ether -5.
(2) nitration reaction
In above formula, R4For person's carboxyl-protecting group, term " protecting group of carboxyl ", which refers to, forms ester group, amide or acyl with carboxyl The blocking group of hydrazine, including but not limited to alkyl, phenyl, alkyl-substituted amino.Wherein, " alkyl " preferably has 1-20 The substituted or unsubstituted straight chain of the substituent group of carbon atom or the alkyl containing branch, such as methyl, ethyl, isopropyl, tert-butyl, two Benzyl, benzyl, to nitrobenzyl, to methoxy-benzyl, 4- pyridine benzyl, trichloroethyl, methylthioethyl, to toluene sulphur Acyl ethyl, p-nitrophenyl thio-ethyl etc.；R5For the protecting group of amino.In the present invention, R5Protecting group as amino can be with Respectively protecting group, including but not limited to alkoxy carbonyl group class protecting group, acyl group class protecting group, alkyls protecting group；R5It can also be with Imines (C=N) is formed with N to protect amino；Both the above protecting group form all should be in " the protection of amino of the present invention Within the scope of the understanding of base ".Wherein, the alkoxy carbonyl group class protecting group includes but is not limited to: benzyloxycarbonyl group (Cbz), tertiary butyloxycarbonyl Base (Boc), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen Carbonyl.The acyl group class protecting group includes but is not limited to: phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoro second Acyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, benzoyl.The alkyls protecting group includes but unlimited In: trityl (Trt), 2,4- dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), benzyl (Bn).Pass through formula III It closes object and obtains formula IV compound through nitration reaction, specifically: formula III compound being dissolved in acid flux material, preferably acetic acid. It is charged with nitrating agent again, 0 DEG C to 70 DEG C reaction obtains formula IV compound.
Wherein, the acid reagent is acetic acid, sulfuric acid, hydrochloric acid, nitric acid and its mixed solvent, preferably acetic acid；The nitre Change reagent is nitric acid, dinitrogen pentoxide etc., preferably fuming nitric aicd；
(3) addition and substitution reaction
In above formula, R6Indicate that Cl, Br, I, OTs, OMs, n are expressed as the carbochain containing 1-5 carbon atom.Specifically, making R1 React the method for obtaining Formula V are as follows: by R1Shown carborane is dissolved in ether or tetrahydrofuran, and alkalinity examination is added at -75 DEG C to 0 DEG C Agent adds formaldehyde (paraformaldehyde or formalin), ethylene oxide, oxetanes and is reacted to obtain Formula V compound.
Wherein, the alkaline reagent is lithium diisopropylamine, double trimethyl silicon substrate lithium amides, double trimethyl silicon substrate ammonia Base sodium, double trimethyl silicon substrate potassamides, n-BuLi, tert-butyl lithium or tetrabutyl ammonium fluoride.
The method for making Formula V compound obtain the compound of Formula IV by reaction are as follows: Formula V compound is dissolved in solvent, is added Enter alkali, halogenating agent, sulfonylation agent or organic phosphonate reagent, reaction obtains Formula IV compound.
Wherein, the solvent is methylene chloride, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane etc.；
The alkali be triethylamine, n,N-diisopropylethylamine, 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene etc., Imidazoles；
The halogenating agent are as follows: N- chlorosuccinimide, N- bromo-succinimide, N- N-iodosuccinimide, bromine Element, iodine, phosphorus trichloride, carbon tetrabromide；
The sulfonylation agent are as follows: paratoluensulfonyl chloride, methylsufonyl chloride.
(4) reduction reaction
In Formula VII compounds process for production thereof, R4, R5With definition same as described above；
Specifically, reacting the method for obtaining Formula VII compound by formula IV compound are as follows: be dissolved in formula IV compound molten In agent, reducing agent is added or catalyst, room temperature obtain Formula VII compound to 60 DEG C of reactions.
Wherein the solvent is acetic acid, concentrated hydrochloric acid, acetone, acetonitrile, N,N-dimethylformamide, toluene, ethyl alcohol, first Alcohol, Isosorbide-5-Nitrae-dioxane, the single or mixed solvent of tetrahydrofuran；
Wherein the reducing agent or catalyst be lithium aluminium hydride, sodium hydrosulfite, sodium borohydride, Raney's nickel, iron powder, zinc powder, One or more reagents of stannous chloride, hydrogen, palladium carbon, hydrazine hydrate, ammonium chloride, boron trifluoride, titanium trichloride etc..
(5) addition and substitution reaction
In Formula VIII compounds process for production thereof, R2, R3, R4, R5, n', n ", n2With definition same as described above；
Specifically, reacting to obtain Formula VIII compound from different nitroimidazole compounds by Formula VII compound Method are as follows: Formula VII compound is dissolved in solvent, alkaline reagent is added, adds catalyst, room temperature obtains formula to 85 DEG C of reactions VIII compound.
Wherein the solvent is acetone, acetonitrile, N,N-dimethylformamide, toluene, ethyl alcohol, methanol, 1,4- dioxy six Ring, the single or mixed solvent of tetrahydrofuran；
Wherein the alkaline reagent is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, vinegar Sour sodium, sodium ethoxide, sodium methoxide.
Wherein the catalyst is tetrabutyl ammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, sodium iodide, iodate Potassium, 18- crown ether -6 and 15- crown ether -5.
(6) substitution reaction
In Formula IX compounds process for production thereof, R1、R2、R4、R5、R6、n、n1、n2With definition same as described above；
Specifically, reacting the method for obtaining Formula IX compound by Formula VIII and Formula IV compound are as follows: by Formula VIII It closes object and Formula IV compound is dissolved in solvent, alkaline reagent, catalyst is added, room temperature obtains Formula IX compound to 120 DEG C of reactions.
Wherein the solvent is acetone, acetonitrile, N,N-dimethylformamide, toluene, ethyl alcohol, methanol, 1,4- dioxy six Ring, the single or mixed solvent of tetrahydrofuran；
Wherein the alkaline reagent is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, vinegar Sour sodium, sodium ethoxide, sodium methoxide.
Wherein the catalyst is tetrabutyl ammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, sodium iodide, iodate Potassium, 18- crown ether -6 and 15- crown ether -5.
(7) deprotection base
By Formula IX compound deprotection base preparation of compounds of formula I, specifically, passing through the method for Formula IX preparation formula I Are as follows: Formula IX compound is dissolved in solvent, acid is added and/or alkali reacts to obtain compound of formula I.
The wherein solvent are as follows: acetone, acetonitrile, N,N-dimethylformamide, toluene, ethyl alcohol, methanol, 1,4- dioxy six Ring, tetrahydrofuran, methylene chloride, the single or mixed solvent of chloroform.
The wherein acid are as follows: formic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid, trimethyl iodine silicon Alkane, trim,ethylchlorosilane, alchlor, dibrominated zinc, the acid such as boron trifluoride and its complex compound or lewis acid；
The wherein alkali are as follows: lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium carbonate, sodium bicarbonate, vulcanization Sodium, NaHS, sodium orthophosphate, disodium hydrogen phosphate.
The present invention is containing more boron phenylalanine class compounds of nitroimidazole or its pharmaceutically acceptable salt in preparing boron Application in muon capture method tumor, i.e., formula (I) compound is suitable for BNCT.It specifically, can be by formula (I) compound What is be applicable in for BNCT includes tumour derived from central nervous system, preferably glioma, such as glioblastoma, nerve Glioma sarcomatosum, low level astrocytoma, hair cell shape astrocytoma, oligodendroglioma or brain stem glioma； Meningioma；Peripheral nerve epithelioma；Intramedullary primitive neuroectodermal tumor；Neuroblastoma；Gonioma；Metastatic encephaloma.
Alternatively, formula (I) compound can be used for treating malignant tumour or metastatic tumo(u)r process, preferred melanoma, preceding Column gland cancer, liver cancer, lung cancer, breast cancer or sarcoma.
The present invention provides purposes of the compound of formula (I) in terms of preparing the drug for treating tumour.
The drug can be used for treating the tumour for being derived from central nervous system, preferably glioma, such as colloid mother Cytoma, human anaplastic astrocytoma, low level astrocytoma, hair cell shape astrocytoma, is dashed forward at atypical hyloma less Glioma or brain stem glioma；Meningioma；Peripheral nerve epithelioma；Intramedullary primitive neuroectodermal tumor；Neuroblast Tumor；Gonioma；Metastatic encephaloma.
Alternatively, the drug can be used for treating malignant tumour or metastatic tumo(u)r process, preferably glioma, recurrent head Tumor colli, malignant mela noma, sarcoma, breast cancer or metastatic hepatic carcinoma.Above mentioned treatment can be used as individually It treats and applies, or other conventional operations or chemotherapy other than boron neutron capture therapy.
The present invention finally additionally provides a kind of pharmaceutical composition, it includes more boron phenylalanine class compounds or its Pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
Pharmaceutically acceptable auxiliary material of the present invention refers to that the various routines needed for being added when preparing different dosage forms are auxiliary Material, such as diluent, binder, disintegrating agent, glidant, lubricant, corrigent, inclusion material, adsorbent material etc. are with routine Formulation method is prepared into any common preparation, such as can be granule, powder, tablet, capsule, pill, takes orally Liquid, decoction, pill, injection etc..
Because carborane has higher boron content, relatively low toxicity and metabolism inertia.The structure of boron-containing compound is excellent Change and functionalized modification is one of the available strategy for improving boron medicine tumour accumulation ability.Therefore the present invention cannot effectively be covered for BPA Lid anoxic zones and the problem of boron content is low and BSH lacks active transport ability and poor chemical stability, in conjunction with tumour cell The microenvironment of locating tissue has the feature of conspicuousness compared with the physiological environment of normal tissue, highly expressed using tumor locus L-amino acid transports receptor 1 (LAT1) as transhipment target spot and nitro imidazole derivatives and carries out structural modification to boron medicine.Nitro miaow Azoles is classical hypoxia markers, can be converted into amine under anoxic conditions, so that adduct is formed with albumen containing sulfydryl, and it is normal Such protein adducts can not generate under physiological environment.Base is identified in conjunction with the recognition group and anoxic to tumour with high specific Group, to obtain related boron-containing compound, collaboration improves boron medicine to the recognition capability of tumor locus, is expected to realize boron medicine in tumour The specific high concentration at position is enriched with.
Technical effect: compared with the existing technology, the present invention provides new boron-containing compound, the compound is former from commercialization Material sets out, and by simply nitrifying, addition, reduction, substitution and deprotection reaction obtain.Reagent used in the method for the present invention It is cheap and easy to get, easy to operate, easily prepared.Its bio-toxicity is lower, and anoxic, normal oxygen tumour cell in boron content have it is bright Significant difference is different, and more traditional BNCT drug BPA is excellent, has a good application prospect in terms of BNCT treatment.
Detailed description of the invention
Fig. 1 compound S5 nuclear magnetic resonance spectroscopy；
Fig. 2 compound s 6 nuclear magnetic resonance spectroscopy；
Fig. 3 compound S8 nuclear magnetic resonance spectroscopy；
MTT experiment figure of Fig. 4 compound Ia to L02 cell line, MCF7 cell line and U87 cell line；
Fig. 5 compound Ia is under anoxic and normal oxygen condition of culture in L02 cell line, MCF7 cell line and U87 cell line Boron content.
Specific embodiment
Embodiment 1
(1) preparation of S1 compound
2- nitroimidazole (500mg, 4.42mmol) is dissolved in 3ml n,N-Dimethylformamide, potassium carbonate is added 1,3- dibromopropane (1.79ml, 17.69mmol), reaction overnight, TLC is added in (1.22g, 8.84mmol) under stirring Monitoring discovery raw material fully reacting.Three times using ethyl acetate (15ml) and water (15ml) extraction, merge organic phase and will subtract The crude product that pressure distillation obtains chromatographs (petroleum ether: ethyl acetate=5:1) isolated tan solid Compound S1 through column, amounts to 760mg, yield 73%.
1H NMR (600MHz, Chloroform-d) δ 7.21 (s, 1H), 7.17 (s, 1H), 4.63 (t, J=6.1Hz, 2H), 3.38 (t, J=5.9Hz, 2H), 2.45-2.38 (m, 2H)
(2) preparation of S2 compound
2- nitroimidazole (500mg, 4.42mmol) is dissolved in 3ml n,N-Dimethylformamide, potassium carbonate is added The bromo- 4- chlorobutane (1.21ml, 10.44mmol) of 1-, reaction overnight, TLC is added in (1.22g, 8.84mmol) under stirring Monitoring discovery raw material fully reacting.Three times using ethyl acetate (15ml) and water (15ml) extraction, merge organic phase and will subtract The crude product that pressure distillation obtains chromatographs (petroleum ether: ethyl acetate=5:1) isolated tan solid Compound S2 through column, amounts to 750mg, yield 83%.
1H NMR (400MHz, Chloroform-d) δ 7.51 (d, J=7.3Hz, 1H), 7.40 (d, J=7.5Hz, 1H), 4.15 (t, J=7.1Hz, 2H), 3.57 (t, J=7.1Hz, 2H), 1.94 (m, 2H), 1.79 (m, 2H)
(3) preparation of S3 compound
4- nitroimidazole (500mg, 4.42mmol) is dissolved in 3ml n,N-Dimethylformamide, potassium carbonate is added Isosorbide-5-Nitrae-dibromobutane (1.32ml, 11.05mmol) is added under stirring in (1.22g, 8.84mmol), reaction overnight, TLC Monitoring discovery raw material fully reacting.Three times using ethyl acetate (15ml) and water (15ml) extraction, merge organic phase and will subtract The crude product that pressure distillation obtains chromatographs (petroleum ether: ethyl acetate=5:1) isolated tan solid Compound S3 through column, amounts to 780mg, yield 71%.
1H NMR (400MHz, Chloroform-d) δ 7.81 (d, J=1.3Hz, 1H), 7.49 (d, J=0.9Hz, 1H), 4.27 (t, J=6.6Hz, 2H), 3.37 (t, J=6.0Hz, 2H), 2.45-2.33 (m, 2H)
(4) preparation of S4 compound
N-Boc methyl-P-tyrosine (500mg, 1.69mmol) is dissolved in 3ml glacial acetic acid, is slowly dropped into thereto at room temperature Fuming nitric aicd (0.098ml, 2.2mmol), after room temperature reaction about 1 hour, TLC monitoring discovery raw material fully reacting.Using full PH value is adjusted to 7 with sodium bicarbonate solution, is reused ethyl acetate (15ml) and water (15ml) extraction three times, is merged organic phase simultaneously The crude product that vacuum distillation is obtained chromatographs (petroleum ether: ethyl acetate=8:1) isolated yellow solid compound S4 through column, altogether Count 400mg, yield 69%.
1H NMR (500MHz, Chloroform-d) δ 7.84-7.90 (m, 1H), 7.37 (dd, J=2.1,8.5Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 4.57 (d, J=6.1Hz, 1H), 3.76 (s, 3H), 3.16-3.02 (m, 2H), 1.42 (s, 9H).
(5) preparation of S5 compound
Intermediate S4 (1.5g, 4.41mmol) is dissolved in 20ml ethyl acetate, 150mg palladium is added under stirring Carbon places reaction liquid into atmosphere of hydrogen, and reaction monitoring finds raw material fully reacting under the conditions of 40 DEG C.Vacuum distillation obtains white Color solid chemical compound S5 amounts to 970mg, yield 76%.
1H NMR (600MHz, Chloroform-d) δ 6.61 (d, J=7.4Hz, 1H), 6.50 (s, 1H), 6.38 (d, J= 7.2Hz, 1H), 5.05 (d, J=8.1Hz, 1H), 4.49 (q, J=6.1Hz, 1H), 3.70 (s, 3H), 2.91 (hept, J= 6.1Hz,2H),1.41(s,9H).
(6) preparation of S6 compound
Intermediate S5 (200mg, 0.644mmol) is dissolved in 5ml acetone, potassium carbonate is added under stirring (267mg, 1.93mmol), tetrabutylammonium iodide (230mg, 0.773mmol) and S1 (226mg, 0.97mmol) is added.In It is reacted at 56 DEG C about 2 hours, TLC monitoring discovery raw material fully reacting.It is extracted using ethyl acetate (15ml) and water (15ml) Three times, merge organic phase and the crude product for obtaining vacuum distillation is isolated through column chromatography (petroleum ether: ethyl acetate=10:1) Pale yellow oily liquid S6 amounts to 126mg, yield 42%.
1H NMR (500MHz, Chloroform-d) δ 7.14 (d, J=7.7Hz, 2H), 6.62 (d, J=7.1Hz, 1H), 6.36 (d, J=9.4Hz, 2H), 4.96 (d, J=7.1Hz, 1H), 4.57 (t, J=7.0Hz, 2H), 4.54-4.48 (m, 1H), 3.71 (s, 4H), 3.19 (s, 2H), 2.97 (d, J=5.7Hz, 2H), 2.26-2.14 (m, 2H), 1.41 (s, 9H)
(7) preparation of S7 compound
Intermediate S5 (200mg, 0.644mmol) is dissolved in 5ml tetrahydrofuran, double trimethyl silicon substrates are added under stirring Amido lithium (1.6ml, 1.6mmol), adds S7'(217mg, 0.74mmol) it is stirred to react.It is small that about 2 are reacted under room temperature When, TLC monitoring discovery raw material fully reacting.Three times using ethyl acetate (15ml) and water (15ml) extraction, merge organic phase And the crude product for obtaining vacuum distillation chromatographs (petroleum ether: ethyl acetate=10:1) isolated pale yellow oily liquid through column S6 amounts to 136mg, yield 44%.
1H NMR (500MHz, Chloroform-d) δ 7.14 (d, J=7.7Hz, 2H), 6.62 (d, J=7.1Hz, 1H), 6.36 (d, J=9.4Hz, 2H), 4.96 (d, J=7.1Hz, 1H), 4.57 (t, J=7.0Hz, 2H), 4.54-4.48 (m, 1H), 3.71 (s, 4H), 3.19 (s, 2H), 2.97 (d, J=5.7Hz, 2H), 2.32-2.16 (m, 2H), 2.26-2.14 (m, 2H), 1.41(s,9H).
(8) preparation of S8 compound
S7 (80mg, 0.24mmol) and S8'(95mg, 0.36mmol) is dissolved in 5ml n,N-Dimethylformamide, It is added sodium hydride (200mg, 0.6mmol), under nitrogen protection back flow reaction 24 hours.Post-processing uses 25ml water and 25ml Ethyl acetate extracts three times, collects organic phase, and vacuum distillation obtains crude product.Crude product is obtained with silica gel column chromatography separating purification white Color solid chemical compound S8,46mg, yield 41%.
1H NMR (500MHz, Chloroform-d) δ 7.15 (d, J=9.4Hz, 2H), 6.61 (d, J=8.1Hz, 1H), 6.40 (d, J=8.0Hz, 1H), 6.30 (s, 1H), 4.94 (d, J=7.8Hz, 1H), 4.58 (t, J=7.1Hz, 2H), 4.56- 4.49 (m, 1H), 3.94 (t, J=5.6Hz, 2H), 3.86 (s, 1H), 3.71 (s, 3H), 3.21 (t, J=5.9Hz, 2H), 3.02–2.91(m,2H),2.50–2.43(m,2H),2.05–1.97(m,2H),2.73-1.59(m,10H),1.40(s,9H).
(9) preparation of Ia compound
Compound S8 (35mg, 0.067mmol) is dissolved in 2ml methanol first, instills hydrogen-oxygen thereto under room temperature Change lithium solution (10mg, 0.42mmol in 3ml H2O).Reaction is then warming up to 70 DEG C, TLC detection is former after reaction 15 hours Material disappears.With 1M hydrochloric acid tune pH value to 3, extracted using 20ml ethyl acetate.Organic phase is collected, crude product is concentrated to get.By crude product It is dissolved in 1.8ml methylene chloride, instills the trifluoroacetic acid of 1.8ml under condition of ice bath thereto, react 30 minutes, detected through TLC Vacuum distillation removes solvent after showing raw material fully reacting, obtains compound Ia, 18mg, two step yield 62%.
1H NMR(500MHz,DMSO-d6) δ 8.07 (dd, J=9.2,7.3Hz, 1H), 7.77 (dd, J=9.2,7.3Hz, 1H), 7.66 (d, J=3.5Hz, 1H), 7.32 (d, J=3.5Hz, 1H), 6.88 (ddt, J=9.0,0.9Hz, 1H), 6.81 (d, J=9.0Hz, 1H), 6.69 (t, J=5.5Hz, 1H), 6.46 (dt, J=2.1,1.0Hz, 1H), 4.24 (td, J=8.1, 0.8Hz, 2H), 4.04 (t, J=7.3Hz, 2H), 3.74 (tt, J=12.9,9.3Hz, 1H), 3.69 (s, 1H), 3.41-3.31 (m, 2H), 3.11-2.97 (m, 2H), 2.82 (t, J=8.2Hz, 2H), 2.08 (m, 2H), 1.91 (tt, J=8.2,7.3Hz, 2H).2.70-1.62(m,10H).
Experimental example: cytotoxicity experiment
By U87 cell, MCF-7 cell and L02 cell culture in addition 10% (v/v) fetal calf serum, penicillin (80U/ Ml), in the incomplete high glucose medium of DMEM of streptomysin (0.08mg/ML), it is placed in 37 DEG C, 5%CO2It is trained in constant incubator It supports.
(1) by U87 cell, MCF-7 cell and L02 cell in logarithmic growth phase at 0.25% pancreatin digestive juice Reason, it is 1 × 10 that concentration, which is made,6Cell suspension, into 96 porocyte culture plates, it is small that 100 μ L cell suspension cultures 24 are added in every hole When.
(2) concentration gradient probe is added after cell is adherent, each concentration designs 5 multiple holes, every block of plate in 96 orifice plates If one group of blank zeroing hole, drug is not added in interior plus cell suspension.Concentration needed for wherein compound is configured to 2 times with culture medium, 100 μ L are added into corresponding hole respectively, pure culture base group is negative control.Normal oxygen group is placed in 37 DEG C, 5%CO2Constant temperature It is incubated in incubator for 24 hours, anoxic group is placed in 37 DEG C, 2%O2Hypoxia culture box in cultivate for 24 hours.
(3) 96 porocyte culture plates are taken out, and inverted microscope observes the MTT (5mg/ of 20 μ L of every hole addition after cell state ML it is put into incubator after) and is incubated for 4h.
(4) 96 porocyte culture plates are taken out, culture medium is sucked out from hole, the DMSO solution of 150 μ L is added in every hole, sets and shakes Low-speed oscillation 15min on bed.
(5) 96 porocyte culture plates are put into microplate reader and are detected.
Fig. 3 is the cell toxicity test of boracic drug as a result, the bio-compatible done well when concentration is no more than 800 μM Property, in different cell lines IC50Value is above 1000 μM.Based on the characteristic of BNCT treatment method, hypotoxicity is such drug Necessary condition.The lower bio-toxicity of such compound is that its further biologic applications is laid a good foundation.
Embodiment: boron element absorbs merit rating to boracic drug in different cell lines
In order to investigate such boron medicine in tumor hypoxia position accumulation ability, by every kind of cell be divided into normal oxygen group and anoxic group into Row experiment.Normal oxygen group is placed in the cell incubator that oxygen concentration is 20%, and anoxic group is placed in three gas that oxygen concentration is 1% Incubator.
(1) by human normal liver cell L 02, human breast cancer cell line Bcap-37, tri- kinds of cell strains of human glioma cell U87 from It is taken out in freezing storing box, is put into quick-thawing in 37 DEG C of water-baths.The liquid to have thawed is taken out at 1000g, 5min is centrifuged, removes Supernatant is removed, 1ml culture medium is added into centrifuge tube and blows and beats cell precipitation uniformly, the cell suspending liquid blown and beaten is added to In Tissue Culture Dish, 7ml DMEM culture medium is added.It rocks and is allowed to be placed in cell incubator culture after mixing for 24 hours.
(2) be incubated for for 24 hours after, by these three attached cells use respectively 2ml trypsin digestion and under the speed of 1000g from Heart 5min, discards supernatant liquid, and suitable culture medium piping and druming is added uniformly, divides and is taped against in six orifice plates, every hole adds 2ml, every kind of cell Two boards are spread, are divided into normal oxygen group and anoxic group, wherein normal oxygen group and anoxic group respectively there are three groups of parallel groups.It is placed on normal oxygen incubator Middle culture is for 24 hours.
(3) configured mother liquor is added into every hole, makes 600 μM of ultimate density of boron medicine.Anoxic group is placed on oxygen In the hypoxia culture box that concentration is 1%, normal oxygen group is placed in the normal oxygen incubator that oxygen concentration is 20%.After culture for 24 hours, take Six orifice plates cultivated out are centrifuged after digesting cell with pancreatin, discard supernatant liquid, and 1ml culture medium is added and blows and beats cell precipitation, Piping and druming carries out cell count with blood counting chamber after mixing and records, and calculates the number of cells in every hole.
(4) different groups of cell suspension is dispensed and is marked with EP pipe, be added 0.3ml's into every group of cell HClO4(60%) and the H of 0.6ml2O2(30%), it is placed in after shaking up in 75 DEG C of water-bath and reacts 2h.
(6) reaction solution is collected, 6ml pure water is added.With 0.45 μm of the membrane filtration reaction solution in aperture, every group take 6ml in Different EP pipes, is calculated with the boron concentration that ICP-OES/MS tester measures each sample in conjunction with the cell number of every group of sample 1×107The boron concentration that a cell is absorbed.
Fig. 4 is compound Ia and tradition BNCT drug BPA boron concentration levels in different tumor cell lines.As can be known from the results No matter the boron content of compound Ia improves a lot under normal oxygen or anoxia condition compared with BPA, illustrates that the compound receives neutron The probability of irradiation capture neutron much larger than BPA and then deduces that it should be much better than BPA to the killing ability of tumour cell.

Claims (10)

1. a kind of as led to more boron phenylalanine class compounds containing nitroimidazole shown in formula (I) or its is pharmaceutically acceptable Salt:
Wherein, R1For carborane, n1=1-5；R2For the imidazoles or imdazole derivatives group of nitration, n2=1-5.
2. more boron phenylalanine class compounds according to claim 1, which is characterized in that the carborane, which is selected from, contains 8- The caged carborane of 11 boron atoms.
3. more boron phenylalanine class compounds according to claim 1, which is characterized in that R1Selected from the carbon boron of flowering structure Alkane:
4. more boron phenylalanine class compounds according to claim 1, which is characterized in that the imidazoles or miaow of the nitration Zole derivatives group is selected from nitroimidazole or nitrobenzimidazole.
5. more boron phenylalanine class compounds according to claim 1, which is characterized in that R2Selected from the nitro of flowering structure The imidazoles or imdazole derivatives group of change:
WhereinExpression is connected to n2Position in shown carbochain.
6. the preparation method of more boron phenylalanine class compounds described in claim 1, which is characterized in that including by compound The position phenyl ring 3- of III is aminated, then successively reacts with compound II and VI, finally sloughs protecting group R4And R5To get；
Wherein, R4For the protecting group of carboxyl, R5For the protecting group of amido, " (H) " represents N atom and is connected with H atom, and passes through Singly-bound and R5H atom is not present in connection, and N atom is directly and R5Connection forms imines or tertiary amine；R3For Cl, Br, I, OTs Or OMs；N'=1-5；R6For Cl, Br, I, OTs or OMs, n=1-5.
7. the preparation method of more boron phenylalanine class compounds according to claim 6, which is characterized in that the R4It is selected from The blocking group of ester group, amide or hydrazides, R can be formed with carboxyl5Selected from alkoxy carbonyl group class protecting group, acyl group class protecting group or Person's alkyls protecting group.
8. the preparation method of more boron phenylalanine class compounds according to claim 6, which is characterized in that the compound The synthetic method of II and VI is as follows:
Substitution reaction:
Wherein, X Cl, Br, I, OTs or OMs, n'=1-5；
Addition and substitution reaction:
Wherein, n=1-5.
9. a kind of pharmaceutical composition, which is characterized in that it includes the described in any item more boron phenylalanine classes of claim 1-4 Close object or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
10. more boron phenylalanine class compounds described in claim 1 containing nitroimidazole or its pharmaceutically acceptable salt exist The application in tumor is prepared, the treatment tumour includes drug being used directly to treatment tumour or using boron neutron Tumour is treated in capture ruling by law, and the tumour includes the tumour, malignant tumour or metastatic tumo(u)r process of central nervous system.
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