CN106083854A - A kind of hypoxia activates AGT protein inhibitor and preparation method and application - Google Patents
A kind of hypoxia activates AGT protein inhibitor and preparation method and application Download PDFInfo
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- JTOKJHHSFJUTCP-UHFFFAOYSA-N [O-][N+](c1ccc(COC(CNc2nc(OCc3cc(Br)c[s]3)c3nc[nH]c3n2)=O)cc1)=O Chemical compound [O-][N+](c1ccc(COC(CNc2nc(OCc3cc(Br)c[s]3)c3nc[nH]c3n2)=O)cc1)=O JTOKJHHSFJUTCP-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention provides a kind of hypoxia that has as shown in logical formula (I) and activate AGT protein inhibitor and preparation method and application of characteristic:R1=R2=H, or R1=H, R2=CH3, or R1=R2=CH3；R3=H, NO2, NH2, OCH3, CH2OH or CO2CH3.This compound has good hypoxia and activates characteristic and tumor cell targeting, it is possible to suppress to targeting the activity of AGT in solid tumor under low-oxygen environment, improves the tumor cell sensitivity to chemotherapeutics；The compounds of this invention and ACNU drug combination all have obvious inhibitory action to multiple solid tumor cell system；When being used in combination with alkylating agent kind anti-cancer drugs thing, the tumor cell sensitivity to cancer therapy drug can be significantly improved, can be used for the targeting combined chemotherapy of malignant tumor.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a kind of novel targeting AGT protein inhibitor, its preparation method and
Application.
Background technology
Containing the multiple enzyme with alkanisation injury repairing effect in mammalian cell, wherein O6-alkylguanine-DNA
Alkyl-transferase (AGT) is one of important DNA repair protein.AGT albumen can be by DNA guanine O6Methyl on position, chloroethene
The covalency such as base, benzyl and benzyl are transferred on the 145th cysteine residues at activity itself center, thus the alkane of DNA plerosis
Change damage.Such as, AGT enzyme can repair the DNA alkylated product O that chloroethylnitrosoureas chemotherapeutics causes6-chloroethyl bird is fast
Purine and N1, O6-ethano-guanine, thus blocked both alkylated products and reacted formation dG-dC further with cytosine
Cross-link between Gu, ultimately result in tumor cell and chemotherapeutics is produced drug resistance.In order to block AGT, DNA of tumor cell alkanisation is damaged
Wound repair to reduce the tumor cell drug resistance to chemotherapeutics, design and develop effective AGT inhibitor and by itself and
Alkylating agent kind anti-cancer drugs thing is united and applied in chemotherapy of tumors, it has also become strengthen tumor cell to the sensitivity of chemotherapeutics, raising
The important channel of chemotherapy effect.
At present, the AGT inhibitor coming into clinical experimental stage mainly includes O6-benzyl guanine and
Lomeguatrib (PaTrin-2), both compounds can consume the AGT enzyme in tumor cell, thus reduce the work of AGT
Property.Such as, O6-benzyl guanine can effectively reduce the AGT in human brain neuroglial cytoma SF767 and colon cancer cell HT29
Level, significantly improves the tumor cell sensitivity to Dichloroethyl nitroso ureas.But, existing AGT inhibitor does not has
Tumor cell targeting, during its being used in combination with chemotherapeutics, the AGT inhibitor of these non-target tropisms is swollen in suppression
Be greatly reduced the activity of AGT in normal cell while oncocyte AGT activity so that normal cell can not repair in time by
The DNA damage that chemotherapeutics causes, thus cause the bone marrow depression toxicity of chemotherapeutics to be obviously enhanced, ultimately result in chemotherapy and lose
Lose.
Hypoxia is the key character in solid tumor evolution, and research shows, the partial pressure of oxygen in more than 70% solid tumor is bright
Aobvious less than normal structure.Utilize tumor tissues to there is the characteristic of hypoxia microenvironment, design and develop have hypoxia activate specific
New A GT inhibitor precursor compound, decomposes release AGT under tumor tissues low-oxygen environment with enabling this compound targeting
Inhibitor, and under normal oxygen environment in the normal tissue, do not play AGT inhibitory action, thus it is medication combined with alkylating agent class
Use the targeted chemotherapy realizing tumor.Therefore, design and develop have hypoxia activate characteristic new A GT inhibitor so that it is can
Specifically act on tumor cell and play AGT inhibitory activity, normal thin for improving sensitivity of tumor cells, simultaneously protection
Born of the same parents are not damaged by chemotherapeutics, thus the chemotherapeutic strategies realizing high-efficiency low-toxicity is significant.
Summary of the invention
It is an object of the invention to provide a kind of novel hypoxia and activate AGT inhibitor, its preparation method and application.
In order to realize the object of the invention, the present invention provide a kind of have hypoxia activate characteristic AGT inhibitor, described in press down
Preparation is to have the compound as shown in logical formula (I) structure:
R1=R2=H, or R1=H, R2=CH3, or R1=R2=CH3；
R3=H, NO2, NH2, OCH3, CH2OH, CO2CH3；
Preferably, R is worked as3=NO2Time, described inhibitor is 4-nitrobenzyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-fast
Purine-2) carbamate (compound 1), 1-(4-Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amino
Formic acid esters (compound 2), 2-(4-Nitrobenzol) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (is changed
Compound 3).
The present invention also provides for the preparation method of described three of the above AGT protein inhibitor, and the reaction mechanism mechanism of reaction of described method is:
The concrete synthesis step inventing provided compound is as follows:
(1) 4-thienylmethanol is dissolved in DMF, in reactant liquor, is sequentially added into sodium hydride and change
Compound a, stirring reaction, after reaction terminates, add ethyl acetate and water and extract according to the mixed liquor that volume is 1:1 composition,
Organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and decompression distillation, gained crude product is dissolved in methanol, mistake
Filter decontamination precipitation, after recrystallization, obtain compound b；
(2) adding the ethanol solution containing Sodium ethylate in compound b makes it dissolve, after stirring reaction 10-45min, and vacuum
Draining solvent, the solid obtained is dissolved in organic solvent, adds chloromethyl pivalate, stirring, after reaction terminates, add in solution
Entering ethyl acetate and water to extract according to the mixed liquor that volume is 1:1 composition, organic facies is after saturated aqueous common salt washs, anhydrous
Sodium sulfate is dried, decompression distillation, obtains crude on silica gel column chromatography isolated and purified, obtains compound c；
(3) the compound c of step (2) gained is dissolved in dichloromethane, adds triphosgene, stir under inert gas shielding
Mix reaction, products therefrom compound d continue withReaction, decompression distillation, obtain crude on silica gel column chromatography
Isolated and purified, obtain compound e；
(4) being dissolved in the methanol solution containing ammonia by the compound e of step (3) gained, stirring reaction, thin layer chromatography is supervised
Measured reaction process, after reaction terminates, is collected by filtration solid, and the hypoxia that has obtaining compound f, the i.e. present invention activates the AGT of characteristic
Protein inhibitor.
In said method:
In described step (1):
Described compound a, sodium hydride are 1:1-4:2-5 with the mol ratio of 4-bromothiophene base methanol, preferential 1:2-3:3-4；
Response time controls at 1-4h, preferably 2-3h；
Reaction temperature controls at 20-35 DEG C, preferably 25-35 DEG C；
Vacuum distillation temperature controls at 30-60 DEG C, preferably 30-40 DEG C.
In described step (2):
Described compound b, Sodium ethylate are 1:1-3:2-5 with the mol ratio of chloromethyl pivalate, preferential 1:1-2:2-3；
Selected organic solvent is DMF or dimethyl sulfoxide, preferably DMF；
Compound b controls at 10-45min with the response time of Sodium ethylate, preferably 20-30min；Reaction temperature controls
20-35 DEG C, preferably 25-35 DEG C；Vacuum distillation temperature controls at 30-60 DEG C, preferably 30-40 DEG C；
Compound b and Sodium ethylate react the response time of solid and the chloromethyl pivalate obtained and control at 1-3h, preferably
1-2h；Reaction temperature controls at 20-35 DEG C, preferably 25-35 DEG C；Vacuum distillation temperature controls at 30-60 DEG C, preferably 30-40 DEG C；
Eluant used by silica gel column chromatography is petroleum ether and ethyl acetate, uses gradient elution, petrol ether/ethyl acetate
Volume ratio is 1:1-1:4.
In described step (3):
Described compound c, triphosgene,Mol ratio be 1:1-4:2-5, preferably 1:1-2:2-3；
Selected inert protective gas is nitrogen or argon, preferably argon；
Compound c controls at 0-25 DEG C with the reaction temperature of triphosgene, and the response time is 3-8h, preferably 4-6h, is changed
Compound d；
Compound d withReaction temperature control at 25-40 DEG C, preferably 25-35 DEG C；
Response time is 3-8h, preferably 4-6h；
Vacuum distillation temperature controls at 25-40 DEG C, preferably 25-35 DEG C；
Eluant used by silica gel column chromatography is petroleum ether and ethyl acetate, uses gradient elution, petrol ether/ethyl acetate
Volume ratio is 1:2-1:5.
In described step (4):
Described compound e is 1:0.1-1 (mmol:mL), preferably 1:0.1-0.5 (mmol:mL) with the mol ratio of ammonia；
Response time controls at 20-40h, preferably 30-40h；
Reaction temperature controls at 20-35 DEG C, preferably 25-35 DEG C.
Present invention also offers a kind of pharmaceutical composition, including a) alkylating agent anti-tumor compounds and b) of the present invention
Have hypoxia activate characteristic targeting AGT protein inhibitor.
Described alkylating agent anti-tumor compounds is nimustine.
Hypoxia of the present invention activates AGT protein inhibitor purposes in preparing antitumor drug and belongs to the present invention's
Protection domain.
The aforementioned pharmaceutical compositions of the present invention purposes in preparing antitumor drug falls within protection scope of the present invention.
Embody hypoxia in an embodiment of the present invention and activate the anti-tumor activity of AGT protein inhibitor, described tumor
For leukemia, pulmonary carcinoma, melanoma, T lymphoma, glioma brain tumour, hepatocarcinoma.
The novel hypoxia that the present invention provides activates AGT inhibitor and has the advantage that
(1) present invention provide formula I compound can optionally under low-oxygen environment by solid tumor cell and also
Protoenzyme activates, and 4-nitrobenzyl is reduced to 4-nitro amino or 4-nitro azanol, the counterfeit substrate O of release AGT6-4-bromothiophene
Methyl guanine, thus the activity of AGT in targeting ground suppression solid tumor, improve the tumor cell sensitivity to chemotherapeutics.
(2) compared with existing AGT protein inhibitor, the formula I compound that the present invention provides has higher targeting
Property, AGT inhibitory activity and water solublity.
(3) the extracorporeal anti-tumor screening test that the compound in formula I is carried out by the present invention shows, under low oxygen conditions
Compound in formula I and ACNU drug combination act on human leukemia cell line HL-60, human lung cancer cell A549, human melanin
Oncocyte A375 cell, human T lymphoma cell HUT102, human brain neuroglial cytoma H4, human liver cancer cell BEL-7402 etc.
Multiple solid tumor cell system all demonstrates obvious inhibitory action；And under aerobic conditions, the compound in formula I is to above-mentioned swollen
The inhibitory action of oncocyte is the most inconspicuous.Therefore, the compound in formula I has good hypoxia activation characteristic and tumor cell
Targeting, when being used in combination with alkylating agent kind anti-cancer drugs thing, can significantly improve the tumor cell sensitivity to cancer therapy drug, available
Targeting combined chemotherapy in malignant tumor.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.Following example relate to
Medicine without specified otherwise, the most commercially available acquisition；The operation related to, without specified otherwise, is the operation that this area is conventional.
The compound 1 that relates in following example, compound 2, compound 3 structural formula as follows:
Embodiment 1 4-nitrobenzyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (compound 1)
Synthesis
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.38g, 7.2mmol) and join in 100mL round-bottomed flask, add 20mL N, N-
Dimethylformamide, adds sodium hydride (0.115g, 4.8mmol) and 2-aminopurine-6-leptodactyline chlorine in reactant liquor
Compound (0.547g, 2.4mmol), 25 DEG C, stirring reaction 2h.After reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.52g, 1.6mmol), productivity 67%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3380.1 (N-H)；2956.8(C-H)；1695.7 (C=C)；1094.8(C-N)；
703.8(C-Br)；610.8(C-S).
1H NMR(400MHz,CDCl3)δ:5.16(s,2H,OCH2)；6.54(s,2H,NH2)；6.65-6.87(s,2H,
C4H2BrS)；8.25(s,1H,H8)；13.25(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.52g, 1.6mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.2mL contains Sodium ethylate (0.218g, 3.2mmol) makes it dissolve.25 DEG C, after reaction 20min, very
Sky drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 10mL.Chloromethyl pivalate is added in solution
(0.692mL, 4.8mmol), 25 DEG C, stirring reaction 1h.After question response terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C, decompression distillation,
Isolated and purified to crude on silica gel column chromatography, eluant is petroleum ether and ethyl acetate, employing gradient elution, petroleum ether/
The volume ratio of ethyl acetate progressively increases to 1:4 from 1:1, obtains (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) valeric acid
Methyl ester (0.505g, 1.15mmol), productivity 72%.
UVλ:266,283nm。
IR (KBr tabletting) v/cm-1:3380.4(N-H)；2956.8(C-H)；1690.8 (C=C)；1215.9(C-O-C)；
1087.5(C-N)；706.3(C-Br)；614.6(C-S).
1H NMR(400MHz,CDCl3) δ: 1.16 (s, 3H, CH3)；5.18(s,2H,OCH2)；5.37(s,2H,NCH2)；
6.56(s,2H,NH2)；6.67-6.88(s,2H,C4H2BrS)；8.21(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) valeric acid first
The synthesis of ester
Weigh triphosgene (0.341g, 1.15mmol) and join in two mouthfuls of flask bottles, add 7mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.505g, 1.15mmol), adds 12mL bis-
Chloromethanes dissolves, and adds 0.5mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene first under conditions of ice bath, argon shield
Epoxide)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25 DEG C,
Stirring reaction 4h；In reactant liquor, add 7mL contain the dichloromethane solution of p nitrobenzyl alcohol (0.352g, 2.3mmol), 25
DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompressions are distilled off solvent, use
Silica gel column chromatography is isolated and purified, and eluant is petroleum ether and ethyl acetate, uses gradient elution, petrol ether/ethyl acetate
Volume ratio progressively increases to 1:5 from 1:2, and 30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene methoxyl group)-2-((((4-
Nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.445g, 0.72mmol), productivity 63%.
UVλ:264,285nm。
IR (KBr tabletting) v/cm-1:3425.6(N-H)；2956.8(C-H)；1791.6 (C=O)；1617.8 (C=C)；
1427.2(N-O)；1224.5(C-O-C)；1094.5(C-N)；713.6(C-Br)；618.1(C-S).
1H NMR(400MHz,CDCl3) δ: 1.19 (s, 3H, CH3)；5.17(s,2H,OCH2)；5.34(s,2H,OCH2Ar)；
5.39(s,2H,NCH2)；6.68-6.89(s,2H,C4H2BrS)；7.76-8.42(m,4H,Ar)；8.06(s,1H,H8)；10.20
(s,H,NH)；.
ESI-MS:m/z619 (M+H)+。
4) synthesis of 4-nitrobenzyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) valeric acid first
Ester (0.445g, 0.72mmol) is dissolved in the 40mL methanol solution containing 0.072mol/L ammonia (0.11mL ammonia), 25 DEG C, stirring
Reaction 40h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid 4-nitrobenzyl
Base-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.305g, 0.605mmol), productivity is 84%.
UVλ:264,281nm。
IR (KBr tabletting) v/cm-1:3418.6(N-H)；2963.5(C-H)；1787.8 (C=O)；1625.3 (C=C)；
1431.7(N-O)；1232.6(C-O-C)；1134.1(C-N)；724.5(C-Br)；615.8(C-S).
1H NMR(400MHz,CDCl3)δ:5.18(s,2H,OCH2)；5.34(s,2H,OCH2Ar)；6.63-6.85(s,
2H,C4H2BrS)；7.74-8.27(m,4H,Ar)；8.06(s,1H,H8)；10.51(s,1H,NHCO)；13.27(s,H,H9).
ESI-MS:m/z505(M+H)+。
Embodiment 2 4-nitrobenzyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (compound 1)
Synthesis
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.32g, 6.9mmol) and join in 100mL round-bottomed flask, add 18mL N, N-
Dimethylformamide, adds sodium hydride (0.110g, 4.6mmol) and 2-aminopurine-6-leptodactyline chlorine in reactant liquor
Compound (0.525g, 2.3mmol), 30 DEG C, stirring reaction 2h.After reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.517g, 1.59mmol), productivity 69%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3385.3(N-H)；2963.5(C-H)；1689.3 (C=C)；1085.3(C-N)；
706.2(C-Br)；614.7(C-S).
1H NMR(400MHz,CDCl3)δ:5.18(s,2H,OCH2)；6.59(s,2H,NH2)；6.62-6.89(s,2H,
C4H2BrS)；8.31(s,1H,H8)；13.21(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.517g, 1.59mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.18mL contains Sodium ethylate (0.216g, 3.18mmol) makes it dissolve.30 DEG C, after reaction 20min,
Vacuum drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 10mL.Chloromethyl pivalate is added in solution
(0.687mL, 4.77mmol), 30 DEG C, stirring reaction 1h.After reaction terminates, add ethyl acetate and water is 1:1 group according to volume
The mixed liquor become extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C, decompression distillation, obtains
Crude on silica gel column chromatography is isolated and purified, uses gradient elution, and the volume ratio of petrol ether/ethyl acetate gradually increases from 1:1
It is added to 1:4, obtains (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.509g, 1.16mmol), productivity
73%.
UVλ:266,283nm。
IR (KBr tabletting) v/cm-1:3385.1(N-H)；2963.6(C-H)；1696.1 (C=C)；1219.3(C-O-C)；
1085.8(C-N)；709.5(C-Br)；617.2(C-S).
1H NMR(400MHz,CDCl3)δ:1.15(s,3H,CH3)；5.19(s,2H,OCH2)；5.39(s,2H,NCH2)；
6.61(s,2H,NH2)；6.64-6.89(s,2H,C4H2BrS)；8.25(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) valeric acid first
The synthesis of ester
Weigh triphosgene (0.344g, 1.16mmol) and join in two mouthfuls of flask bottles, add 6mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.509g, 1.16mmol), adds 11mL bis-
Chloromethanes dissolves, and adds 0.45mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene under conditions of ice bath, argon shield
Methoxyl group)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25
DEG C, stirring reaction 4h；Adding 6mL in reactant liquor, to contain the dichloromethane of p nitrobenzyl alcohol (0.355g, 2.32mmol) molten
Liquid, 30 DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompressions are distilled off molten
Agent, isolated and purified with silica gel column chromatography, eluant is petroleum ether and ethyl acetate, uses gradient elution, petroleum ether/acetic acid second
The volume ratio of ester progressively increases to 1:5 from 1:2, and 30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene methoxyl group)-2-
(((4-nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.464g, 0.75mmol), productivity 65%.
UVλ:264,284nm。
IR (KBr tabletting) v/cm-1:3429.3(N-H)；2964.2(C-H)；1782.8 (C=O)；1625.3 (C=C)；
1435.1(N-O)；1236.8(C-O-C)；1081.3(C-N)；718.5(C-Br)；613.7(C-S).
1H NMR(400MHz,CDCl3)δ:1.18(s,3H,CH3)；5.19(s,2H,OCH2)；5.37(s,2H,OCH2Ar)；
5.42(s,2H,NCH2)；6.65-6.87(s,2H,C4H2BrS)；7.74-8.45(m,4H,Ar)；8.09(s,1H,H8)；10.34
(s,H,NH)；.
ESI-MS:m/z619(M+H)+。
4) synthesis of 4-nitrobenzyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-nitrobenzyl) oxygen) carbonyl) amino-9 hydrogen-purine-9) valeric acid first
Ester (0.464g, 0.75mmol) is dissolved in the 40mL methanol solution containing 0.075mol/L ammonia (0.12mL ammonia), 30 DEG C, stirring
Reaction 38h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid 4-nitrobenzyl
Base-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.322g, 0.638mmol), productivity is 85%.
UV λ: 264,282nm.
IR (KBr tabletting) v/cm-1:3426.2(N-H)；2972.1(C-H)；1779.3 (C=O)；1631.6 (C=C)；
1437.9(N-O)；1235.6(C-O-C)；1128.5(C-N)；721.7(C-Br)；613.6(C-S).
1H NMR(400MHz,CDCl3)δ:5.19(s,2H,OCH2)；5.37(s,2H,OCH2Ar)；6.61-6.87(s,
2H,C4H2BrS)；7.72-8.26(m,4H,Ar)；8.09(s,1H,H8)；10.52(s,1H,NHCO)；13.25(s,H,H9).
ESI-MS:m/z505(M+H)+。
Embodiment 3 1-(4-Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (is changed
Compound 2)
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.50g, 7.8mmol) and join in 100mL round-bottomed flask, add 20mLN, N-bis-
Methylformamide, adds sodium hydride (0.125g, 5.2mmol) and 2-aminopurine-6-leptodactyline chlorination in reactant liquor
Thing (0.593g, 2.6mmol), 25 DEG C, stirring reaction 2h.After reaction terminates, add ethyl acetate and water is 1:1 group according to volume
The mixed liquor become extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.585g, 1.8mmol), productivity 69%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3375.4(N-H)；2967.3(C-H)；1683.4 (C=C)；1086.4(C-N)；
705.2(C-Br)；615.3(C-S).
1H NMR(400MHz,CDCl3)δ:5.18(s,2H,OCH2)；6.57(s,2H,NH2)；6.61-6.87(s,2H,
C4H2BrS)；8.23(s,1H,H8)；13.24(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.585g, 1.8mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.6mL contains Sodium ethylate (0.245g, 3.6mmol) makes it dissolve, 25 DEG C, stirring reaction 20min
After, vacuum drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 12mL.Pivalic acid chloromethane is added in solution
Ester (0.778mL, 5.4mmol), 25 DEG C, stirring reaction 1h.After reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C, decompression distillation,
Isolated and purified to crude on silica gel column chromatography, use gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 gradually
Increase to 1:4, obtain (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.584g, 1.33mmol), productivity
74%.
UVλ:267,283nm。
IR (KBr tabletting) v/cm-1:3349.5(N-H)；2972.3(C-H)；1685.9 (C=C)；1226.5(C-O-C)；
1093.4(C-N)；709.2(C-Br)；626.8(C-S).
1H NMR(400MHz,CDCl3)δ:1.15(s,3H,CH3)；5.19(s,2H,OCH2)；5.36(s,2H,NCH2)；
6.58(s,2H,NH2)；6.69-6.87(s,2H,C4H2BrS)；8.25(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) valeric acid
The synthesis of methyl ester
Weigh triphosgene (0.395g, 1.33mmol) and join in two mouthfuls of flask bottles, add 9mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.584g, 1.33mmol), adds 14mL bis-
Chloromethanes dissolves, and adds 0.6mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene first under conditions of ice bath, argon shield
Epoxide)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25 DEG C,
Stirring reaction 4h；In reactant liquor, add 9mL contain the dichloromethane to 1-(4-nitrobenzophenone) ethanol (0.445g, 2.66mmol)
Alkane solution, 25 DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompression distillations remove
Removing solvent, isolated and purified with silica gel column chromatography, eluant is petroleum ether and ethyl acetate, uses gradient elution, petroleum ether/second
The volume ratio of acetoacetic ester progressively increases to 1:5 from 1:2,30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene methoxyl group)-
2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.512g, 0.81mmol), productivity 61%.
UVλ:267,285nm。
IR (KBr tabletting) v/cm-1:3468.3(N-H)；2937.9(C-H)；1764.2 (C=O)；1636.4 (C=C)；
1435.6(N-O)；1237.5(C-O-C)；1125.7(C-N)；721.3(C-Br)；624.5(C-S).
1H NMR(400MHz,CDCl3)δ:1.15(s,3H,C(CH3)3)；1.65(d,3H,CH3)；5.16(s,2H,
OCH2)；5.45(s,2H,NCH2)；6.06(s,H,CH3 CH)；6.61-6.84(s,2H,C4H2BrS)；7.56-8.26(m,4H,
Ar)；8.04(s,1H,H8)；10.34(s,H,NH).
ESI-MS:m/z633(M+H)+。
4) synthesis of 1-(4-Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) valeric acid
Methyl ester (0.512g, 0.81mmol) is dissolved in the 45mL methanol solution containing 0.081mol/L ammonia (0.14mL ammonia), 25 DEG C, stirs
Mix reaction 40h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid 1-(4-
Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.357g, 0.69mmol), productivity is
85%.
UVλ:267,280nm。
IR (KBr tabletting) v/cm-1:3425.3(N-H)；2974.8(C-H)；1769.6 (C=O)；1639.1 (C=C)；
1435.3(N-O)；1237.4(C-O-C)；1136.7(C-N)；728.2(C-Br)；621.5(C-S).
1H NMR(400MHz,CDCl3)δ:1.84(d,3H,CH3)；5.19(s,2H,OCH2)；5.96(q,H,CH3 CH)；
6.64-6.88(s,2H,C4H2BrS)；7.76-8.31(m,4H,Ar)；8.09(s,1H,H8)；10.34(s,H,NHCO)；13.22
(s,H,H9)。
ESI-MS:m/z519(M+H)+。
Embodiment 4 1-(4-Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (is changed
Compound 2)
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.56g, 8.1mmol) and join in 100mL round-bottomed flask, add 25mLN, N-bis-
Methylformamide, adds sodium hydride (0.130g, 5.4mmol) and 2-aminopurine-6-leptodactyline chlorination in reactant liquor
Thing (0.616g, 2.7mmol), 30 DEG C, stirring reaction 2h.After reaction terminates, add ethyl acetate and water is 1:1 group according to volume
The mixed liquor become extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.605g, 1.86mmol), productivity 69%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3352.6(N-H)；2968.1(C-H)；1685.2 (C=C)；1087.3(C-N)；
708.1(C-Br)；618.1(C-S).
1H NMR(400MHz,CDCl3)δ:5.19(s,2H,OCH2)；6.58(s,2H,NH2)；6.62-6.84(s,2H,
C4H2BrS)；8.24(s,1H,H8)；13.25(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.605g, 1.86mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.72mL contains Sodium ethylate (0.253g, 3.72mmol) makes it dissolve, 30 DEG C, stirring reaction 20min
After, vacuum drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 15mL.Pivalic acid chloromethane is added in solution
Ester (0.804mL, 5.58mmol), 30 DEG C, stirring reaction 1h.After reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C, decompression distillation,
Isolated and purified to crude on silica gel column chromatography, use gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 gradually
Increase to 1:4, obtain (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.615g, 1.4mmol), productivity
75%.
UVλ:266,283nm。
IR (KBr tabletting) v/cm-1:3342.4(N-H)；2975.3(C-H)；1686.3 (C=C)；1231.7(C-O-C)；
1087.5(C-N)；712.5(C-Br)；624.3(C-S).
1H NMR(400MHz,CDCl3)δ:1.16(s,3H,CH3)；5.24(s,2H,OCH2)；5.34(s,2H,NCH2)；
6.59(s,2H,NH2)；6.64-6.89(s,2H,C4H2BrS)；8.27(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) valeric acid
The synthesis of methyl ester
Weigh triphosgene (0.415g, 1.4mmol) and join in two mouthfuls of flask bottles, add 10mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.615g, 1.4mmol), adds 15mL bis-
Chloromethanes dissolves, and adds 0.7mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene first under conditions of ice bath, argon shield
Epoxide)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25 DEG C,
Stirring reaction 4h；In reactant liquor, add 10mL contain the dichloromethane to 1-(4-nitrobenzophenone) ethanol (0.468g, 2.8mmol)
Alkane solution, 30 DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompression distillations remove
Removing solvent, isolated and purified with silica gel column chromatography, eluant is petroleum ether and ethyl acetate, uses gradient elution, petroleum ether/second
The volume ratio of acetoacetic ester progressively increases to 1:5 from 1:2,30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene methoxyl group)-
2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.556g, 0.88mmol), productivity 63%.
UVλ:267,285nm。
IR (KBr tabletting) v/cm-1:3471.2(N-H)；2935.8(C-H)；1758.5 (C=O)；1627.5 (C=C)；
1438.4(N-O)；1239.2(C-O-C)；1128.5(C-N)；725.1(C-Br)；625.6(C-S).
1H NMR(400MHz,CDCl3)δ:1.18(s,3H,C(CH3)3)；1.66(d,3H,CH3)；5.18(s,2H,
OCH2)；5.47(s,2H,NCH2)；6.08(s,H,CH3 CH)；6.63-6.85(s,2H,C4H2BrS)；7.54-8.28(m,4H,
Ar)；8.05(s,1H,H8)；10.35(s,H,NH).
ESI-MS:m/z633(M+H)+。
4) synthesis of 1-(4-Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) valeric acid
Methyl ester (0.556g, 0.88mmol) is dissolved in the 48mL methanol solution containing 0.088mol/L ammonia (0.16mL ammonia), 30 DEG C, stirs
Mix reaction 38h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid 1-(4-
Nitrobenzol) ethyl-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.394g, 0.76mmol), productivity is
86%.
UVλ:267,281nm。
IR (KBr tabletting) v/cm-1:3429.4(N-H)；29741.5(C-H)；1765.8 (C=O)；1635.4 (C=C)；
1438.2(N-O)；1235.6(C-O-C)；1084.7(C-N)；723.6(C-Br)；625.2(C-S).
1H NMR(400MHz,CDCl3)δ:1.86(d,3H,CH3)；5.17(s,2H,OCH2)；5.94(q,H,CH3 CH)；
6.61-6.87(s,2H,C4H2BrS)；7.73-8.31(m,4H,Ar)；8.07(s,1H,H8)；10.32(s,H,NHCO)；13.21
(s,H,H9)。
ESI-MS:m/z519(M+H)+。
Embodiment 5 2-(4-nitrobenzyl) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
The synthesis of (compound 3)
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.44g, 7.5mmol) and join in 100mL round-bottomed flask, add 20mLN, N-bis-
Methylformamide, adds sodium hydride (0.12g, 5.0mmol) and 2-aminopurine-6-leptodactyline chloride in reactant liquor
(0.570g, 2.5mmol), stirring, 25 DEG C, react 2h.After reaction terminates, add ethyl acetate and water is 1:1 group according to volume
The mixed liquor become extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.553g, 1.7mmol), productivity 68%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3432.6(N-H)；2947.2(C-H)；1670.1 (C=C)；1098.5(C-N)；
707.3(C-Br)；615.4(C-S).
1H NMR(400MHz,CDCl3)δ:5.18(s,2H,OCH2)；6.53(s,2H,NH2)；6.67-6.83(s,2H,
C4H2BrS)；8.25(s,1H,H8)；13.21(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.553g, 1.7mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.4mL contains Sodium ethylate (0.231g, 3.4mmol) makes it dissolve, 25 DEG C, stirring reaction 20min
After, vacuum drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 12mL.Pivalic acid chlorine is added in reactant liquor
Methyl ester (0.735mL, 5.1mmol), 25 DEG C, stirring reaction 1h, after reaction terminates, add ethyl acetate and water is 1 according to volume:
The mixed liquor of 1 composition extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C of decompression distillations,
Isolated and purified to crude on silica gel column chromatography, use gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 gradually
Increase to 1:4, obtain (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.544g, 1.24mmol), productivity
73%.
UVλ:266,283nm。
IR (KBr tabletting) v/cm-1:3438.3(N-H)；2942.4(C-H)；1685.7 (C=C)；1236.3(C-O-C)；
1094.6(C-N)；712.5(C-Br)；609.7(C-S).
1H NMR(400MHz,CDCl3)δ:1.15(s,3H,CH3)；5.19(s,2H,OCH2)；5.35(s,2H,NCH2)；
6.58(s,2H,NH2)；6.69-6.85(s,2H,C4H2BrS)；8.25(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) propoxyl group) carbonyl) amino-9 hydrogen-purine-9) valeric acid
The synthesis of methyl ester
Weigh triphosgene (0.368g, 1.24mmol) and join in two mouthfuls of flask bottles, add 8mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.544g, 1.24mmol), adds 14mL bis-
Chloromethanes dissolves, and adds 0.55mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene under conditions of ice bath, argon shield
Methoxyl group)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25
DEG C, stirring reaction 4h；In reactant liquor, add 8mL contain 2-'s (4-nitrobenzophenone)-2-propanol (0.449g, 2.48mmol)
Dichloromethane solution, 25 DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompressions
Solvent is distilled off, and isolated and purified with silica gel column chromatography, eluant is petroleum ether and ethyl acetate, uses gradient elution, stone
The volume ratio of oil ether/ethyl acetate progressively increases to 1:5 from 1:2, and 30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene
Methoxyl group)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.504g, 0.78mmol),
Productivity 63%.
UVλ:268,285nm。
IR (KBr tabletting) v/cm-1:3445.3(N-H)；2948.5(C-H)；1784.7 (C=O)；1627.4 (C=C)；
1431.7(N-O)；1219.8(C-O-C)；1083.6(C-N)；715.7(C-Br)；614.3(C-S).
1H NMR(400MHz,CDCl3)δ:1.13(s,3H,CH3)；1.87(s,3H,CH3)；5.18(s,2H,OCH2)；
5.58(s,2H,NCH2)；6.63-6.87(s,2H,C4H2BrS)；7.29-8.19(m,4H,Ar)；7.97(s,1H,H8)；10.36
(s,H,NH)。
ESI-MS:m/z647(M+H)+。
4) synthesis of 2-(4-Nitrobenzol) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) propoxyl group) carbonyl) amino-9 hydrogen-purine-9) valeric acid
Methyl ester (0.504g, 0.78mmol) is dissolved in the 45mL methanol solution containing 0.078mol/L ammonia (0.135mL ammonia), 25 DEG C,
Stirring reaction 40h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid 2-
(4-Nitrobenzol) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.353g, 0.663mmol), produces
Rate is 85%.
UVλ:268,283nm。
IR (KBr tabletting) v/cm-1:3439.2(N-H)；2958.9(C-H)；1792.5 (C=O)；1637.2 (C=C)；
1426.8(N-O)；1235.9(C-O-C)；1095.6(C-N)；715.8(C-Br)；627.4(C-S).
1H NMR(400MHz,CDCl3)δ:1.84(s,3H,CH3)；5.18(s,2H,OCH2)；6.67-6.85(s,2H,
C4H2BrS)；7.46-8.34(m,4H,Ar)；8.19(s,1H,H8)；10.36(s,1H,NHCO)；13.21(s,H,H9).
ESI-MS:m/z533(M+H)+。
Embodiment 6 2-(4-nitrobenzyl) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
The synthesis of (compound 3)
1) synthesis of (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine
Weigh 4-bromothiophene base methanol (1.27g, 6.6mmol) and join in 100mL round-bottomed flask, add 18mLN, N-bis-
Methylformamide, adds sodium hydride (0.106g, 4.4mmol) and 2-aminopurine-6-leptodactyline chlorination in reactant liquor
Thing (0.502g, 2.2mmol), stirring, 30 DEG C, react 2h.After reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, and 30 DEG C of decompressions are steamed
Evaporating, gained crude product is dissolved in methanol, is filtered to remove contamination precipitation, obtains (6-(4-bromothiophene methoxyl group)-9 hydrogen-fast after recrystallization
Purine-2) amine (0.494g, 1.52mmol), productivity 69%.
UVλ:246,283nm。
IR (KBr tabletting) v/cm-1:3429.2(N-H)；2937.5(C-H)；1675.3 (C=C)；1085.9(C-N)；
709.5(C-Br)；618.1(C-S).
1H NMR(400MHz,CDCl3)δ:5.19(s,2H,OCH2)；6.56(s,2H,NH2)；6.64-6.85(s,2H,
C4H2BrS)；8.25(s,1H,H8)；13.25(s,H,NH).
ESI-MS:m/z326(M+H)+。
2) synthesis of (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate
Weigh (6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) amine (0.494g, 1.52mmol) in 100mL round-bottomed flask
In, the ethanol solution that addition 3.04mL contains Sodium ethylate (0.207g, 3.04mmol) makes it dissolve, 30 DEG C, stirring reaction 20min
After, vacuum drains solvent, and the solid obtained is dissolved in the anhydrous DMF of 10mL.Pivalic acid chloromethane is added in solution
Ester (0.657mL, 4.56mmol), 30 DEG C, stirring reaction 1h, after reaction terminates, add ethyl acetate and water is 1:1 according to volume
The mixed liquor of composition extracts, and organic facies is after saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, 30 DEG C of decompression distillations,
Isolated and purified to crude on silica gel column chromatography, use gradient elution, the volume ratio of petrol ether/ethyl acetate is from 1:1 gradually
Increase to 1:4, obtain (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.492g, 1.12mmol), productivity
74%.
UVλ:266,283nm。
IR (KBr tabletting) v/cm-1:3426.1(N-H)；2937.5(C-H)；1674.2 (C=C)；1247.5(C-O-C)；
1105.7(C-N)；713.6(C-Br)；613.2(C-S).
1H NMR(400MHz,CDCl3)δ:1.16(s,3H,CH3)；5.21(s,2H,OCH2)；5.37(s,2H,NCH2)；
6.56(s,2H,NH2)；6.65-6.84(s,2H,C4H2BrS)；8.26(s,1H,H8).
ESI-MS:m/z440(M+H)+。
3) (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) propoxyl group) carbonyl) amino-9 hydrogen-purine-9) valeric acid
The synthesis of methyl ester
Weigh triphosgene (0.332g, 1.12mmol) and join in two mouthfuls of flask bottles, add 5mL dichloromethane and dissolve, will
Gained solid (2-amino-6-(4-bromothiophene methoxyl group)-9 hydrogen-9) methyl valerate (0.492g, 1.12mmol), adds 10mL bis-
Chloromethanes dissolves, and adds 0.4mL anhydrous pyridine, by (2-amino-6-(4-bromothiophene first under conditions of ice bath, argon shield
Epoxide)-9 hydrogen-9) methyl valerate solution is dropwise added drop-wise in triphosgene solution, after dropping, temperature is slowly raised to 25 DEG C,
Stirring reaction 4h；In reactant liquor, add 5mL contain two to 2-(4-nitrobenzophenone)-2-propanol (0.406g, 2.24mmol)
Chloromethanes solution, 30 DEG C, stirring reaction 4h, thin layer chromatography monitoring reaction process.After question response is without raw material point, 30 DEG C of decompressions are steamed
Evaporating removing solvent, isolated and purified with silica gel column chromatography, eluant is petroleum ether and ethyl acetate, uses gradient elution, oil
The volume ratio of ether/ethyl acetate progressively increases to 1:5 from 1:2, and 30 DEG C of vacuum drying obtain white solid (6-(4-bromothiophene first
Epoxide)-2-(((4-Nitrobenzol) ethyoxyl) carbonyl) amino-9 hydrogen-purine-9) methyl valerate (0.470g, 0.728mmol), produces
Rate 65%.
UVλ:268,285nm。
IR (KBr tabletting) v/cm-1:3425.4(N-H)；2935.2(C-H)；1785.9 (C=O)；1632.6 (C=C)；
1435.6(N-O)；1215.6(C-O-C)；1085.1(C-N)；716.8(C-Br)；617.4(C-S).
1H NMR(400MHz,CDCl3)δ:1.14(s,3H,CH3)；1.89(s,3H,CH3)；5.19(s,2H,OCH2)；
5.57(s,2H,NCH2)；6.62-6.87(s,2H,C4H2BrS)；7.28-8.17(m,4H,Ar)；8.03(s,1H,H8)；10.35
(s,H,NHCO)；.
ESI-MS:m/z 647(M+H)+。
4) synthesis of 2-(4-Nitrobenzol) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate
By (6-(4-bromothiophene methoxyl group)-2-(((4-Nitrobenzol) propoxyl group) carbonyl) amino-9 hydrogen-purine-9) valeric acid
Methyl ester (0.470g, 0.728mmol) is dissolved in the 40mL methanol solution containing 0.0728mol/L ammonia (0.112mL ammonia), and 30
DEG C, stirring reaction 40h, thin layer chromatography monitoring reaction process, after question response is extremely without raw material point, solid is collected by filtration, obtains solid
2-(4-Nitrobenzol) propyl group-(6-(4-bromothiophene methoxyl group)-9 hydrogen-purine-2) carbamate (0.333g, 0.626mmol),
Productivity is 86%.
UVλ:268,283nm。
IR (KBr tabletting) v/cm-1:3418.7(N-H)；2943.5(C-H)；1783.2 (C=O)；1629.7 (C=C)；
1435.3(N-O)；1238.1(C-O-C)；1127.6(C-N)；718.2(C-Br)；614.9(C-S).
1H NMR(400MHz,CDCl3)δ:1.85(s,3H,CH3)；5.17(s,2H,OCH2)；6.65-6.87(s,2H,
C4H2BrS)；7.45-8.36(m,4H,Ar)；8.21(s,1H,H8)；10.35(s,1H,NHCO)；13.23(s,H,H9).
ESI-MS:m/z533(M+H)+。
Embodiment 7 AGT protein inhibitor is to cellular biology of tumor activity rating
1, experiment material and instrument
Test compound: the compound 1,2 and 3 prepared in above-mentioned preparation embodiment；
Cell line: human leukemia cell line HL-60, human lung cancer cell A549, human melanoma cell A375 cell, people T drench
Bar oncocyte HUT102, human brain neuroglial cytoma H4, human liver cancer cell BEL-7402.
2, experimental technique is respectively under normal oxygen and hypoxia condition, arranges nimustine (ACNU) group (experimental group 1), ACNU+
Compound 1 drug combination group (experimental group 2), ACNU+ compound 2 drug combination group (experimental group 3), ACNU+ compound 3 combine use
Medicine group (experimental group 4), arranges blank group and matched group simultaneously.
Six kinds of tumor cells inoculate 96 orifice plates with 2000/ hole respectively, at 37 DEG C, and 5%CO2After cultivating 24 hours, experimental group 1
Cell is processed with the ACNU of series concentration (0.05mM, 0.1mM, 0.2mM, 0.4mM, 0.6mM, 0.8mM, 1.0mM, 1.2mM)
24h；Experimental group 2,
3,4 respectively after compound 1,2,3 processes cell 3h, changes and processes cell 24h (normal oxygen bar with the ACNU of series concentration
Under part, oxygen content is about 21%, and under hypoxia condition, oxygen content is about 1%).Then, in every hole, add 10 μ L and contain CCK-8
Culture medium, act on 4 hours.Finally, measure the absorbance at 450nm, calculate cytoactive as follows, and pass through
Regression analysis calculates half suppression ratio IC50。
Cell survival rate (%)=(AExperimental group–ABlank group)/(AMatched group–ABlank group)×100
AExperimental groupFor having the absorbance in the hole of tumor cell, CCK-8 and medicine (ACNU+ compound 1/2/3)；
ABlank groupFor only culture medium and CCK-8, there is no the absorbance in the hole of tumor cell and medicine；
AMatched groupFor having tumor cell and CCK-8, there is no the absorbance in the hole of medicine.
3, experimental result: be shown in Table 1
Half suppression ratio (the IC of table 1 tumor cell50,μM)
Table 1 result shows, under normal oxygen environment, compared with ACNU group, compound 1,2 or 3 and ACNU drug combination are to six
Plant the IC of tumor cell50Being worth close, show under the conditions of normal oxygen, compound 1,2 and 3 is to AGT activity in six kinds of tumor cells
Inhibitory action is the most weak.
But under low-oxygen environment, compared with ACNU group, compound 1,2 or 3 and ACNU drug combination are thin to six kinds of tumors
The IC of born of the same parents50Value significantly reduces, and shows that compound 1,2 and 3 can specifically be reduced and discharge O under low-oxygen environment6-benzyl
Base guanine analog, as AGT inhibitor, reduces the activity of AGT in tumor cell, thus effectively enhances tumor cell
Sensitivity to ACNU, improves the inhibitory activity of drug on tumor cell.
Contrast the IC of compound 1,2 and 3 under normal oxygen and hypoxia condition50Value, it can be seen that under the conditions of hypoxia condition is than normal oxygen
The AGT inhibitory activity of six kinds of tumor cells is significantly improved by three kinds of compounds, shows that compound 1,2 and 3 can specifically exist
It is activated under hypoxia condition.Therefore, compound 1,2 and 3 can targeting in the tumor cell being under hypoxia, it is to avoid
Affect the AGT activity in normal cell, thus reach chemotherapeutics targeting in the purpose of tumor cell.
Test result indicate that, the compound that the present invention provides has stronger AGT protein inhibiting activity under low oxygen conditions,
Without obvious inhibiting effect under the conditions of normal oxygen.With existing AGT protein inhibitor O6-benzyl guanine is compared, and has significantly
Hypoxia targeting, and preferably water solublity and AGT inhibitory activity.Therefore, the compound that the present invention provides is used as alkane
The accessory drugs of agent based chemotherapy medicine, acts on to targeting tumor cell, thus improves quick to chemotherapeutics of tumor cell
Perception, enhances the chemotherapy effect of alkylating agent class medicine.
Although, the most with a general description of the specific embodiments the present invention is made
Detailed description, but on the basis of the present invention, it can be made some modifications or improvements, this is to people in the art
It is apparent from for Yuan.Therefore, without departing from present invention spirit
On the basis of these modifications or improvements, belong to the scope of protection of present invention.
Claims (10)
1. hypoxia activates an AGT protein inhibitor, and described AGT protein inhibitor has the chemical combination as shown in logical formula (I) structure
Thing:
Wherein, R1=R2=H, or R1=H, R2=CH3, or R1=R2=CH3；
R3=H, NO2, NH2, OCH3, CH2OH or CO2CH3。
2. AGT protein inhibitor as claimed in claim 1, it is characterised in that described AGT protein inhibitor is:
3. the hypoxia described in claim 1 or 2 activates the preparation method of AGT protein inhibitor, it is characterised in that described method
The reaction mechanism mechanism of reaction is:
Including following reactions steps:
(1) 4-thienylmethanol is dissolved in DMF, in reactant liquor, is sequentially added into sodium hydride and compound
A, stirring reaction, after question response terminates, add ethyl acetate and water and extract according to the mixed liquor that volume is 1:1 composition, have
Machine, after saturated ammonium chloride solution washs, is dried through anhydrous sodium sulfate, decompression distillation, is recrystallized to give compound b；
(2) adding the ethanol solution containing Sodium ethylate in compound b makes it dissolve, and after stirring reaction 10-45min, vacuum is drained
Solvent, is dissolved in the solid obtained in organic solvent, and adds chloromethyl pivalate, stirring, after reaction terminates, add in solution
Ethyl acetate and water extract according to the mixed liquor that volume is 1:1 composition, organic facies after saturated aqueous common salt washs, anhydrous sulfur
Acid sodium is dried, decompression distillation, obtains crude on silica gel column chromatography isolated and purified, obtains compound c；
(3) being dissolved in dichloromethane by the compound c of step (2) gained, add triphosgene, under inert gas shielding, stirring is anti-
Should, products therefrom compound d withReaction, decompression distillation, obtain crude on silica gel column chromatography isolated and purified,
Obtain compound e；
(4) being dissolved in the methanol solution containing ammonia by the compound e of step (3) gained, stirring reaction, thin layer chromatography monitoring is anti-
Answer process, after reaction terminates, solid is collected by filtration, obtain hypoxia and activate AGT protein inhibitor i.e. compound f.
4. the preparation method described in claim 3, it is characterised in that in described step (1), compound a, sodium hydride and 4-bromine thiophene
The mol ratio of fen base methanol is 1:1-4:2-5；The temperature of stirring reaction controls at 20-35 DEG C, and vacuum distillation temperature is 30-60
℃。
5. the preparation method described in claim 3, it is characterised in that in described step (2), described compound b, Sodium ethylate are with special
The mol ratio of valeric acid chloromethyl ester is 1:1-3:2-5, and organic solvent is DMF or dimethyl sulfoxide, two stirrings
Reaction temperature all controls at 20-35 DEG C, and vacuum distillation temperature is 30-60 DEG C；Eluant used by described silica gel column chromatography
For petroleum ether and ethyl acetate, using gradient elution, petroleum ether and ethyl acetate volume ratio are 1:1-1:4.
6. the arbitrary described preparation method of claim 3-5, it is characterised in that step (3) described compound c, triphosgene,Mol ratio be 1:1-4:2-5；
Compound c controls at 0-25 DEG C with the reaction temperature of triphosgene, and the response time is 3-8h, obtains compound d；
Compound d withReacting under the conditions of 25-40 DEG C, the response time is 3-8h；
Eluant used by silica gel column chromatography is petroleum ether and ethyl acetate, uses gradient elution, petrol ether/ethyl acetate body
Long-pending ratio is 1:2-1:5.
7. the arbitrary described preparation method of claim 3-5, it is characterised in that compound e described in step (4) rubs with ammonia
That ratio is 1:0.1-1 (mmol:mL)；Response time is 20-40h；Reaction temperature controls at 20-35 DEG C.
8. a pharmaceutical composition, it is characterised in that include a) alkylating agent anti-tumor compounds；B) claim 1-2 is any
One described hypoxia that has activates the targeting AGT inhibitor of characteristic.
9. the drug regimen described in claim 6, it is characterised in that described alkylating agent anti-tumor compounds is nimustine.
10. the hypoxia described in claim 1 or 2 activates the pharmaceutical composition described in AGT protein inhibitor or claim 8 or 9
Purposes in preparing antitumor drug.
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| CN116178392A (en) * | 2023-03-10 | 2023-05-30 | 中国药科大学 | Hypoxia activated BRD4 protein degradation agent, and preparation method and application thereof |
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