CN108276415A - A kind of alkoxide triazol tetrazine kind compound and its preparation method and application - Google Patents
A kind of alkoxide triazol tetrazine kind compound and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of alkoxide triazol tetrazine kind compounds and its preparation method and application, belong to technical field of medicine synthesis.In order to solve the problems, such as it is existing such compound activity do not study, a kind of alkoxide triazol tetrazine kind compound and its preparation method and application is provided, the preparation method of the compound includes by 6 (3,5 dimethyl pyrazole, 1 base) [1,2,4] triazole [4,3 b] heating balanced class compound and alkylol R1OH is reacted, and product type I compound alkoxide triazol tetrazine kind compound is obtained, and can be used in the drug or functional food that prepare prevention and treatment antitumor activity.The compound of the present invention structure novel and have preferable bioactivity, especially to tumour cell have preferable resistancing action.Method has reaction route short, and cost of material is low, easily operated, and the yield and purification effect reacted.
Description
Technical field
The present invention relates to a kind of alkoxide triazol tetrazine kind compounds and its preparation method and application, belong to pharmaceutical synthesis
Technical field.
Background technology
Heating balanced derivative compound, which is one kind, to be had compared with the active compound of Johnson ＆ Johnson's reason, is had by many document reports
Preferable antibacterial, antitumor activity, cause the extensive concern of many scholars and researcher.As Rao, G.W. et al. exist
Bioorganic＆Medicinal Chemi stryLetters, the 1- acyl groups-3,6- reported in 2005,15,3174-3176.
Disubstituted benzenes -1,2- dihydro-heating balanced class compound also has preferable inhibition antitumaous effect, wherein 1- monoxones acyl group -3,
6- phenyl -1,2- dihydro heating balanceds have stronger anti-tumor capacity to its mouse leukemia cell P-388 and adenocarcinoma of lung A-549
(its inhibiting rate under the concentration of 10-5mol/L is 100% and 95.8% respectively).For another example Xu, F. et al. once reported [1,2,
4] triazole [4,3-b] heating balanced derivative compound has stronger antitumor activity, has stronger inhibition to c-Met receptors
Activity.Bekker et al. once reported that triazol tetrazine kind compound had good inhibiting effect to tubercle bacillus.And it is existing
[1,2,4] triazole [4,3-b] heating balanced derivative compound is often to bicyclic 3 or 6 progress structural modifications, especially pair
More in 6 modifications, synthetic method is generally：Contain easy leaving group (such as 3,5- dimethyl pyrazole -1- bases, miaow by 6
Azoles -1- bases etc.) [1,2,4] triazole [4,3-b] heating balanced derivative compound and alkylamino or nitrogen heterocyclic ring be obtained by the reaction 6
Alkanamine or [1,2,4] triazole [4,3-b] heating balanced derivative compound of arylamine substitution.
Chinese patent (the Authorization Notice No. applied such as the present inventor：CN103012410B it) discloses a kind of with antitumor
Active [1,2,4] triazole [4,3-b] heating balanced derivative compound and preparation method thereof, by contain leaving group on 6-
The progress such as [1,2,4] triazole [4,3-b] heating balanced derivative compound of 3,5- dimethyl pyrazole -1- bases and alkylamino or fragrant amino
It is obtained by the reaction.Although there have alkylamino or fragrant amino group to have by the substitution at 6- to be preferable active, in existing report
It is by introducing the unit structures such as alkane ammonia, but is extremely that the heating balanced replaced there are no 6- alkoxies of document report spreads out so far
The bioactivity of biology, and also without reporting the similar synthetic method by introducing alkoxy at 6-.
Invention content
The present invention is directed to the above defect existing in the prior art, propose a kind of alkoxide triazol tetrazine kind compound and
Preparation method and application one of solve the problems, such as it is how to improve a kind of new compound with anti-tumor activity；It solves
The problem of second is that synthetic method how to be made to have reaction route short and by-product is few.
An object of the present invention technical scheme is that, a kind of alkoxide triazol tetrazine class
Close object, which is characterized in that the structural formula of the compound is as shown in following formula I：
In above-mentioned formula I, R1Selected from C1~C5Alkyl；R2Selected from phenyl, substituted-phenyl or substituted benzene alkyl.
Alkoxide triazol tetrazine kind compound of the present invention (is authorized public in patent document in further research the present inventor
Announcement number：CN103012410B [1,2,4] triazole [4,3-b] the heating balanced derivative compounds with anti-tumor activity provided in)
The a new class of compound with triazole heating balanced structure parent nucleus class being had been surprisingly found that during object, due in the patent document
Compound building-up process in the solvent that uses containing alcoholic solvent when, [1,2,4] triazole [4,3-b] heating balanced for will obtaining
It was found that the presence of a small amount of alkoxide triazol tetrazine compound (at that time only during derivative compound progress structural analysis
Analyzed with impurity), and carry out antitumor activity analysis during, finding the presence of the impurity, there is no to active constituent
Generate excessive influence.Therefore, in order to study the alkoxide triazol tetrazine compound whether have bioactivity, the present inventor
The alkoxide triazol tetrazine kind compound that the present invention is filtered out after largely studying, by drawing on the positions the 6- of heating balanced
After entering alkoxy grp, it is found that it equally exists preferable bioactivity, and the alkoxide triazol tetrazine class that the present invention screens
Closing object there is higher inhibiting effect can reach comparable inhibition, even compared with generally acknowledged cis-platinum tumour cell
It will be far better than the function and effect of cis-platinum to the inhibiting effect of some tumour cells.Such as the alkoxide triazol tetrazine class of the present invention
Compound will be much better than the inhibiting effect of human breast carcinoma MCF-7 the effect of cis-platinum.This is just current research antitumor activity
Drug provide higher medicament selection space, make that there are more selectivity, make to be conducive to study safer, more reliable
Antitumor drug ensures the safety of medication.
In above-mentioned alkoxide triazol tetrazine kind compound, the substituted-phenyl can be halogenophenyl, as chlorine takes
It can be monosubstituted or polysubstituted for phenyl, fluorine substituted-phenyl, and on the phenyl ring of phenyl, can also be C1-C3Alkyl-substituted benzene
Base, such as o-, m- or p- aminomethyl phenyl or ethylphenyl equally can be monosubstituted or polysubstituted；Benzene alkyl can be benzene second
Base or benzyl etc..Preferably, the R1Selected from methyl, ethyl, isobutyl group or isopropyl；R2It is selected from phenyl, to methoxy
Base phenyl, phenethyl, 2,4 dichloro benzene base, rubigan or p-fluorophenyl.Not only there is preferable antitumor activity, and pass through
It is easier to introduce these alkoxy grps, makes to be more advantageous to synthesis.
The second object of the present invention is achieved by the following technical programs, a kind of alkoxide triazol tetrazine class
Close object preparation method, which is characterized in that this method include by II compound 6- of formula (3,5- dimethyl pyrazole -1- bases)-[1,2,
4] triazole [4,3-b] heating balanced class compound and alkylol R1OH is reacted, and product type I compound is obtained；
R described above1Selected from C1~C5Alkyl；The R2Selected from phenyl, substituted-phenyl or substituted benzene alkyl.
By directly using alkylol and 6- (3,5- dimethyl pyrazole -1- bases)-[1,2,4] triazole [4,3-b] heating balanced
Class compound is reacted, and can be very good to make the easy leaving group 3 on the wherein positions 6-, 5- dimethyl pyrazole -1- bases to be taken by alkoxy
In generation, is used while more importantly can also directly being made as reactant using alkoxy as solvent, anti-without in addition addition
Solvent is answered, the selectivity of reaction is substantially increased, avoids the generation of other by-products, can preferably improve the quality of product,
Certainly, be not limited in here in alkoxy and additionally incorporate a small amount of solvent in solution system because this have no effect on reaction into
Row.
In the preparation method of above-mentioned alkoxide triazol tetrazine kind compound, preferably, the alkylol R1OH is selected
From methanol, ethyl alcohol, isopropanol or isopropanol.The alkoxide triazol tetrazine kind compound enabled to has higher anti-swollen
Tumor activity, and these alkylols have steric hindrance small, are more advantageous to introducing, are conducive to the conversion ratio of raw material, improve product
Yield and purity Coriolis mass requirement；And also have the advantages that toxicity is low and at low cost.
In the preparation method of above-mentioned alkoxide triazol tetrazine kind compound, preferably, the temperature of the reaction is
40 DEG C~80 DEG C.Substantially make to be maintained at the recovered temperature of alkylol or less and carry out, has reaction condition mild, it is easily operated
Effect.As a further preference, temperature 50 C~reflux temperature of the reaction.
In the preparation method of above-mentioned alkoxide triazol tetrazine kind compound, preferably, the alkylol R1OH is same
Shi Zuowei reactants and solvent use, the alkylol R1OH is excessive.Dosage by the way that alkylol is added is excessive state, one
Reaction is participated in when aspect can ensure it as reactant, can make (3,5- dimethyl pyrazole -1- bases)-[1,2,4] raw material 6-
Triazole [4,3-b] heating balanced class compound can be more fully converted, and improve conversion ratio and product purity, and can also conduct
Solvent makes the progress of reaction milder, without additionally incorporating other class solvents, makes to be more advantageous to operation.As further excellent
Choosing, II compound quality (g) of the formula and alkylol R1The volume (mL) of OH is than being 1：20~30.Here alkylol can be with
It recycles and reuses.
In the preparation method of above-mentioned alkoxide triazol tetrazine kind compound, preferably, further including after reaction
Post-processing, the post-processing are specially：
Reaction solution after reaction is carried out alkylol is distilled off, adding ice ethyl alcohol makes precipitation solid, is produced
Object type I compound.Product can be made preferably to be precipitated by the way that ice ethyl alcohol is added, improve the yield of product.
The specific reaction synthetic route of the preparation method of the above-mentioned alkoxide triazol tetrazine kind compound of the present invention can be with
It is indicated using following reaction equation：
The third object of the present invention technical scheme is that, a kind of alkoxide triazol tetrazine class
Close the application of object, which is characterized in that above-mentioned alkoxide triazol tetrazine kind compound is used to prepare the antitumor work of prevention and treatment
The drug or functional food of property.Due to outstanding representation of this alkoxide triazol tetrazine kind compound in terms of antitumor activity,
Here antitumor activity mainly for tumour include human lung cancer (A549), human placenia cancer cell line (Bewo) and human milk
Gland cancer (MCF-7), all has preferable inhibition.As a further preference, the drug of the antitumor activity includes upper
State the active constituent of alkoxide triazol tetrazine kind compound and pharmaceutically acceptable auxiliary material.Here the dosage of active constituent can
To carry out selective adjustment according to actual drug effect dosage, required there is no having limitation.It can also be according to different drug agent
Type selects the dosage situation of active medicine, and pharmaceutical dosage form here can be tablet, liquid preparation or capsule and injection etc.
Deng dosage form.Certainly, pharmaceutically acceptable auxiliary material described above can also be according to different auxiliary of different dosage form selections
Expect ingredient and dosage situation.
In conclusion compared with prior art, the present invention haing the following advantages：
1. the present invention alkoxide triazol tetrazine kind compound be a kind of compound with novel structure, with compared with
Good bioactivity especially has preferable resistancing action to tumour cell.
2. being that raw material had not only been used as reactant to participate in reaction, but also can directly act on solvent use by using alkylol, have
Conducive to the generation of by-product is reduced, the yield and purification effect of reaction is improved, and reaction route is short, only need single step reaction real
Existing, cost of material is low, easily operated, is conducive to industrialized production.
Specific implementation mode
Below by specific embodiment, the technical solutions of the present invention will be further described, but the present invention is simultaneously
It is not limited to these embodiments.
Embodiment 1
The present embodiment is specially 3- p-fluorophenyl -6- isobutoxies-[1,2,4] triazole [4,3-b] heating balanced compound,
Structural formula is as shown in following formula I-a：
The specific of above-mentioned Formulas I-a compounds 3- p-fluorophenyl -6- isobutoxies-[1,2,4] triazole [4,3-b] heating balanced is adopted
It obtains using the following method：
In the clean reaction bulb of 100mL, addition raw material 3- p-fluorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,
2,4] triazole [4,3-b] heating balanced 1g (3.4mmol) and isobutanol 30mL, then carries out heat temperature raising, and temperature is made to rise to 80 DEG C
Carry out reaction 5h；After reaction, it carries out removing extra solvent under reduced pressure, then obtained residue is added into residue
A small amount of ice ethyl alcohol, makes a large amount of yellow solids of precipitation, filters, drying, obtain target product 3- p-fluorophenyl -6- isobutoxies-[1,
2,4] triazole [4,3-b] heating balanced, yield 0.64g, yield 65.3%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：128~130 DEG C.
IRνmax(KBr)/cm-1：3074.3,2973.5,1605.5,1546.8,1057.4,860.5.
1H-NMR(D6-DMSO,400MHz)δ：8.45 (t, 2H, J=8.8Hz), 7.52 (t, 2H, J=8.8Hz), 4.29
(d, 2H, J=6.3Hz), 2.23 (m, 1H), 1.06 (d, 2H, J=6.3Hz).
13C-NMR(D6-DMSO,100MHz)δ：165.2,159.4,152.1,144.3,130.1(2C),121.6,117.0
(2C),75.9,27.6,19.3(2C)。
MS(EI)：M/z (%):289.2[(M+H)+,100]。
Anal.calcd for C13H13FN6O：C,54.16；H,4.55；N,29.15；O,5.55；Found：C,54.25；
H,4.54；N,29.12；O,5.57.
Embodiment 2
The present embodiment is specially 3- (2,4 dichloro benzene base) -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced chemical combination
Object, structural formula is as shown in following formula I-b：
The tool of above-mentioned Formulas I-b compounds 3- (2,4 dichloro benzene base) -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced
Preparation is as follows：
In the reaction bulb of 100mL cleanings, raw material 2,4- dichlorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-is added
[1,2,4] triazole [4,3-b] heating balanced 1g (2.8mmol) and absolute ethyl alcohol 30mL, carries out heat temperature raising by reaction solution, makes temperature
Reaction 8h is carried out under conditions of rising to 70 DEG C, after reaction, is evaporated under reduced pressure, and extra solvent is evaporated off, obtains residue,
A small amount of ice ethyl alcohol is added into residue again, makes a large amount of yellow solid of precipitation, filters, obtains target product 3- (2,4- dichloros
Phenyl) -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced compound, yield 0.62g, yield 71.2%.
Obtained compound is subjected to relevant structural analysis, concrete analysis result is as follows：
Wherein fusing point mp is：146~148 DEG C；
IRνmax(KBr)/cm-1：3098.3,2979.0,1595.8,1549.1,1051.5,826.0.
1H-NMR(D6-DMSO,400MHz)δ：7.97 (s, 1H), 7.80 (d, 1H, J=8.8Hz), 7.71 (d, 1H, J=
8.8Hz), 4.40 (q, 2H, J=7.0Hz), 1.06 (t, 3H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.5,151.5,143.7,137.6,134.8,134.1,130.7,
128.6,122.7,66.5,14.2。
MS(EI)：M/z (%)：311.1[(M+H)+,100],333.1[(M+Na)+,50]。
Anal.calcd for C11H8Cl2N6O：C,42.46；H,2.59；N,27.01；O,5.14；Found：C,42.57；
H,2.59；N,26.93；O,5.13.
Embodiment 3
The present embodiment is specially 3- (2,4- dichlorophenyl) -6- isopropoxies-[1,2,4] triazole [4,3-b] heating balanced,
Structural formula is as shown in following formula I-c：
The specific system of above-mentioned Formulas I-c compounds 3- (2,4 dichloro benzene base) -6- isopropoxies-[1,2,4] triazoles [4,3-b]
Preparation Method is as follows：
In the reaction bulb of 100mL cleanings, raw material 2,4- dichlorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-is added
Then mixed reaction solution is carried out heating and risen by [1,2,4] triazole [4,3-b] heating balanced 1g (2.8mmol) and isopropanol 40mL
Temperature makes to carry out reaction 5h under conditions of being heated to 75 DEG C；After reaction, it then carries out that extra solvent is evaporated off, obtain
To residue, it is generally advisable to control temperature at 45 DEG C hereinafter, that a small amount of ice ethyl alcohol is added into residue is molten in vacuum distillation process
Agent makes a large amount of yellow solid of precipitation, filter, drying, obtain target product 3- (2,4- dichlorophenyl) -6- isopropoxies-[1,
2,4] triazole [4,3-b], yield 0.68g, yield 74.7%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：128~130 DEG C.
IRνmax(KBr)/cm-1：3094.1,2988.3,1546.8,1398.9,1053.1,824.2.
1H-NMR(D6-DMSO,400MHz)δ：7.98 (s, 1H), 7.79 (d, 1H, J=8.4Hz), 7.72 (d, 1H, J=
8.4Hz), 5.06 (sext, 1H, J=6.1Hz), 1.42 (d, 6H, J=4.1Hz).
13C-NMR(D6-DMSO,100MHz)δ：158.9,151.4,143.6,137.5,134.8,134.1,130.7,
128.5,122.7,74.8,21.5(2C)。
MS(EI)：M/z (%)：325.1[(M+H)+,100],347.1[(M+Na)+,23]。
Anal.calcd for C12H10Cl2N6O：C,44.33；H,3.10；N,25.85；O,4.92.Found：C,
44.43；H,3.11；N,25.92；O,4.91.
Embodiment 4
The present embodiment is specially 3- (4- fluorophenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, structural formula
As shown in following formula I-d：
The specific system of above-mentioned Formulas I-d compounds 3- (4- fluorophenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced
Preparation Method is as follows：
In the reaction bulb of 100mL cleanings, addition raw material 4- fluorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,2,
Mixed reaction solution is carried out heat temperature raising, makes to be warming up to 60 by 4] triazole [4,3-b] heating balanced 1g (3.2mmol) and methanol 30mL
DEG C reaction 6h is carried out, after reaction, carries out that solvent is evaporated off, then a small amount of ice ethyl alcohol is added into residue, make analysis
Go out a large amount of yellow solids, filtering, drying, drying temperature is controlled at 40 DEG C -45 DEG C, obtains target product 3- (4- fluorophenyls) -6-
Methoxyl group-[1,2,4] triazole [4,3-b] heating balanced, yield 0.58g, yield 73.4%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：178~180 DEG C.
IR νmax(KBr)/cm-1：3098.6,2976.7,1605.0,1559.2,1051.8,851.5.
1H-NMR(D6-DMSO,400MHz)δ：8.47-8.50(m,2H),7.51(dd,2H,J1=10.0, J2=
8.0Hz),4.19(s,3H)。
13C-NMR(D6-DMSO,100MHz)δ：165.3,159.9,152.1,144.3,130.2(2C),121.5,117.0
(2C),57.2。
MS(EI)：M/z (%)：247.2[(M+H)+,100]。
Anal.calcd for C10H7FN6O：C,48.78；H,2.87；N,34.13；O,6.50；Found：C,48.69；
H,2.86；N,34.20；O,6.48.
Embodiment 5
The present embodiment is specially 3- (4- chlorphenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, structural formula
As shown in following formula I-e：
The preparation method of 3- (4- chlorphenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced of the present embodiment is such as
Under：
In the reaction bulb of 100mL cleanings, addition raw material 4- chlorphenyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,2,
4] triazole [4,3-b] heating balanced 1g (3.1mmol) and ethyl alcohol 30mL, heating, by the temperature of reaction solution be warming up to 65 DEG C -70 DEG C into
Row reaction 8h carries out that extra alcohol solvent is evaporated off, then absolute ethyl alcohol is added into residue after reaction
10mL, then slow cooling makes a large amount of yellow solids of precipitation to 0 DEG C of -5 DEG C of stirring and crystallizing under stirring, filters, drying obtains
To target product 3- (4- chlorphenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, yield 0.52g, yield
68.4%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：220~222 DEG C.
IR νmax(KBr)/cm-1：3089.9,2994.3,1538.6,1538.6,1053.9,851.3.
1H-NMR(D6-DMSO,400MHz)δ：8.41 (d, 2H, J=8.6Hz), 7.73 (d, 2H, J=8.6Hz), 4.56
(q, 2H, J=7.0Hz), 1.50 (t, 3H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.2,152.2,144.1,136.5,130.0(2C),129.3(2C),
123.9,66.5,14.3。
MS(EI)：M/z (%)：247.2[(M+H)+,100]。
Anal.calcd for C11H9ClN6O：C,47.75；H,3.28；N,30.37；O,5.78；Found：C,47.90；
H,3.27；N,30.27；O,5.77.
Embodiment 6
The present embodiment is specially 3- (4- chlorphenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, structural formula
As shown in following formula I-f：
The specific system of 3- (2,4- dichlorophenyl) -6- isobutyl groups-[1,2,4] triazole [4,3-b] heating balanced of the present embodiment
Preparation Method is as follows：
In the reaction bulb of 100mL cleanings, raw material 2,4- dichlorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-is added
[1,2,4] triazole [4,3-b] heating balanced 1g (2.8mmol) and isobutanol 50mL, after mixing, reheating are to slowly warm up to 80
DEG C carry out reaction 5h, after reaction, be evaporated under reduced pressure, extra iso-butanol solvent is evaporated off, then, then into residue plus
Enter a small amount of ice ethyl alcohol, the temperature of ice ethyl alcohol keeps a large amount of yellow of precipitation solid it is generally advisable to control to carry out crystallization processing at 5 DEG C or less
Body, filtering, drying, obtains target product 3- (2,4- dichlorophenyl) -6- isobutyl groups-[1,2,4] triazole [4,3-b] heating balanced,
Yield is 0.70g, mass yield 73.7%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：168~170 DEG C.
IR νmax(KBr)/cm-1：3058.3,2976.9,1582.6,1538.4,1038.4,821.4.
1H-NMR(D6-DMSO,400MHz)δ：7.97 (s, 1Hz), 7.80 (d, 1H, J=8.4Hz), 7.22 (d, 1H, J=
8.4Hz), 4.13 (d, 2H, J=6.4Hz), 2.14 (m, 1H), 1.00 (d, 6H, J=6.7Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.7,151.5,143.6,137.6,134.8,134.0,130.7,
128.5,122.7,75.9,27.6,19.2(2C)。
MS(EI)：M/z (%)：340.2[(M+2)+,100],361.2[(M+Na)+,25]。
Anal.calcd for C13H12Cl2N6O：C,46.03；H,3.57；N,24.78；O,4.72；Found：C,
46.12；H,3.57；N,24.70；O,4.70.
Embodiment 7
The present embodiment is specially 3- phenyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, structural formula such as following formula
Shown in I-g：
The specific preparation method of the 3- phenyl -6- ethyoxyls of the present embodiment-[1,2,4] triazole [4,3-b] heating balanced is as follows：
In the reaction bulb of 100mL cleanings, (3,5- dimethyl pyrazole -1- bases)-[1,2,4] raw material 3- phenyl -6- is added
Triazole [4,3-b] heating balanced 1g (3.4mmol) and absolute ethyl alcohol 30mL, reaction mixture, which is carried out heating, makes temperature rise to 40
Reaction 10h is carried out in DEG C -45 DEG C, after reaction, is evaporated under reduced pressure, extra alcohol solvent is evaporated off, then into residue
A small amount of 5mL ice ethyl alcohol is added, and to be stirred crystallization complete, and a large amount of yellow solid of precipitation, filtering, drying is made to obtain target product
3- phenyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, yield 0.50g, mass yield 61.0%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：120~122 DEG C.
IRνmax(KBr)/cm-1：3068.0,2986.4,1573.3,1540.8,1053.7,746.7,704.7.
1H-NMR(D6-DMSO,400MHz)δ：8.43-8.45 (m, 2H), 7.65~7.71 (m, 3H, ArH), 4.58 (q,
2H, J=7.0Hz), 1.53 (t, 3H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.2,154.3,152.2,151.5,144.9,144.1,131.8,
130.7,129.8,129.1,127.6,126.9,125.0,66.4,14.3.
MS(EI):M/z (%)：243.1[(M+H)+,100]。
Anal.calcd for C11H10N6O：C,54.54；H,4.16；N,34.69；O,6.60；Found：C,54.61；H,
4.14；N,34.75；O,6.58.
Embodiment 8
The present embodiment is specially 3- phenethyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, and structural formula is as follows
Shown in Formulas I-h：
The specific preparation method of the 3- phenethyl -6- ethyoxyls of the present embodiment-[1,2,4] triazole [4,3-b] heating balanced is such as
Under：
In the clean reaction bulb of 100mL, addition raw material 3- phenethyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,2,
4] triazole [4,3-b] heating balanced 1g (3.1mmol) and absolute ethyl alcohol 40mL, heat temperature raising, make the temperature of reaction mixture rise to
70 DEG C of heat preservations carry out reaction 7h, after reaction, are evaporated under reduced pressure, and extra alcohol solvent are evaporated off, then add into residue
Enter a small amount of ice ethyl alcohol stirring and carry out crystallization, a large amount of yellow solid of precipitation, filtering, drying is made to obtain target product 3- phenethyls-
6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, yield 0.69g, mass yield 82.1%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：83~85 DEG C.
IR νmax(KBr)/cm-1：3023.6,2998.7,1601.3,1541.2,1037.4,748.3,698.2.
1H-NMR(D6-DMSO,400MHz)δ：7.15-7.26 (m, 5H, ArH), 4.47 (q, 2H, J=7.0Hz), 3.36
(t, 2H, J=7.7Hz), 3.13 (t, 2H, J=7.7Hz), 1.46 (t, 6H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.1,151.5,147.7,140.5,128.9(2C),128.8(2C),
126.6,66.2,31.6,25.4,14.2.
MS(EI)：M/z (%)：271.5[(M+H)+,100],293.3[(M+Na)+,83]。
Anal.calcd for C13H14N6O：C,57.77；H,5.22；N,31.09；O,5.92；Found：C,57.90；H,
5.20；N,31.15；O,5.93.
Embodiment 9
The present embodiment is specially 3- phenethyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, and structural formula is as follows
Shown in Formulas I-i：
The specific preparation method of the 3- phenethyl -6- ethyoxyls of the present embodiment-[1,2,4] triazole [4,3-b] heating balanced is such as
Under：
In the reaction bulb of 100mL cleanings, addition raw material 3- phenethyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,2,
Reaction mixture is heated to 70 DEG C of progress insulation reactions by 4] triazole [4,3-b] heating balanced 1g (3.1mmol) and methanol 30mL
7h is evaporated under reduced pressure after reaction, and extra methanol solvate is evaporated off, and a small amount of ice ethyl alcohol is added into residue and is stirred
Crystallization is mixed, a large amount of yellow solid of precipitation, filtering, drying is made to obtain target product 3- phenethyl -6- ethyoxyls-[1,2,4] three
Azoles [4,3-b] heating balanced, yield 0.55g, mass yield 69.6%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：98~100 DEG C.
IR νmax(KBr)/cm-1：3097.9,2945.4,1579.6,1551.0,1040.9,744.8,707.4.
1H-NMR(D6-DMSO,400MHz)δ：7.15-7.26 (m, 5H), 4.47 (q, 2H, J=7.0Hz), 3.36 (t, 2H,
J=7.7Hz), 3.13 (t, 2H, J=7.7Hz), 1.46 (t, 6H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.8,151.5,147.8,140.5,128.9(2C),128.8(2C),
126.8,57.0,31.6,25.4。
MS(EI)：M/z (%)：257.3[(M+H)+,100]。
Anal.calcd for C12H12N6O：C,56.24；H,4.72；N,32.79；O,6.24；Found：C,56.35；H,
4.71；N,32.85；O,6.22.
Embodiment 10
The present embodiment is specially 3- (4- aminomethyl phenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, structure
Formula is as shown in following formula I-j：
The preparation side of 3- (4- methoxyphenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced of the present embodiment
Method is as follows：
In the reaction bulb of 100mL cleanings, addition raw material 4- methylphenyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,
The temperature of reaction solution is warming up to reflux and carried out by 2,4] triazole [4,3-b] heating balanced 1g (3.3mmol) and ethyl alcohol 50mL, heating
Back flow reaction 7h carries out that extra alcohol solvent is evaporated off, then absolute ethyl alcohol is added into residue after reaction
10mL, then slow cooling makes a large amount of yellow solids of precipitation to 0 DEG C of -5 DEG C of stirring and crystallizing under stirring, filters, drying obtains
To target product 3- (4- aminomethyl phenyls) -6- methoxyl groups-[1,2,4] triazole [4,3-b] heating balanced, yield 0.45g, yield
52.9%.
Obtained product is subjected to corresponding structural analysis, concrete analysis structure is as follows：
Wherein fusing point mp is：143~145 DEG C.
IR νmax(KBr)/cm-1：3085.9,2991.3,1528.6,1043.6,850.3.
1H-NMR(D6-DMSO,400MHz)δ：8.38 (d, 2H, J=8.6Hz), 7.19 (d, 2H, J=8.6Hz), 4.56
(q, 2H, J=7.0Hz), 3.83 (t, 3H, J=7.0Hz).
13C-NMR(D6-DMSO,100MHz)δ：159.2,152.2,144.3,136.2,129.5(2C),125.7(2C),
123.6,66.4,21.3,14.2。
MS(EI)：M/z (%)：257.2[(M+H)+,100]。
Anal.calcd for C12H12N6O：C,56.24；H,4.72；N,32.79；O,6.24；Found：C,56.44；H,
4.71；N,32.65；O,6.26.
Embodiment 11
The present embodiment is specially 3- p-fluorophenyl -6- isobutoxies-[1,2,4] triazole [4,3-b] heating balanced compound,
Structural formula is as shown in following formula I-a：
The specific preparation method of the compound is as follows：
In the clean reaction bulb of 1000mL, addition raw material 3- p-fluorophenyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,
2,4] triazole [4,3-b] heating balanced 10g (34mmol) and isobutanol 300mL, then carries out heat temperature raising, and temperature is made to rise to 40 DEG C
Insulation reaction 6.0h is carried out under conditions of~45 DEG C；After reaction, it carries out removing extra iso-butanol solvent under reduced pressure, decompression is steamed
During evaporating control temperature 50 DEG C hereinafter, most solvent is evaporated off after, obtained residue, then, into residue
The ice ethyl alcohol of 100mL is added, then, being stirred keeps crystallization complete, and a large amount of yellow solid is precipitated, and filters, drying, drying temperature
Degree is 40 DEG C~45 DEG C, obtains target product 3- p-fluorophenyl -6- isobutoxies-[1,2,4] triazole [4,3-b] heating balanced, is produced
Amount is 7.1g, yield 72.4%.
Obtained product is subjected to corresponding structural analysis, concrete analysis result is the same as corresponding analysis result in embodiment 1
Unanimously, which is not described herein again.
Embodiment 12
The present embodiment is specially 3- phenethyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, and structural formula is as follows
Shown in Formulas I-i：
The specific preparation method of the 3- phenethyl -6- ethyoxyls of the present embodiment-[1,2,4] triazole [4,3-b] heating balanced is such as
Under：
In the reaction bulb of 1000mL cleanings, addition raw material 3- phenethyls -6- (3,5- dimethyl pyrazole -1- bases)-[1,2,
Reaction mixture is heated to flowing back, is maintained at reflux by 4] triazole [4,3-b] heating balanced 10g (31mmol) and methanol 300mL
Heat preservation back flow reaction 6h is carried out under state to be evaporated under reduced pressure after reaction, extra methanol solvate is evaporated off, toward residue
The middle a small amount of 150mL ice ethyl alcohol of addition is stirred crystallization, and a large amount of yellow solid of precipitation, filtering, drying is made to obtain target product
3- phenethyl -6- ethyoxyls-[1,2,4] triazole [4,3-b] heating balanced, yield 6.5g, mass yield 82.2%.
Obtained product is subjected to corresponding structural analysis, concrete analysis result is the same as corresponding analysis result in embodiment 10
Unanimously, which is not described herein again.
Application Example 1
Using the respective compound obtained in above-described embodiment 1-12 as active constituent, medicine with anti-tumor activity is prepared
Object, specific drug agent system can be capsule, tablet or liquid preparation etc., can also be the form of dispersion.In the present embodiment
It is illustrated by specific implementation process of capsule.
This capsule is using the arbitrary compound that embodiment 1-12 is obtained as active constituent and pharmaceutically acceptable auxiliary
Material composition.The content of general active constituent is adjusted below 50%, preferably makes active constituent according to actual needs
Content controls below 10%.Here pharmaceutically acceptable auxiliary material can be plasticizer, adhesive, filler, lubricant,
Stabilizer, short taste agent etc..Filler therein is selected from lactose, sucrose, microcrystalline cellulose, starch, pre-paying starch, dextrin etc.
Deng；
Adhesive is selected from ethyl cellulose, polyvinylpyrrolidone (PVP) etc.；
Lubricant is selected from magnesium stearate, talcum powder, superfine silica gel powder etc.；Plasticizer is selected from glycerine, castor oil etc..
Short taste agent can be the pharmaceutically common short taste auxiliary material such as fructose, Abbas's sweet tea.
The compound I-a to I-j obtained in above-described embodiment is chosen to show with apparent antitumor work through vitro detection
Property.
Specific test method uses tetrazolium reduction method (mtt assay), selects human lung cancer A549, human placenia cancer thin
Born of the same parents strain Bewo and human breast carcinoma MCF-7, action time are 72 hours.
Specific test result is as shown in table 1, and the data in following table 1 are using I-a to I-h as drugs with function, to above-mentioned
Inhibiting effect (the IC of the corresponding tumor cell in vitro strain of the cell strain of selection50：μ g/mL) test result：With cis-platinum
(Cisplatin) it is check analysis to the inhibiting effect of corresponding tumor cell line.It is specific that test result is as follows shown in table 1：
Table 1：
| Samples | A549 | Bewo | MCF-7 |
| I-a | 14.27 | 25.00 | 4.15 |
| I-b | 27.51 | 28.28 | 7.31 |
| I-c | 14.92 | 23.42 | 2.24 |
| I-d | 1.99 | 26.32 | 3.05 |
| I-e | 12.00 | 23.00 | 2.70 |
| I-f | 18.58 | 23.48 | 7.96 |
| I-g | 20.75 | 28.88 | 6.46 |
| I-h | 5.86 | 5.60 | 0.76 |
| I-i | 20.37 | 22.49 | 2.48 |
| I-j | 16.4 | 14.6 | 1.21 |
| Cisplatin | 9.97 | 10.46 | 15.03 |
Data result in above-mentioned table 1 is the mean value for carrying out parallel laboratory test result three times.
Can be seen that cis-platinum from the data in above-mentioned table 1 has stronger resistance to make in the cell of A549, Bewo and MCF-7
With IC50Respectively 9.97 μ g/mL, 10.46 μ g/mL and 15.03 μ g/mL are suitable with document report.And relative to cis-platinum
To the inhibiting effect of above-mentioned tumour cell, corresponding chemical combination of the invention equally there is preferable inhibition to make above-mentioned tumour cell
With, and there is some compound on tumor cell of the present invention stronger inhibiting effect, bioactivity higher, such as present invention to implement
The corresponding alkoxide compound obtained in example compares cis-platinum to the inhibiting effect (0.76-7.96 μ g/mL) of MCF-7 cancer cells
(15.03 μ g/mL) is eager to excel；And part of compounds such as I-d to the inhibiting effect (1.99 μ g/mL) of A549 and is better than cis-platinum (9.97 μ
g/mL).Thus, alkoxide triazol tetrazine compound of the invention has good antitumor activity, some even have
Good application prospect.As it can be seen that [1,2,4] triazole [4,3-b] heating balanced derivative compound of the present invention is expected to apply and prevent
With treatment tumor disease.
Specific embodiment described in the present invention is only an illustration of the spirit of the invention.Technology belonging to the present invention is led
The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method
In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
It is skilled to this field although present invention has been described in detail and some specific embodiments have been cited
For technical staff, as long as it is obvious that can make various changes or correct without departing from the spirit and scope of the present invention.
Claims (10)
1. a kind of alkoxide triazol tetrazine kind compound, which is characterized in that the structural formula of the compound is as shown in following formula I：
In above-mentioned formula I, R1Selected from C1~C5Alkyl；R2Selected from phenyl, substituted-phenyl or substituted benzene alkyl.
2. alkoxide triazol tetrazine kind compound according to claim 1, which is characterized in that the R1Selected from methyl, second
Base, isobutyl group or isopropyl；R2It is selected from phenyl, p-methoxyphenyl, phenethyl, 2,4 dichloro benzene base, rubigan or right
Fluorophenyl.
3. a kind of preparation method of alkoxide triazol tetrazine kind compound, which is characterized in that this method includes by II chemical combination of formula
Object 6- (3,5- dimethyl pyrazole -1- bases)-[1,2,4] triazole [4,3-b] heating balanced class compounds and alkylol R1OH carries out anti-
It answers, obtains product type I compound；
R described above1Selected from C1~C5Alkyl；The R2Selected from phenyl, substituted-phenyl or substituted benzene alkyl.
4. the preparation method of alkoxide triazol tetrazine kind compound according to claim 3, which is characterized in that the alkyl
Alcohol R1OH is selected from ethyl alcohol, methanol, isopropanol or isobutanol.
5. the preparation method of alkoxide triazol tetrazine kind compound according to claim 3, which is characterized in that the reaction
Temperature be 40 DEG C~80 DEG C.
6. according to claim 3 or the preparation method of the 4 or 5 alkoxide triazol tetrazine kind compounds, which is characterized in that institute
State alkylol R1OH is used as reactant and solvent simultaneously, the alkylol R1OH is excessive.
7. the preparation method of alkoxide triazol tetrazine kind compound according to claim 6, which is characterized in that the formula II
Compound and alkylol R1The mass ratio of OH is 1：20~30.
8. according to claim 3 or the preparation method of the 4 or 5 alkoxide triazol tetrazine kind compounds, which is characterized in that anti-
Further include post-processing after answering, the post-processing is specially：
Reaction solution after reaction is carried out alkylol is distilled off, adding ice ethyl alcohol makes precipitation solid, obtains product formula I
Compound.
9. a kind of application of alkoxide triazol tetrazine kind compound, which is characterized in that alkoxide as claimed in claim 1 or 2
Triazol tetrazine kind compound is used to prepare the drug or functional food of prevention and treatment antitumor activity.
10. the application of alkoxide triazol tetrazine kind compound according to claim 9, which is characterized in that described antitumor
Active drug includes the active constituent of alkoxide triazol tetrazine kind compound as claimed in claim 1 or 2 and pharmaceutically may be used
The auxiliary material of receiving.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101945874A (en) * | 2007-12-18 | 2011-01-12 | 法米诺克斯有限公司 | 3-substituted-4-0x0-3, 4-dihydro-imidazo- [5, 1-d] [1,2,3,5] -tetrazine-8-carboxylic acid amides as anticancer agents |
| CN102532141A (en) * | 2010-12-08 | 2012-07-04 | 中国科学院上海药物研究所 | (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof |
| CN103012410A (en) * | 2012-12-22 | 2013-04-03 | 台州职业技术学院 | [1,2,4] triazole [4,3-b] sym-tetrazine derivation compound and preparation method thereof |
| CN105968064A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(m-methylphenyl) tetrazine dicarboxamide compound as well as preparation and application thereof |
-
2018
- 2018-02-08 CN CN201810128673.3A patent/CN108276415B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101945874A (en) * | 2007-12-18 | 2011-01-12 | 法米诺克斯有限公司 | 3-substituted-4-0x0-3, 4-dihydro-imidazo- [5, 1-d] [1,2,3,5] -tetrazine-8-carboxylic acid amides as anticancer agents |
| CN102532141A (en) * | 2010-12-08 | 2012-07-04 | 中国科学院上海药物研究所 | (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof |
| CN103012410A (en) * | 2012-12-22 | 2013-04-03 | 台州职业技术学院 | [1,2,4] triazole [4,3-b] sym-tetrazine derivation compound and preparation method thereof |
| CN105968064A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(m-methylphenyl) tetrazine dicarboxamide compound as well as preparation and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| XU, FENG 等: ""Synthesis, antitumor evaluation and 3D-QSAR studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XU, FENG 等: ""Synthesis, antitumor evaluation and molecular docking studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 陈辉等: ""新型［1，2，4］三唑［4，3- b］均四嗪类化合物的合成及其抗癌活性"", 《合成化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113788835A (en) * | 2021-10-21 | 2021-12-14 | 台州职业技术学院 | Triazole tetrazine compound containing morpholine and quinoline ring and preparation method and application thereof |
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