CN109748923A - Containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and preparation method thereof and purposes - Google Patents
Containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and preparation method thereof and purposes Download PDFInfo
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Abstract
The present invention provides one kind and contains benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt, and structure is as shown in general formula I.The invention also discloses the preparation method containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its applications in terms of preparing anti-tumor drug and preparing PARP inhibitor medicaments.
Description
Technical field
The present invention relates to medical compounds and preparation method thereof and purposes, more particularly to it is a kind of containing benzo [4,5] imidazoles [1,
2-a] pyrazinones derivative and preparation method thereof and preparing the purposes in PARP inhibitor medicaments and anti-tumor drug.
Background technique
Poly adenosine diphosphate-ribose polymerase-1 (PARP) is a multifunctional protein being present in most eukaryocytes
Posttranslational modification enzyme, the family is it has been found that hypotype totally 18 at present, and wherein PARP-1 proportion is maximum, is related to centering
The treatment of the diseases such as wind, neurodegenerative disease, myocardial ischemia, cancer, inflammation and diabetes plays master in DNA damage reparation
Lead effect.For olaparib in 2014 by U.S. FDA and Europe EMA approval listing, this is the PARP-1 of first clinical application
Inhibitor.PARP-1 and PARP-2 structure are closely similar, and many inhibitor are effective simultaneously to the two, also have and select PARP-1/-2
Selecting property inhibits the report of research, but the function of injury repair process nearly 90% is completed by PARP-1.PARP-1 can be identified simultaneously
The gap portions that DNA is damaged are integrated to, and catalysis NAD+ resolves into niacinamide and ADP- ribose rapidly, then with ADP- core
Sugar is substrate, and nuclear receptor protein and ADP- ribose is made to form polymer to start the injury repair of DNA.PARP-1 inhibitor is made
There is good prospect to improve anti-tumor drug curative effect for sensitizer.
Since most of antineoplastic is all to inhibit the growth of tumour cell to cause the mechanism of DNA damage, and PARP-
1 DNA that can repair damage makes repressed tumour cell generate certain drug resistance, therefore by PARP-1 inhibitor and changes
The combination for treating drug can have the function that reduce dosage and heighten the effect of a treatment.Meanwhile there is preclinical study to show that PARP-1 inhibits
Agent has played the effect of synthetic lethal in the tumour of BRCA1/2 gene mutation, makes it in addition to the putting that can be used as general tumour
It treats outside sensitizer, is alternatively arranged as certain single therapy agent such as BRCA1/2 mutated tumor.Due to existing PARP-1 inhibitor pair
Tumour cell has selectivity, only generates inhibiting effect to the tumour cell of BRCA1/2 gene defect, therefore generally existing drug resistance
The problem of, and its bioactivity and water solubility are to be improved.
Summary of the invention
Goal of the invention: the first object of the present invention is to provide a kind of derivative containing benzo [4,5] imidazoles [1,2-a] pyrazinones
Object；
The second object of the present invention is to provide the preparation method of the analog derivative；
The third object of the present invention is to provide the purposes of the analog derivative.
Technical solution: present invention offer one kind is containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically
Acceptable salt, structure is as shown in general formula I:
Wherein R is monosubstituted, disubstituted or three replace；R is H, F, Cl, Br, OCH3、CH3、Or
One of.
Preferably, the R is F, CH3、OrOne of.
Further, described benzo [4,5] imidazoles [1,2-a] the pyrazinones derivative that contains includes following compound, chemical combination
The chemical name and structural formula of object are shown in Table 2.
The chemical name and structural formula of 2. compound of table
The above-mentioned preparation method containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative, when R be H, F, Cl, Br,
OCH3Or CH3One of when, reaction equation is as follows:
Include the following steps: benzo [4,5] imidazoles [1,2-a] pyrazine, i.e. the fluoro- 5- of compound IV, 2- ((oxo -3 4-,
4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid, i.e. after compound V and condensing agent mixed dissolution, be added acid binding agent carry out it is anti-
It answers, after completion of the reaction, reaction solution is added to the water agitation and filtration, obtain described containing benzo [4,5] imidazoles [1,2-a] pyrazinones
Derivative.
Wherein the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, 1- hydroxy benzo three
Azoles, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, N'- carbonyl dimidazoles
One of；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, sodium acetate, carbonic acid
One of sodium or potassium carbonate；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；The addition acid binding agent
The reaction dissolvent reacted afterwards is one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
Preferably, it is prepared from starting material II, step further include:
(1) starting material II is added in acid after dissolving and glycine is added, be heated to reflux to complete and react, it is cooling, it filters
After wash filter cake, obtain compound III；
(2) compound III and tetrabutylammonium bromide are added in NaOH aqueous solution, adds and is dissolved in the 1,2- of reaction dissolvent
Reaction solution at 20~30 DEG C is after completion of the reaction filtered, obtains benzo [4,5] imidazoles [1,2-a] pyrazine by Bromofume solution,
That is compound IV；
The reaction equation of above-mentioned reaction are as follows:
Wherein, in the step (1) of synthesis compound III, acid is hydrochloric acid；In the step of synthesizing compound IV (2),
The alkali is sodium hydroxide solution, and the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide, benzyl triethyl ammonium chlorine
Change ammonium, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyltrimethylammonium chlorination
One of ammonium, the reaction dissolvent are one of n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide.
Preferably, in the step (1) of synthesis compound III, the concentration of hydrochloric acid is 5~6mol/L, and heating is anti-
Answering temperature is 95~105 DEG C；In the step of synthesizing compound IV (2), alkali is that the sodium hydroxide that mass fraction is 40~50% is molten
Liquid.
Above-mentioned one kind contains the preparation method of benzo [4,5] imidazoles [1,2-a] pyrazinones derivative, wherein when R isWhen, reaction equation is as follows:
Include the following steps:
By 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formamide, i.e. fluoro- the 5- ((4- of compound X, 2-
Oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid, i.e. after compound V and condensing agent mixed dissolution, acid binding agent is added
It is reacted, after completion of the reaction, reaction solution is poured into water agitation and filtration, obtained described containing benzo [4,5] imidazoles [1,2-a] pyrrole
Zionoes derivative, i.e. compound I-9；
Wherein the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, 1- hydroxy benzo three
Azoles, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, N'- carbonyl dimidazoles
One of；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, sodium acetate, carbonic acid
One of sodium or potassium carbonate；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；The addition acid binding agent
The reaction dissolvent reacted afterwards is one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
Preferably, it is prepared from starting material VI, step further include:
Wherein, by compound VI through restore prepare compound VII process, reducing agent used be selected from iron powder/concentrated hydrochloric acid,
Iron powder/ammonium chloride, zinc powder/concentrated hydrochloric acid, stannous chloride, hydrogen/palladium carbon, ammonium formate/palladium carbon, hydrogen/Raney's nickel or hydrazine hydrate/thunder
Buddhist nun's nickel, preferably hydrogen/palladium carbon；It is molten that solvent is selected from methanol, ethyl alcohol, ethyl acetate, tetrahydrofuran, acetonitrile or any the two mixing
Agent, preferably methanol.
The process of prepare compound VIII, condensing agent choosing used are reacted with N- carbobenzoxyglycine by compound VII
From PyBOP, HOBT/EDCI, DCC or CDI, preferential CDI；Solvent is selected from methylene chloride, chloroform, acetonitrile, tetrahydrofuran, 1,4- bis-
Six ring of oxygen, n,N-Dimethylformamide or glycol dimethyl ether, preferably acetonitrile；Reaction temperature is 25 DEG C~80 DEG C, preferably 40 DEG C
~50 DEG C.
By compound VIII by removing benzyloxycarbonyl group prepare compound IX process, reducing agent used be selected from hydrogen/
Palladium carbon or ammonium formate/palladium carbon, preferably hydrogen/palladium carbon；Solvent is selected from methanol, ethyl alcohol, ethyl acetate, tetrahydrofuran, acetonitrile or appoints
Both meanings mixed solvent, preferably methanol.
By compound IX and 1,2- Bromofume reacts the process of prepare compound X, and alkali used is that mass percent is
20~60% sodium hydrate aqueous solution；Phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide, benzyl triethyl ammonium chlorine
Change ammonium, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyltrimethylammonium chlorination
One of ammonium, the reaction dissolvent are one of n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide.
Above-mentioned one kind contains the preparation method of benzo [4,5] imidazoles [1,2-a] pyrazinones derivative, when R isWhen, with compound I-10, reaction equation is as follows:
Include the following steps:
(1) by 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formonitrile HCN, the i.e. fluoro- 5- of compound XI, 2-
After ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid, i.e. compound V and condensing agent mixed dissolution, addition is tied up
Sour agent is reacted, and after completion of the reaction, reaction solution is poured into water agitation and filtration, is obtained compound XII；
(2) compound XII is dissolved in solvent, is passed through hydrogen chloride gas, after reaction evaporating solvent under reduced pressure, in residue
Solvent dissolution is added, add ammonia source carry out ammonolysis reaction obtain it is described derivative containing benzo [4,5] imidazoles [1,2-a] pyrazinones
Object, i.e. compound I-10；
Wherein, in step (1), the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, 1-
Hydroxybenzotriazole, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, N'-
One of carbonyl dimidazoles；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, vinegar
One of sour sodium, sodium carbonate or potassium carbonate；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；It is described to add
Entering the reaction dissolvent reacted after acid binding agent is one in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide
Kind；In step (2), the solvent be ethyl alcohol and methylene chloride mixed solvent, the ammonia source be ammonia, ammonium carbonate, ammonium formate,
One of ammonium chloride or ammonium sulfate.
Preferably, it is prepared from starting material compound X, it is further comprising the steps of: in 1,2,3,4- tetrahydro benzo [4,5] miaow
Azoles [1,2-a] pyrazine -9- formamide, i.e. compound X addition, which is dissolved in the phosphorus oxychloride of reaction dissolvent, obtains compound after reaction
XI, i.e., 1,2,3,4- tetrahydro benzos [4,5] imidazoles [1,2-a] pyrazine -9- formonitrile HCN；
The reaction equation is as follows:
Preferably, by during compound X and phosphorus oxychloride reaction prepare compound XI, reaction dissolvent be selected from acetonitrile,
Dioxane, toluene or phosphorus oxychloride, preferably phosphorus oxychloride；Reaction temperature is 80 DEG C~120 DEG C, preferably 100 DEG C~110 DEG C.
It is above-mentioned to contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative pharmaceutically acceptable salt, it can pharmaceutically connect
The salt received is by the salt containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and sour addition, wherein for the acid at salt
Are as follows: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid,
Methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
Preferably, the solvent of the salt-forming reaction is methanol, ethyl alcohol, methylene chloride, acetone, ethyl acetate, toluene or four
Hydrogen furans, or any several mixed solvent.
The above-mentioned medicine group containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt
Object is closed, by containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and/or its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier of receiving forms.
It is of the present invention to contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt
Pharmaceutically acceptable carrier can be added, common pharmaceutical formulation is made, such as tablet, capsule, pulvis, syrup, liquor, suspension
The common medicinal supplementary materials such as fragrance, sweetener, liquid or solid filler or diluent can be added in agent, freeze-dried powder, injection.
It is above-mentioned to be prepared containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt
Purposes in PARP inhibitor medicaments.
It is above-mentioned anti-in preparation containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt
Purposes in cancer drug, wherein the cancer is colon cancer and BRCA-1/2 deficiency breast cancer.
It is of the present invention to contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt
Administration mode clinically can be using modes such as oral, injections.
Generally, of the invention containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable
Salt is for when treating, people to be 1mg~1000mg/ days with dosage range；It can also be made according to the difference and disease severity of dosage form
Exceed the range with dosage.
The utility model has the advantages that provided by the invention contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically may be used
The salt of receiving can be used as the single therapy agent of tumour, or be combined with other anti-tumor drugs, so that it is existing anti-swollen to reach raising
Tumor medicine curative effect and the effect for reducing dosage and toxicity；Compared with existing PARP-1 inhibitor, the PARP-1 of such structure novel
Inhibitor improves dissolubility, solves the drug resistance problems of existing PARP-1 inhibitor, improves in the intracorporal biology benefit of people
Expenditure, in addition, also having expanded its application in oncotherapy；Pharmacology inhibition of enzyme activity effect experimental result is shown, contains benzo
[4,5] imidazoles [1,2-a] pyrazinones derivative maintains higher inhibitory activity to PARP-1, wherein compound I-4 and I-8
To the IC of PARP-150Value is better than positive drug olaparib Olaparib；The overwhelming majority contains benzo [4,5] imidazoles [1,2-a] pyrazine
Ketones derivant is superior to positive control drug olaparib to the inhibitory activity of three kinds of tumor cell lines, wherein compound I-1, I-
2 and I-3 reaches nanomole rank to the inhibitory activity of HCT116 cell strain.Also, compound is equal to MDA-MB-468 cell strain
Exhibit improvements over the inhibitory activity of MDA-MB-231, it was demonstrated that such compound to BRCA-1/2 deficient cell has stronger suppression
Production is used.
Specific embodiment
Embodiment 1
4- (the fluoro- 3- of 4- (1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl) benzyl) phthalazines -1
The synthesis of (2H) -one (I-1)
The synthesis of (1H- benzo [d] imidazoles -2- base) methylamine hydrochloride (III-1)
II-1 compound o-phenylenediamine (2.0g, 18.49mmol) is added in 100mL reaction flask, 5.5mol/L salt is added
Sour 20mL, stirring and dissolving, 100 DEG C back flow reaction 1 hour, be added glycine (2.77g, 36.90mmol), heating reflux reaction 48
Hour.TLC monitoring (methylene chloride: methanol=10:1) raw material is reacted completely, is cooled to room temperature, and a large amount of light green solids are precipitated,
It filters, a small amount of ice ethanol washing filter cake, dry white solid (III-1) 3.23g, yield 95.1%.m.p.>250℃.1H-
NMR(300MHz,DMSO-d6)δ(ppm):8.97(brs,2H,NH2),7.96-7.65(m,2H,ArH),7.64-7.19(m,
2H,ArH),4.46(s,2H,CH2),1.21(s,1H,NH).1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):7.80-
7.54(m,2H,ArH),7.54-7.21(m,2H,ArH),4.37(s,2H,CH2)
The synthesis of 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine (IV-1)
In 100mL three-necked bottle, it is added NaOH (15g, 0.38mol) and 15mL water, III- is added after dissolved clarification in mechanical stirring
1 (2.63g, 14.32mmol), tetrabutylammonium bromide (185mg, 0.57mmol), 25 DEG C are stirred to react 1 hour, and 1,2- bis- is added dropwise
Bromoethane (5.38g, 28.64mmol) is dissolved in the resulting solution of 50mL DMF, and drop finishes, and 25 DEG C are reacted 4 hours, and it is inorganic to filter removing
Salt, is concentrated under reduced pressure to obtain white solid, and column chromatographs (methylene chloride: methanol: ammonium hydroxide=50:1:0.05~40:1:0.05) purifying, obtains
Compound IV-1 mass is 1.25g, yield 50.4%.m.p.:131-132℃.1H-NMR(300MHz,CDCl3)δ(ppm):
7.75-7.66 (m, 1H, ArH), 7.38-7.27 (m, 3H, ArH), 4.34 (s, 2H, CCH2NH), 4.12 (t, J=5.6Hz, 2H,
), NCH2CH2NH 3.42 (t, J=5.6Hz, 2H, NCH2CH2NH) .MS (ESI (+) 70V) m/z:174.1 [M+H]+
4- (the fluoro- 3- of 4- (1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl) benzyl) phthalazines -1
The synthesis of (2H) -one (I-1)
The fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid (534mg, 1.79mmol) is made
For intermediate V, tetrahydro benzo [4,5] imidazoles [1, the 2-a] pyrazine (310mg, 1.79mmol) of IV-1 compound 1,2,3,4- and
PyBOP (1.12g, 2.15mmol) be added 100mL reaction flask in, be added 20mL DMF stirring and dissolving, add DIEA (0.81g,
6.27mmol), 10 DEG C of reactions.TLC (methylene chloride: methanol=20:1) monitors raw material end of reaction, and reaction solution is poured into 100mL
In water, a large amount of yellow solids are precipitated, stir 10min, filter, wash, it is dry, crude product column chromatography (methylene chloride: methanol=100:
1~80:1 gradient elution) purifying, obtaining I-1 compound quality is 420mg, yield 51.7%.M.p.:158~160 DEG C .1H-NMR
(300MHz, DMSO-d6) δ (ppm): 12.60 (s, 1H, CONH), 8.25 (t, J=6.7Hz, 1H, ArH), 8.01-7.77 (m,
3H,ArH),7.66-7.40(m,4H,ArH),7.37-7.15(m,3H,ArH),5.03(brs,1H,1/2NCH2ArH),4.69
(s,1H,1/2NCH2ArH),4.43-4.29(m,2H,NCH2CH2N),4.24(s,2H,ArCH2),4.07-3.97(m,1H,1/
2NCH2CH2N),3.81-3.69(m,1H,1/2NCH2CH2N).HRMS(ESI):m/z[M+H]+.Calcd for
C26H20FN5O2:454.1674；Found:454.1673.
Embodiment 2
4- (the fluoro- 3- of 4- (fluoro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl of 7-) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-2)
The synthesis of (fluoro- 1H- benzo [d] imidazoles -2- base of 6-) methylamine hydrochloride (III-2)
It is with II-2 compound 4- fluorine o-phenylenediamine (3.17g, 25.13mmol) and glycine (3.77g, 50.22mmol)
Raw material obtains compound III-2 mass 2.6g, yield 51.3% with the preparation method of III-1.m.p.:200-204℃
.1H-NMR(300MHz,DMSO-d6)δ(ppm):10.61(brs,2H,NH2),8.85(s,1H,NH),7.79-7.59(m,1H,
ArH),7.59-7.38(m,1H,ArH),7.27-7.04(m,1H,ArH),4.36(s,2H,CH2).1H-NMR(300MHz,
DMSO-d6+D2O)δ(ppm):7.67-7.56(m,1H,ArH),7.49-7.36(m,1H,ArH),7.18-7.06(m,1H,
ArH),4.29(s,2H,CH2).
The synthesis of fluoro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine (IV-2) of 7-
With compound III-2 (1.13g, 5.60mmol) and 1,2- Bromofume (4.23g, 22.52mmol) is raw material, fortune
With the preparation method of IV-1, obtaining compound IV-2 mass is 0.46g, yield 43.0%.m.p.>250℃.1H-NMR
(300MHz,CDCl3)δ(ppm):7.66-7.31(m,1H,ArH),7.25-6.92(m,2H,ArH),4.29(s,2H,
CCH2NH),4.14-4.01(m,2H,NCH2CH2NH),3.47-3.32(m,2H,NCH2CH2NH).
4- (the fluoro- 3- of 4- (fluoro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl of 7-) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-2)
Using the fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid as intermediate V (406mg,
1.36mmol) and compound IV-2 (260mg, 1.36mmol) is raw material, and with the preparation method of I-1,50 DEG C of reactions obtain chemical combination
Object I-2 mass is 320mg, yield 49.9%.M.p.:142~144 DEG C .1H-NMR (300MHz, DMSO-d6) δ (ppm):
12.59(s,1H,CONH),8.32-8.16(m,1H,ArH),8.05-7.73(m,3H,ArH),7.69-7.18(m,5H,ArH),
7.17-6.94(m,1H,ArH),5.02(brs,1H,1/2NCH2ArH),4.67(s,1H,1/2NCH2ArH),4.50-4.29
(m,2H,NCH2CH2N),4.23(s,2H,ArCH2),4.08-3.88(m,1H,1/2NCH2CH2N),3.82-3.68(m,1H,
1/2NCH2CH2N).HRMS(ESI):m/z[M+H]+.Calcd for C26H19F2N5O2:472.1580；Found:
472.1582.
Embodiment 3
4- (the fluoro- 3- of 4- (chloro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl of 7-) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-3)
The synthesis of (chloro- 1H- benzo [d] imidazoles -2- base of 6-) methylamine hydrochloride (III-3)
It is original with II-3 compound 4-chloro o-phenylenediamine (2g, 14.03mmol) and glycine (2.11g, 28.11mmol)
Material, with the preparation method of III-1, obtaining compound III-3 mass is 2.49g, yield 81.4%.m.p.:214-219℃
.1H-NMR(300MHz,DMSO-d6)δ(ppm):11.80(brs,1H,NH),8.91(s,2H,NH2),7.80-7.73(m,1H,
ArH),7.73-7.64(m,1H,ArH),7.38-7.28(m,1H,ArH),4.37(s,2H,CH2).1H-NMR(300MHz,
DMSO-d6+D2O)δ(ppm):7.72-7.66(m,1H,ArH),7.66-7.58(m,1H,ArH),7.33-7.24(m,1H,
ArH),4.31(s,2H,CH2).
The synthesis of chloro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine (IV-3) of 7-
With compound III-3 (1.96g, 8.99mmol) and 1,2- Bromofume (6.76g, 35.98mmol) is raw material, fortune
With the preparation method of IV-1, obtaining dark red oil compound IV-3 mass is 0.78g, yield 41.7%.1H-NMR
(300MHz,CDCl3)δ(ppm):7.70-7.56(m,1H,ArH),7.33-7.17(m,2H,ArH),4.30(s,2H,
), CCH2NH 4.06 (dd, J1=11.5Hz, J2=5.8Hz, 2H, NCH2CH2NH), 3.40 (t, J=5.5Hz, 2H,
NCH2CH2NH).
4- (the fluoro- 3- of 4- (chloro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl of 7-) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-3)
Using the fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid as intermediate V (677mg,
2.27mmol) and compound IV-3 (470mg, 2.27mmol) is raw material, and with the preparation method of I-1, reaction temperature is 40 DEG C,
Obtaining compound I-3 mass is 570mg, yield 51.4%.M.p.:158~160 DEG C .1H-NMR (300MHz, DMSO-d6) δ
(ppm):12.62(s,1H,CONH),8.34-8.18(m,1H,ArH),7.98-7.81(m,3H,ArH),7.71-7.45(m,
4H,ArH),7.35-7.23(m,2H,ArH),5.05(brs,1H,1/2NCH2ArH),4.70(s,1H,1/2NCH2ArH),
4.45-4.31(m,2H,NCH2CH2N),4.25(s,2H,ArCH2),4.12-3.99(m,1H,1/2NCH2CH2N),3.85-
3.68(m,1H,1/2NCH2CH2N).HRMS(ESI):m/z[M+H]+.Calcd forC26H19ClFN5O2:488.1284；
Found:488.1285.
Embodiment 4
4- (the fluoro- 3- of 4- (7- methyl-1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-5)
The synthesis of (6- methyl-1 H- benzo [d] imidazoles -2- base) methylamine hydrochloride (III-5)
With 4- methyl-o-phenylenediamine (II-5) (2g, 16.37mmol) and glycine (2.46g, 32.77mmol) for raw material,
With the preparation method of III-1, obtaining compound III-5 mass is 2.8g, yield 86.4%.m.p.:219-221℃.1H-
NMR (300MHz, DMSO-d6) δ (ppm): 8.24 (brs, 2H, NH2), 7.43 (d, J=7.7Hz, 1H, ArH), 7.35 (s, 1H,
), ArH 7.01 (d, J=7.6Hz, 1H), 4.25 (s, 2H, CH2), 3.32 (s, 1H, NH), 2.39 (s, 3H, CH3) .1H-NMR
(300MHz, DMSO-d6+D2O) δ (ppm): 7.44 (d, J=8.1Hz, 1H, ArH), 7.34 (s, 1H, ArH), 7.04 (d, J=
8.5Hz,1H,ArH),4.22(s,2H,CH2),2.35(s,3H,CH3).
The synthesis of chloro- 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine (IV-5) of 7-
With compound III-5 (2.8g, 14.17mmol) and 1,2- Bromofume (10.65g, 56.80mmol) is raw material,
With the preparation method of IV-1, obtaining compound IV-5 mass is 1.05g, yield 39.6%.m.p.:184-186℃.1H-NMR
(300MHz,CDCl3+D2O)δ(ppm):7.65-7.40(m,1H,ArH),7.29-7.16(m,1H,ArH),7.13-7.04(m,
1H,ArH),4.27(s,2H,CCH2NH),4.16-3.89(m,2H,NCH2CH2NH),3.43-3.25(m,2H,
NCH2CH2NH),2.47(s,3H,CH3).
4- (the fluoro- 3- of 4- (7- methyl-1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -2- carbonyl) benzyl) phthalein
The synthesis of piperazine -1 (2H) -one (I-5)
Using the fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid as intermediate V (988mg,
3.31mmol) and intermediate compound IV -5 (620mg, 3.31mmol) is raw material, and with the preparation method of I-1, reaction temperature is 10 DEG C,
Obtaining compound I-5 mass is 750mg, yield 48.5%.m.p.:164-166℃.1H-NMR(300MHz,DMSO-d6)δ
(ppm): 12.60 (s, 1H, CONH), 8.25 (t, J=6.6Hz, 1H, ArH), 7.97-7.79 (m, 3H, ArH), 7.51-7.25
(m,5H,ArH),7.09-6.97(m,1H,ArH),5.00(brs,1H,1/2NCH2ArH),4.66(s,1H,1/2NCH2ArH),
4.34-4.27(m,2H,NCH2CH2N),4.21(s,2H,ArCH2),4.03-3.93(m,1H,1/2NCH2CH2N),3.79-
3.68(m,1H,1/2NCH2CH2N),2.43-2.38(m,3H,CH3).
HRMS(ESI):m/z[M+H]+.Calcd for C26H20FN5O2:454.1674；Found:454.1673.
Embodiment 5
2- (the fluoro- 5- of 2- ((4- oxo -3,4- dihydro phthalazines -1- substitution) methylene) benzoyl) -1,2,3,4- tetrahydro
The synthesis of benzo [4,5] imidazo [1,2-a] pyrazine -9- formamide (I-9)
The synthesis of 2,3- diaminobenzene formamide (VII)
2- amino -3- nitrobenzamide VI (10g, 55.20mmol) is added in 1L reaction flask, it is anhydrous that 500mL is added
Methanol stirring and dissolving is slowly added to 10%Pd/C (1g, dry), 25 DEG C of hydrogenation reactions.TLC (methylene chloride: methanol=20:1) prison
Survey raw material fully reacting, stops reaction, filters and removes palladium carbon, reduced pressure filtrate, column chromatography (methylene chloride: methanol=200:
1) it purifies, obtains product (VII) 5.0g, yield 60.0%.m.p.:100-102℃.1H-NMR(300MHz,DMSO-d6)δ
(ppm): 7.60 (brs, 1H, CONH2), 6.97 (brs, 1H, CONH2), 6.88 (dd, J1=8.0Hz, J2=1.2Hz, 1H,
), ArH 6.60 (dd, J1=7.5Hz, J2=1.2Hz, 1H, ArH), 6.34 (t, J=7.7Hz, 1H, ArH), 6.07 (brs, 2H,
ArNH2),4.60(brs,2H,ArNH2).
The conjunction of benzyl ((4- carbamoyl -1H- benzo [d] imidazoles -2- substitution) methylene) carbamate (VIII)
At
Cbz- glycine (2.92g, 13.89mmol) and 120mL acetonitrile are added in 250mL reaction flask, stirring and dissolving is delayed
Slow that CDI (2.57g, 15.85mmol) is added, 45 DEG C are reacted 1.5 hours.It is anti-that TLC (methylene chloride: methanol=10:1) monitors raw material
It after having answered, is added intermediate VII (2g, 13.23mmol), 45 DEG C are reacted 4 hours.TLC (methylene chloride: methanol=10:1) monitoring
Raw material has reacted, and produces a large amount of white solids, filters, dry.It is added into 100mL reaction flask, is added 50mL glacial acetic acid, 120
DEG C back flow reaction is concentrated under reduced pressure after TLC (methylene chloride: methanol=10:1) monitoring raw material react and removes glacial acetic acid, addition
The dissolution of 100mL water, ethyl acetate extract (100mL × 2), merge organic layer, and saturated sodium-chloride washs (150mL), anhydrous slufuric acid
Sodium is dry.It filters, concentration filtrate obtains crude product (VIII) 4.18g, yield 97.4%.m.p.:166-168℃.1H-NMR
(300MHz,DMSO+D2O-d6)δ(ppm):12.75(s,1H,NH),9.22(s,1H,NH),7.96(s,1H,ArH),7.80
(d, J=7.5Hz, 1H, ArH), 7.66 (d, J=7.9Hz, 2H, ArH), 7.47-7.06 (m, 5H, ArH), 5.07 (s, 2H,
), CH2 4.49 (s, 2H, CH2) .1H-NMR (300MHz, DMSO+D2O-d6) δ (ppm): 7.79 (d, J=7.1Hz, 1H, ArH),
7.67 (d, J=8.0Hz, 1H, ArH), 7.43-7.18 (m, 5H, ArH), 7.09 (brs, 1H, ArH), 5.05 (s, 2H, CH2),
4.49(s,2H,CH2).
The synthesis of 2- (aminomethyl) -1H- benzo [d] imidazoles -4- formamide (IX)
Compound VIII (3g, 9.25mmol) is added in 250mL reaction flask, 100mL anhydrous methanol stirring and dissolving is added,
It is slowly added to 10%Pd/C (0.3g, dry), 30 DEG C of hydrogenation reactions.TLC (methylene chloride: methanol=10:1) monitors raw material reaction
It after complete, filter and removes palladium carbon, filtrate is concentrated under reduced pressure and obtains (IX) 1.4g, yield 79.5%.m.p.:>250℃.1H NMR
(300MHz, DMSO-d6) δ (ppm): 9.19 (s, 1H, CONH2), 7.76 (d, J=7.3Hz, 1H, ArH), 7.64 (d, J=
7.9Hz, 1H, ArH), 7.22 (t, J=7.8Hz, 1H, ArH), 3.97 (s, 2H, CH2)
The synthesis of 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formamide (X)
In 100mL three-necked bottle, it is added NaOH (8g, 0.20mol) and 8mL water, IX is added after dissolved clarification in mechanical stirring
(1.4g, 7.36mmol), tetrabutylammonium bromide (94mg, 0.29mmol), 25 DEG C are stirred to react 1 hour, and 1,2- dibromo second is added dropwise
Alkane (5.53g, 29.44mmol) is dissolved in the resulting solution of 40mL DMF, and drop finishes, and 25 DEG C are reacted 4 hours, filters and removes inorganic salts,
White solid is concentrated under reduced pressure to obtain, column chromatographs (methylene chloride: methanol: ammonium hydroxide=50:1:0.05~40:1:0.05) purifying, must produce
Product (X) 0.75g, yield 47.2%.m.p.:>250℃.1H-NMR(300MHz,DMSO-d6)δ(ppm):9.15(s,1H,
), ArH 7.84 (d, J=7.5Hz, 1H, ArH), 7.74-7.63 (m, 2H, CONH2), 7.30 (t, J=7.7Hz, 1H, ArH),
4.12(s,2H,CCH2NH),4.11-3.98(m,4H,NCH2CH2NH),3.25-3.12(m,2H,NCH2CH2NH).
MS(ESI(+)70V)m/z:239.1[M+Na]+,217.1[M+H]+.
2- (the fluoro- 5- of 2- ((4- oxo -3,4- dihydro phthalazines -1- substitution) methylene) benzoyl) -1,2,3,4- tetrahydro
The synthesis of benzo [4,5] imidazo [1,2-a] pyrazine -9- formamide (I-9)
Using the fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour benzene diazine -1- base) methyl) benzoic acid as intermediate V (648mg,
2.17mmol), intermediate X (470mg, 2.17mmol) and PyBOP (1.36g, 2.61mmol) are added in 100mL reaction flask, add
Enter 30mL DMF stirring and dissolving, adds DIEA (0.98g, 7.58mmol), 25 DEG C of reactions.TLC (methylene chloride: methanol=20:
1) raw material end of reaction is monitored, reaction solution is poured into 120mL water, a large amount of yellow solids are precipitated, stirs 10min, is filtered, water
It washes, it is dry.Crude product column chromatographs (methylene chloride: methanol=100:1~20:1) purifying, and obtaining compound I-9 mass is 470mg, receives
Rate 43.6%.m.p.:238-240℃.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.59(s,1H,CONH),9.12-
8.83(m,2H,CONH2),8.30-8.20(m,1H,ArH),7.96-7.69(m,5H,ArH),7.53-7.46(m,2H,ArH),
7.39-7.24(m,2H,ArH),5.12(brs,1H,1/2NCH2ArH),4.77(s,1H,1/2NCH2ArH),4.40-4.01
(m,5H,NCH2CH2N,ArCH2,1/2NCH2CH2N),3.84-3.70(m,1H,1/2NCH2CH2N).HRMS(ESI):m/z[M
+H]+.Calcd for C27H21FN6O3:497.1732；Found:497.1733.
Embodiment 6
2- (the fluoro- 5- of 2- ((4- oxo -3,4- dihydro phthalazines -1- substitution) methylene) benzoyl) -1,2,3,4- tetrahydro
The synthesis of benzo [4,5] imidazo [1,2-a] pyrazine -9- carbonamidine (I-10)
The synthesis of 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formonitrile HCN (XI)
Intermediate X (500mg, 2.31mmol) is added in 100mL reaction flask, is cooled to 0 DEG C, 20mL POCl3 is added and stirs
Dissolution is mixed, temperature rising reflux reacts 2 hours.TLC (methylene chloride: methanol=20:1) monitors raw material after completion of the reaction, stops heating.
It is cooled to room temperature, pours into 100mL ice water, with 30% NaOH solution tune pH to 9, ethyl acetate extracts (30mL × 3), merges
Organic layer, water washing is primary (80mL), and saturated salt solution washed once (80mL), and anhydrous sodium sulfate is dry.It filters, filtrate is concentrated
Obtain yellow oil (XI) 350mg, yield 76.4%.m.p.:212-214℃.1H NMR(300MHz,CDCl3)δ(ppm):
7.64-7.50(m,2H,ArH),7.34-7.28(m,1H,ArH),4.40(s,2H,CCH2NH),4.20-4.10(m,2H,
NCH2CH2NH),3.48-3.37(m,2H,NCH2CH2NH).MS(ESI(+)70V)m/z:221.1[M+Na]+.
2- (the fluoro- 5- of 2- ((4- oxo -3,4- dihydro phthalazines -1- substitution) methylene) benzoyl) -1,2,3,4- tetrahydro
The synthesis of benzo [4,5] imidazoles [1,2-a] pyrazine -9- formonitrile HCN (XII)
By intermediate V (1.05g, 3.52mmol), intermediate X I (0.7g, 3.53mmol) and PyBOP (2.21g,
It 4.25mmol) is added in 100mL reaction flask, 40mL DMF stirring and dissolving is added, adds DIEA (1.59g, 12.30mmol),
25 DEG C of reactions.TLC (methylene chloride: methanol=20:1) monitors raw material end of reaction, and reaction solution is poured into 160mL water, is precipitated
A large amount of yellow solids.10min is stirred, is filtered, filter cake washing is dry.Crude product column chromatography (methylene chloride: methanol=100:1~
It 80:1) purifies, obtains product (XII) 1.04g.Yield 61.9%.m.p.:192-194℃.1H-NMR(300MHz,DMSO-d6)δ
(ppm): 12.61 (s, 1H, CONH), 8.25 (t, J=6.6Hz, 1H, ArH), 8.00-7.76 (m, 4H, ArH), 7.73 (d, J=
7.5Hz, 1H, ArH), 7.55-7.44 (m, 2H, ArH), 7.39 (t, J=7.8Hz, 1H, ArH), 7.31 (t, J=8.7Hz, 1H,
ArH),5.11(brs,1H,1/2ArCH2N),4.78(s,1H,1/2ArCH2N),4.45-4.14(m,4H,CH2),4.14-
4.04(m,1H,1/2CH2),3.85-3.67(m,1H,1/2CH2).
2- (the fluoro- 5- of 2- ((4- oxo -3,4- dihydro phthalazines -1- substitution) methylene) benzoyl) -1,2,3,4- tetrahydro
The synthesis of benzo [4,5] imidazo [1,2-a] pyrazine -9- carbonamidine (I-10)
Intermediate X II (270mg, 0.56mmol) is added in 50mL three-necked bottle, 20mL (dehydrated alcohol: dichloromethane is added
Alkane=8:1) mixed solvent stirring and dissolving, it is cooled to 0 DEG C, is passed through dry HCl gas to saturation.TLC (methylene chloride: methanol
=20:1) monitoring raw material end of reaction, removing solvent is concentrated under reduced pressure and obtains yellow oil.20mL mixing is added in residue
Solvent (dehydrated alcohol: methylene chloride=8:1) stirring and dissolving is added ammonium carbonate (700mg, 7.29mmol), 25 DEG C of reaction 8h.Stop
It only reacts, reaction solution is concentrated under reduced pressure, column chromatographs (methylene chloride: methanol=80:1~40:1) purifying, obtains compound I-10 mass
For 105mg, yield 37.8%, while measuring the water-soluble of I-10 and increasing.M.p.:178~180 DEG C .1H-NMR (300MHz,
DMSO-d6)δ(ppm):12.59(brs,1H,CONH),9.60(brs,3H,C(NH)NH2),8.25(s,1H,ArH),8.13-
8.09(m,1H,ArH),8.06-7.67(m,4H,ArH),7.62-7.38(m,3H,ArH),7.38-7.22(m,1H,ArH),
5.15(s,1H,1/2NCH2ArH),4.80(s,1H,1/2NCH2ArH),4.47-4.18(m,4H,NCH2CH2N,ArCH2),
4.18-4.06(m,1H,1/2NCH2CH2N),3.87-3.72(m,1H,1/2NCH2CH2N).
HRMS(ESI):m/z[M+H]+.Calcd for C27H23FN7O2:496.1892；Found:496.1892.
Embodiment 7
Detection compound inhibits the IC of PARP-1 in enzyme level50Value.
1. experimental method:
It takes out in 96 orifice plates of pre-coated histone, the inhibition of following enzyme reaction system and various concentration is added in every hole
Agent, comprising: the reaction buffer Tris*HCl, pH 8.0, NAD+ of 50 μ L, the activated dna of biotin labeling, PARP-1 enzyme and suppression
Preparation；After reacting 1h at room temperature, the HRP of 50 μ L Avidins label is added in every hole, reacts 30min；Add 100 μ L's
HRP substrate detects values of chemiluminescence on SpectraMax M5 instrument.
Drug concentration is diluted according to three times concentration gradient, and each concentration detects two multiple holes.Using drug concentration as cross
Coordinate, the corresponding enzymatic activity percentage of each concentration is ordinate, does nonlinear regression using GRAPHPAD PRISM 5, calculates
Inhibit the IC50 value of PARP-1 to each compound.
2. experimental result
Inhibition of enzyme activity effect experimental result is shown, most of to contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative
Higher inhibitory activity is maintained to PARP-1, wherein IC of the compound I-4 and I-8 to PARP-150Value is better than positive drug Aura
Pa Buddhist nun Olaparib.
Experimental result is shown in Table 3
The IC of 3. part test-compound of table inhibition PARP-150
Embodiment 8
Detection compound inhibits human colon cancer cell HCT11, human breast cancer cell MDA-MB-231 and human breast cancer cell
The IC50 value of MDA-MB-468.
1. experimental method:
Cell in logarithmic growth phase is connected in 96 orifice plates (200 hole μ L/) with certain amount, culture is allowed to paste for 24 hours
Dosing after wall.Each drug concentration sets 3 multiple holes, and sets corresponding zeroing hole and blank control.After drug effect 72 hours, patch
50%TCA (50 hole μ l/) is added in parietal cell, and 4 DEG C are fixed 1 hour, outwells fixer, with distillation washing 5 times, spontaneously dries.Often
100 μ L 4mg/mL SRB are added in hole, and room temperature dyes 15 minutes, abandons it, washed 5 times with 1% glacial acetic acid, spontaneously dry.Last every hole
150 μ L 10mM Tris solution are added, shake up, are declined orifice plate microplate reader (VERSAmaxTM, Molecular with wavelengthtunable
Device OD value) is measured under 565nm wavelength.Inhibitory rate of cell growth is calculated with above formula.
2. experimental result
Experimental result shows that the overwhelming majority is thin to three kinds of tumours containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative
The inhibitory activity of born of the same parents' strain is superior to positive control drug olaparib, and wherein compound I-1, I-2 and I-3 is to HCT116 cell strain
Inhibitory activity reaches nanomole rank.Also, compound all shows better than MDA-MB-231's MDA-MB-468 cell strain
Inhibitory activity, it was demonstrated that such compound to BRCA-1/2 deficient cell has stronger inhibiting effect.Experimental result is shown in Table 4
The IC of 4. part test-compound of table inhibition tumour cell50
Claims (10)
1. one kind exists containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable salt, feature
In structure is as shown in general formula I:
Wherein R is monosubstituted, disubstituted or three replace；R is H, F, Cl, Br, OCH3、CH3、 In
It is a kind of.
2. according to claim 1 containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable
Salt, it is characterised in that: wherein R be F, CH3、One of.
3. according to claim 1 containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable
Salt, it is characterised in that: it is described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative include following compound, compound
Chemical name and structural formula be shown in Table 1.
The chemical name and structural formula of 1. compound of table
4. one kind described in claim 1 contains the preparation method of benzo [4,5] imidazoles [1,2-a] pyrazinones derivative,
It is characterized in that, when R is H, F, Cl, Br, OCH3Or CH3One of when, reaction equation is as follows:
Include the following steps: benzo [4,5] imidazoles [1,2-a] pyrazine, the fluoro- 5- of 2- ((4- oxo -3,4- dihydro neighbour's benzene diazine -
1- yl) methyl) after benzoic acid and condensing agent mixed dissolution, acid binding agent is added and is reacted, after completion of the reaction, reaction solution is poured into
Agitation and filtration in water obtains described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative；
Wherein the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, I-hydroxybenzotriazole, 1-
(3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, one in N'- carbonyl dimidazoles
Kind；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, sodium acetate, sodium carbonate or carbon
One of sour potassium；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；It is reacted after the addition acid binding agent
Reaction dissolvent be one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
5. one kind described in claim 1 contains the preparation method of benzo [4,5] imidazoles [1,2-a] pyrazinones derivative,
In as R beWhen, reaction equation is as follows:
Include the following steps:
By 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formamide, the fluoro- 5- of 2- ((4- oxo -3,4- dihydro
Adjacent benzene diazine -1- base) methyl) after benzoic acid and condensing agent mixed dissolution, acid binding agent is added and is reacted, it after completion of the reaction, will
Reaction solution is poured into water agitation and filtration, obtains described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative I -9；
Wherein the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, I-hydroxybenzotriazole, 1-
(3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, one in N'- carbonyl dimidazoles
Kind；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, sodium acetate, sodium carbonate or carbon
One of sour potassium；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；It is reacted after the addition acid binding agent
Reaction dissolvent be one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
6. one kind described in claim 1 contains the preparation method of benzo [4,5] imidazoles [1,2-a] pyrazinones derivative,
It is characterized in that, when R isWhen, reaction equation is as follows:
Include the following steps:
(1) by 1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine -9- formonitrile HCN, the fluoro- 5- of 2- ((4- oxo -3,4- dihydro
Adjacent benzene diazine -1- base) methyl) after benzoic acid and condensing agent mixed dissolution, acid binding agent is added and is reacted, it after completion of the reaction, will
Reaction solution is poured into water agitation and filtration, obtains compound XII；
(2) compound XII is dissolved in solvent, is passed through hydrogen chloride gas, after reaction evaporating solvent under reduced pressure, is added in residue
Solvent dissolution, add ammonia source carry out ammonolysis reaction obtain it is described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative I-
10；
Wherein, in step (1), the condensing agent is hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, 1- hydroxyl
Benzotriazole, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, N'- carbonyl
One of diimidazole；The acid binding agent is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine, acetic acid
One of sodium, sodium carbonate or potassium carbonate；The reaction temperature reacted after the addition acid binding agent is 20~30 DEG C；The addition
The reaction dissolvent reacted after acid binding agent is one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；
In step (2), the solvent is the mixed solvent of ethyl alcohol and methylene chloride, and the ammonia source is ammonia, ammonium carbonate, ammonium formate, chlorine
Change one of ammonium or ammonium sulfate.
7. claims 1 to 3 it is any containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative it is pharmaceutically acceptable
Salt, it is characterised in that: pharmaceutically acceptable salt is by adding containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and acid
At salt, wherein at salt acid are as follows: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid,
Lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
8. claims 1 to 3 it is any containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically acceptable
Salt pharmaceutical composition, it is characterised in that: by contain benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and/or its pharmacy
Upper acceptable salt and pharmaceutically acceptable carrier composition.
Described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically may be used 9. claims 1 to 3 is any
The salt of receiving is preparing the purposes in PARP inhibitor medicaments.
Described containing benzo [4,5] imidazoles [1,2-a] pyrazinones derivative and its pharmaceutically may be used 10. claims 1 to 3 is any
The salt of receiving is preparing the purposes in anticancer drug, it is characterised in that: the cancer is colon cancer and BRCA-1/2 deficiency mammary gland
Cancer.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251204A (en) * | 2017-07-13 | 2019-01-22 | 中国药科大学 | PARP inhibitor, its preparation method and medical usage containing phthalazines -1 (2H) -one structure |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009093032A1 (en) * | 2008-01-23 | 2009-07-30 | Astrazeneca Ab | Phthalazinone derivatives |
| WO2012019426A1 (en) * | 2010-08-09 | 2012-02-16 | 上海恒瑞医药有限公司 | Phthalazinone derivative, and preparation method and pharmaceutical use thereof |
| CN102898377A (en) * | 2012-02-14 | 2013-01-30 | 南京圣和药业有限公司 | Novel phthalazinone derivatives and uses thereof |
| CN106458988A (en) * | 2014-05-07 | 2017-02-22 | 默克专利股份公司 | Heterocyclyl-butanamide derivatives |
| WO2017101796A1 (en) * | 2015-12-16 | 2017-06-22 | 四川科伦博泰生物医药股份有限公司 | Phthalazinone derivative, and preparation method and use thereof |
| CN109251204A (en) * | 2017-07-13 | 2019-01-22 | 中国药科大学 | PARP inhibitor, its preparation method and medical usage containing phthalazines -1 (2H) -one structure |
-
2019
- 2019-01-31 CN CN201910095249.8A patent/CN109748923A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009093032A1 (en) * | 2008-01-23 | 2009-07-30 | Astrazeneca Ab | Phthalazinone derivatives |
| WO2012019426A1 (en) * | 2010-08-09 | 2012-02-16 | 上海恒瑞医药有限公司 | Phthalazinone derivative, and preparation method and pharmaceutical use thereof |
| CN102898377A (en) * | 2012-02-14 | 2013-01-30 | 南京圣和药业有限公司 | Novel phthalazinone derivatives and uses thereof |
| CN106458988A (en) * | 2014-05-07 | 2017-02-22 | 默克专利股份公司 | Heterocyclyl-butanamide derivatives |
| WO2017101796A1 (en) * | 2015-12-16 | 2017-06-22 | 四川科伦博泰生物医药股份有限公司 | Phthalazinone derivative, and preparation method and use thereof |
| CN109251204A (en) * | 2017-07-13 | 2019-01-22 | 中国药科大学 | PARP inhibitor, its preparation method and medical usage containing phthalazines -1 (2H) -one structure |
Non-Patent Citations (1)
| Title |
|---|
| 王超杰 等: "酞嗪类化合物的合成及活性研究进展", 《中国药房》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251204A (en) * | 2017-07-13 | 2019-01-22 | 中国药科大学 | PARP inhibitor, its preparation method and medical usage containing phthalazines -1 (2H) -one structure |
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