CN107266426A - 2 ammonia alkyl pyrimidines and its production and use - Google Patents
2 ammonia alkyl pyrimidines and its production and use Download PDFInfo
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- CN107266426A CN107266426A CN201710694618.6A CN201710694618A CN107266426A CN 107266426 A CN107266426 A CN 107266426A CN 201710694618 A CN201710694618 A CN 201710694618A CN 107266426 A CN107266426 A CN 107266426A
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- ammonia alkyl
- pyrimidines
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- methyl
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- 0 C*=C(C=CN)c1c[n](C)c2ccccc12 Chemical compound C*=C(C=CN)c1c[n](C)c2ccccc12 0.000 description 1
- WPOFZGLDIRVUHX-UHFFFAOYSA-N CN(C)CCN(C)c(cc(c(N(C)c1nccc(-c2c[n](C)c3ccccc23)n1)c1)OC)c1NC(C=C)=O Chemical compound CN(C)CCN(C)c(cc(c(N(C)c1nccc(-c2c[n](C)c3ccccc23)n1)c1)OC)c1NC(C=C)=O WPOFZGLDIRVUHX-UHFFFAOYSA-N 0.000 description 1
- SGRATTFVCNFYJC-UHFFFAOYSA-N CN(c(cc(c(F)c1)[N+]([O-])=O)c1OC)c1nccc(-c2c[n](C)c3ccccc23)n1 Chemical compound CN(c(cc(c(F)c1)[N+]([O-])=O)c1OC)c1nccc(-c2c[n](C)c3ccccc23)n1 SGRATTFVCNFYJC-UHFFFAOYSA-N 0.000 description 1
- OECMKYFTFXRAMQ-UHFFFAOYSA-N CNc(c(OC)c1)cc([N+]([O-])=C)c1F Chemical compound CNc(c(OC)c1)cc([N+]([O-])=C)c1F OECMKYFTFXRAMQ-UHFFFAOYSA-N 0.000 description 1
- OJYSIZJDVILBSX-UHFFFAOYSA-N CNc(cc(c(F)c1)[N+]([O-])=O)c1OC Chemical compound CNc(cc(c(F)c1)[N+]([O-])=O)c1OC OJYSIZJDVILBSX-UHFFFAOYSA-N 0.000 description 1
- FYSIGSQCZXQTIH-UHFFFAOYSA-N COc(cc(c([N+]([O-])=O)c1)F)c1N Chemical compound COc(cc(c([N+]([O-])=O)c1)F)c1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 1
- IIBWXYHPBMUNJP-UHFFFAOYSA-N C[n]1c2ccccc2c(-c2nc(Cl)ncc2)c1 Chemical compound C[n]1c2ccccc2c(-c2nc(Cl)ncc2)c1 IIBWXYHPBMUNJP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a kind of 2 ammonia alkyl pyrimidines, its structure is shown in formula I：
Description
Technical field
The present invention relates to a kind of 2- ammonia alkyl pyrimidines and its production and use, belong to medicine synthesis technique
Field.
Background technology
AZD9291 targets medicine as the third generation lung cancer that efficient selective EGFR mutant inhibitor is AstraZeneca exploitation
Thing (WO2013014448A1, WO2015195228A1), its molecular structure is as follows：
AZD9291 is the third generation TKI class targeted drugs for T790M gene mutations, is mainly used in treatment late period non-small
Cell lung cancer (NSCLC).T790M gene mutations are most commonly in the patient for taking Iressa or Erlotinib, if patient exists
T790M gene mutations are found during taking Iressa or Erlotinib, target medicine originally will be invalid, and tumour will be uncontrolled
System, at this moment AZD9291 just can provide new therapeutic scheme for patient.Meanwhile, it is found that the patient for there are T790M gene mutations is not having
In the case of having received any treatment, AZD9291 is also one of therapeutic scheme.
Under the enlightenment of AZD9291 structures, have mercy on Radiance-of-fire, Yang Xinglin, Wang Tingliang of Tsing-Hua University is disclosed with following structure
Novel molecular (CN105585557A)：
R can be H, OH, NR ', carbon number be 1~3 alkyl, carbon number be 1~3 alkenyl, aryl or heterocycle,
R ' is the alkyl that carbon number is 1~3.
The content of the invention
For existing known structure, it is an object of the invention to provide a kind of new 2- ammonia alkyl pyrimidines and its system
Preparation Method and purposes.
The present invention is achieved by the following technical solutions：
A kind of 2- ammonia alkyl pyrimidines, its structure is shown in formula I：
Preferably, the R is the alkyl that carbon number is 1~5, including methyl, ethyl, propyl group, butyl, penta
Base, pi-allyl, Cvclopropvlmethvl, cyclobutylmethyl etc..
A kind of preparation method of 2- ammonia alkyl pyrimidines as the aforementioned, it is according to following reaction scheme：
A kind of EGFR mutant inhibitor, it includes the foregoing 2- ammonia alkyl pyrimidines of effective dose, or 2-
The medically acceptable salt and compound of ammonia alkyl pyrimidines.
Compared with prior art, the present invention has following beneficial effect：
It is that the inhibitor of EGFR mutant is carried the invention provides a kind of 2- ammonia alkyl pyrimidines of new structure
For new optional compound.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that to the ordinary skill of this area
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection domain.
Experimental method is conventional method unless otherwise specified used in following embodiments.
Experiment material, reagent are that commercial sources are obtained unless otherwise specified used in following embodiments.
The preparation of embodiment compound 1:
The synthetic route of compound 1：
Embodiment 1
The synthesis of intermediate (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-)-methyl amine
The fluoro- 2- methoxyl groups -5- nitroanilines of 500 milligrams of 4- (CAS 1075705-01-9,2.69mmol) are dissolved in 50 millis
Rise in methanol, then add 0.5 milliliter 37% of formalin (6.16mmol), add 338 milligrams of sodium cyanoborohydrides
(5.38mmol), reaction solution is stirred at room temperature 2 hours, after TLC shows that reaction terminates, reaction solution is spin-dried for, residue is through silicon
Plastic column chromatography (EA/PE=1/6~1/3), obtains 250 milligrams of orange solids products, yield 46.6%.
1HNMR(400MHz,CDCl3)δ:7.14 (d, J=7.2Hz, 1H), 6.60 (d, J=12.4Hz, 1H), 4.27
(brs, 1H), 3.93 (s, 3H), 2.89 (d, J=5.2Hz, 3H)；
MS:201.1(M+H)+。
Embodiment 2
Intermediate (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-)-methyl-[4- (1- Methyl-1H-indole -3- bases)-pyrimidine -
2- yls]-amine synthesis
Under nitrogen protection, 200 milligrams of (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-)-methyl amines are sequentially added in reaction bulb
(1.0mmol), 244 milligrams of 3- (2- chlorine pyrimidine-4-yl) -1- methyl indols (CAS 1032452-86-0,
1.0mmol), 207 milligrams of p-methyl benzenesulfonic acid monohydrates (1.2mmol) and 5 milliliters of 2- amylalcohols.Mixture is stirred at 105 DEG C
Show that reaction terminates to TLC within two hours.Reaction solution is cooled to room temperature, and obtained solid is collected by filtration；Filtrate continues cold with ice-water bath
But, obtained solid is collected by filtration.Two batches solid is washed after merging with acetonitrile, obtains 367 milligrams of gray solids, yield 90%.
The crude product being collected into is directly used in the next step.MS:408.1(M+H)+。
Embodiment 3
Intermediate N4- [2- (dimethylamino) ethyl] -2- methoxyl groups-N1, N4- dimethyl-N1- [4- (1- methyl indols -
3- yls) pyrimidine -2-base] -5- nitrobenzene -1,4- diamines synthesis
Nitrogen protection under, by 300 milligrams of intermediates (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-)-methyl-[4- (1- methyl -
1H- indol-3-yls)-pyrimidine -2-base]-amine (0.74mmol) is suspended in 5 milliliters of DMF, is subsequently added 76 milligrams of N, N, N'- tri-
Methyl ethylenediamine (0.74mmol) and 258 milligrams of N, N- diisopropyl ethyl amines (2.0mmol).Reaction solution reacts 4 at 85 DEG C
Hour shows that consumption of raw materials is finished to TLC.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography (mobile phase：DCM/
MeOH=10/1 188 grams of Orange red solid products, yield 51.9%) are obtained.
1HNMR(400MHz,CDCl3)δ:8.25 (d, J=4.4Hz, 1H), 7.99 (s, 1H), 7.68 (m, 1H), 7.00-
7.40 (m, 4H), 6.87 (d, J=5.2Hz, 2H), 6.68 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.53 (s, 3H),
3.41 (t, J=6.8Hz, 2H), 2.96 (s, 3H), 2.69 (t, J=6.8Hz, 2H), 2.32 (s, 6H)；
MS:490.2(M+H)+。
Embodiment 4
Intermediate N1- [2- (dimethylamino) ethyl] -5- methoxyl groups-N1, N4- dimethyl-N4- [4- (1- methyl indols -
3- yls) pyrimidine -2-base] benzene -1,2,4- triamines synthesis
By 300 milligrams of intermediate N4- [2- (dimethylamino) ethyl] -2- methoxyl groups-N1, N4- dimethyl-N1- [4- (1-
Methyl indol -3- bases) pyrimidine -2-base] -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (0.61mmol) is dissolved in 10 milliliters of MeOH, adds 90 millis
Gram 10%Pd/C.Reaction solution 1 atmospheric pressure nitrogen atmosphere and stir 2 hours at room temperature, untill TLC shows that reaction is finished.
Diatomite is filtered, and filtrate is spin-dried for, and obtains 291 milligrams of dark red solids, yield 100%.Crude product is directly used in the next step.
MS:460.3(M+H)+。
Embodiment 5
Compound N-(2- [(2- dimethylaminoethyls)-methylamino] -4- methoxyl groups -5- { methyl-[4- (1- methyl isophthalic acids H-
Indol-3-yl)-pyrimidine -2-base]-amine-phenyl)-acrylamide (compound 1) synthesis
Under nitrogen protection, 250 milligrams of intermediate N1- [2- (dimethylamino) ethyl] -5- methoxyl groups-N1, N4- dimethyl -
N4- [4- (1- methyl indol -3- bases) pyrimidine -2-base] benzene -1,2,4- triamines (0.54mmol) are dissolved in 5 milliliters of DCM, ice-water bath
System is as cold as 5 DEG C, 84 milligrams of N, the propylene of N- diisopropyl ethyl amines (0.65mmol), then 54 milligrams of dropwise addition are then added
Acyl chlorides (0.59mmol).React and stir 3 hours at 5 DEG C after adding.After TLC shows that reaction terminates, reaction solution is spin-dried for, it is remaining
Thing obtains 180 milligrams of white products, yield 64% through silicagel column purifying.
1HNMR(400MHz,CDCl3)δ:10.09 (brs, 1H), 8.59 (s, 1H), 8.25 (d, J=5.6Hz, 1H), 7.71
(s, 1H), 7.2~7.4 (m, 3H), 7.00~7.16 (m, 1H), 6.90 (s, 1H), 6.84 (d, J=5.6Hz, 1H), 6.25~
6.45(m,2H),5.66(dd,J1=2.0Hz, J2=10.0Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.57 (s, 3H),
2.95(m,2H),2.80(s,3H),2.42(m,2H),2.30(s,6H).
13CNMR(400MHz,CDCl3)δ:163.29,162.31,161.79,156.66,151.97,141.16,
137.72,131.94,131.75,130.68,129.17,126.26,126.10,122.70,122.17,121.24,120.60,
114.38,109.28,106.47,105.41,57.46,56.75,56.07,45.73,42.47；
MS:514.3(M+H)+。
Using with the identical synthetic method of compound 1, can obtain the compound 2~4 shown in table 1：
Table 1
Embodiment 6
Inhibitory activity of the compound 1 to kinases
Kinases model is as shown in table 2
Table 2
| Kinases model | Source and article No. |
| EGFR(ErbB1) | Thermophisher, PR7295B |
| EGFR(ErbB1)[T790M][L858R] | Thermophisher, PR8911A |
External activity detection is carried out to EGFR inhibitor with both the above kit.According to kit operation instruction, successively
It is equipped with enzyme buffer liquid, enzyme/substrate peptide fragment solution, ATP solution and the complete phosphorylated substrate peptide fragment solution of respective concentration.With distillation
Water prepares the solution of compound 1~4.
To the enzyme/substrate peptide fragment solution and complete phosphorylated substrate peptide fragment solution configured, 2.5 microlitres of addition orifice plates are taken,
1.25 microlitres of ATP solution and 1.25 microlitres of solution of compound 1 are added in experimental group, it is micro- to add 1.25 in complete inhibition control group
Rise enzyme buffer solution and 1.25 microlitres of respective concentration DMSO solutions, added in No inhibition control group 1.25 microlitres of ATP solution and
1.25 microlitres of respective concentration DMSO solutions, add 1.25 microlitres of enzyme buffer solutions and 1.25 in complete phosphorylated substrate control group
Microlitre respective concentration DMSO solution.Each orifice plate is sealed and shakes uniform rear incubation at room temperature 1 hour.By operation instruction, reaction is tried
Agent is made into developing solution by corresponding proportion, and each 2.5 microlitres of reacting hole is added after being well mixed, and seals and shakes uniform, incubation at room temperature 1
Hour.It is last that 2.5 microlitres of terminate liquids are added per hole, mix, use 400nm fluorescence excitations, with respective filter in 445nm and
Fluorescence data is read at 520nm.
The fluorescence data of compound 2~4 is obtained with same method.
The activity of the compounds of this invention 1 is determined by above method, gained IC50Value is as shown in table 3：
Table 3
| Compound | EGFR(ErbB1)(nM) | EGFR(ErbB1)[T790M][L858R](nM) |
| 1 | 30.1 | 5.9 |
| 2 | 50.9 | 10.1 |
| 3 | 150.5 | 12.9 |
| 4 | 210.2 | 15.6 |
As a result show that two kinds of enzymes of compound 1~4 pair have certain inhibitory activity.
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring the substantive content of the present invention.
Claims (4)
1. a kind of 2- ammonia alkyl pyrimidines, it is characterised in that structure is shown in formula I：
2. 2- ammonia alkyl pyrimidines as claimed in claim 1, it is characterised in that the R is that carbon number is 1~5
Alkyl.
3. a kind of preparation method of 2- ammonia alkyl pyrimidines as claimed in claim 1, it is characterised in that according to as follows
Reaction scheme：
。
4. a kind of EGFR mutant inhibitor, it is characterised in that the 2- ammonia alkyl described in the claim 1 comprising effective dose is phonetic
Pyridine class compound, or 2- ammonia alkyl pyrimidines medically acceptable salt and compound.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104974140A (en) * | 2014-04-14 | 2015-10-14 | 上海海雁医药科技有限公司 | 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof |
| CN106117185A (en) * | 2015-08-31 | 2016-11-16 | 广州科擎新药开发有限公司 | 2,4 2 nitrogen-containing group substituted pyrimidines compounds and its preparation method and application |
| CN108473496A (en) * | 2015-12-03 | 2018-08-31 | 上海亦恩生物科技有限公司 | Heterocyclic compound and application thereof |
-
2017
- 2017-08-15 CN CN201710694618.6A patent/CN107266426A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104974140A (en) * | 2014-04-14 | 2015-10-14 | 上海海雁医药科技有限公司 | 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof |
| CN106117185A (en) * | 2015-08-31 | 2016-11-16 | 广州科擎新药开发有限公司 | 2,4 2 nitrogen-containing group substituted pyrimidines compounds and its preparation method and application |
| CN108473496A (en) * | 2015-12-03 | 2018-08-31 | 上海亦恩生物科技有限公司 | Heterocyclic compound and application thereof |
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Effective date of registration: 20180928 Address after: 730000 No. 222 Tianshui South Road, Chengguan District, Lanzhou, Gansu Applicant after: Lanzhou University Applicant after: Nantong Norwich Medical Technology Co Ltd Address before: 226100 100 Dongting Lake Road, Linjiang Town, Haimen, Nantong, Jiangsu Applicant before: Nantong Norwich Medical Technology Co Ltd Applicant before: The Second Hospital of Lanzhou University |
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