CN102875462B - Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof - Google Patents
Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof Download PDFInfo
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- CN102875462B CN102875462B CN201210384090.XA CN201210384090A CN102875462B CN 102875462 B CN102875462 B CN 102875462B CN 201210384090 A CN201210384090 A CN 201210384090A CN 102875462 B CN102875462 B CN 102875462B
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Abstract
The invention provides a novel anti-tumor drug which is represented by the molecular formula (I) and specifically relates to anti-tumor 2-amino nicotinonitrile. The invention further provides a synthetic method of the anti-tumor drug. The method includes dissolving 2mmol of vanillic aldehyde or 2mmol of syringaldehyde, 2mmol of acetophenone and 2mmol of malononitrile in 1, 4-dioxane, then adding 4mmol of ammonium acetate, heating a mixture at the temperature of 120 DEG C for reaction for 20 minutes by using a microwave with the length of 300W as an assistant, adding ice water to the reaction mixture to separate out a product, and finally subjecting the mixture to recrystallization to obtain the 2-amino nicotinonitrile. The synthetic method of the anti-tumor drug is simple, and the anti-tumor drug can be rapidly and efficiently synthesized by means of a one-pot four-component reaction assisted by the microwave. The anti-tumor drug which is represented by the molecular formula (I) is capable of obviously inhibiting activities of proliferation of liver cancer cells, gastric cancer cells, breast cancer cells, pancreatic cancer cells, brain cancer cells, lung cancer cells and ovarian cancer cells.
Description
One, technical field
The invention provides a class Novel 2 Amino nicotinic acid nitrile antitumor drug, the pharmaceutical composition that contains this compound and as the purposes of antineoplastic agent, belong to medical technical field.
Two, background technology
The malignant tumour serious threat mankind's life and health, the annual whole world approximately has 7,000,000 people to die from cancer, accounts for 1/4th of total death toll.Cancer of the stomach is the modal a kind of malignant tumour of China, and its mortality ratio accounts for the first place of various malignant tumours.Liver cancer is China's second cancer " killer ", and the position that leapt to the first in part High Phc Incidence Area, accounts for 45% of whole world PLC mortality number.Current existing cancer patients's mortality ratio exceedes 30%, has become the second largest factor of China's death.Carcinoma of the pancreas is one of cancer that current mortality ratio is the highest.
Pharmacological agent has become a kind of methods for the treatment of that malignant tumour effectively and is generally used.The sales volume of global antitumor drug in 2010 is about 60,000,000,000 dollars.
The antitumor drug of application is of a great variety clinically, and wherein chemotherapeutics mainly contains alkylating agent platinum complex antitumor drug, anthracycline antitumor drugs thing, destroys the microbiotic of DNA etc.In addition, the research of natural antitumor medicine also occupies sizable ratio, as commonly used clinically at present some medicines, has camptothecine, vincristine(VCR), taxol etc.
Yet existing tumour medicine exists the problems such as selectivity is poor, toxic side effect, resistance.The antitumor drug of finding high-efficiency low-toxicity is still the important topic that scientist faces.The structure that the invention provides a kind of novel amino nicotinic acid nitrile of the 2-with anti-tumor activity, has important development prospect.
Three, summary of the invention
The object of the present invention is to provide the amino nicotinic acid nitrile class of 2-new type antineoplastic medicine structure, this compound has obvious restraining effect to carcinoma of the pancreas, cancer of the stomach, liver cancer, lung cancer, breast cancer cell.
Medicines structure general formula of the present invention is as follows:
In above formula, substituent R
1and R
2for H or OMe.One of them preferred compound is a (being numbered W11): substituent R
1and R
2be OMe; Another preferred compound is b (being numbered W12): substituent R
1and R
2be respectively H and OMe.
Term of the present invention " the acceptable salt of medicine, derivative, prodrug " refers to the acceptable salt of any medicine, fat, solvated compounds, hydrate or any other compound that compound described herein can (directly or indirectly) when giving receptor be provided.Yet, be appreciated that the acceptable salt of non-medicine also falls into scope of the present invention, because it can be used for preparing the acceptable salt of medicine.The preparation of salt, prodrug and derivative can be undertaken by methods known in the art.
For example, the acceptable salt of the medicine of compound provided in this article is synthetic by conventional chemical method and the parent compound that contains alkalescence and acidic-group.Conventionally, such salt is by for example reacting the free acid of these compounds or alkali form to prepare in water or organic solvent or the two miscellany with suitable alkali or the acid of stoichiometric quantity.Conventionally, preferred non-aqueous media is as ether, ethyl acetate, ethanol, Virahol or acetonitrile.The example of acid salt comprises mineral acid additive salt for example hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt, and organic acid addition salt for example acetate, trifluoroacetate, maleate, fumarate, Citrate trianion, oxalate, succinate, tartrate, malate, mandelate, methane sulfonates and tosilate.The example of alkali salt adding comprises inorganic salt for example sodium salt, sylvite, calcium salt and ammonium salt, and organic alkali salt for example quadrol, thanomin, N, N-bis-alkylidene group thanomins, trolamine and alkaline amino acid salt.
Compound of the present invention can be used to provide conjoint therapy with composition together with other medicines.Other medicines can form a part for unified composition or provide as independent composition, administration during for while or difference.
The anti-tumor activity of compound of the present invention comprises leukemia, lung cancer, colorectal carcinoma, kidney, prostate cancer, ovarian cancer, the cancer of the brain, mammary cancer, carcinoma of the pancreas, cervical cancer, cancer of the stomach, liver cancer, sarcoma and melanoma.
The method of the amino nicotinic acid nitrile of synthetic 2-involved in the present invention is: utilizing aromatic aldehyde (Vanillin or syringic aldehyde), methyl phenyl ketone, the third two eyeballs and ammonium acetate is that raw material just can obtain the amino nicotinic acid nitrile of target compound 2-through one pot of four component reaction, this reaction has simply, high-level efficiency, the advantage of highly selective and atom economy, reaction equation represents with following general formula:
Synthetic method specifically comprises the following steps:
By Vanillin or syringic aldehyde (2 mmol), with methyl phenyl ketone (2 mmol), propane dinitrile (2 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane, then adds ammonium acetate (4 mmol), 120 ℃ of reaction 20 min of microwave (300 W) boosting.In reaction mixture, add frozen water, product is separated out, then can obtain target product through recrystallization, the amino nicotinic acid nitrile of 2-.
Said medicine can add one or more pharmaceutical carriers or vehicle, is prepared into tablet, capsule, powder, pill, granule, injection, nanometer formulation or emulsion.By such medicine of Pharmacodynamics in vitro evidence, the cells such as carcinoma of the pancreas, cancer of the stomach, liver cancer, lung cancer, mammary cancer are had to obvious restraining effect, there is good antitumour activity.
Beneficial effect:
1, two kinds of amino nicotinic acid nitrile compounds of 2-with potential anti-tumor activity have been synthesized;
2, adopt the method for one pot of four component reaction of microwave-assisted, this reaction has and is swift in response, simple, high-level efficiency, and the advantage of highly selective and atom economy, this reaction can efficiently complete in 20 min;
3, the amino nicotinic acid nitrile compounds of above-mentioned synthetic novel 2-has significant restraining effect to the growth in vitro of the cell strains such as people's liver cancer HepG2, people's cancer of the stomach SGC-7901, human pancreas cancer KP4, people's lung cancer NCI-H292.
Accompanying drawing explanation
Fig. 1. Fig. 2. be respectively the amino nicotinic acid nitrile of 4-(4-hydroxyl-3,5-Dimethoxyphenyl)-6-phenyl-2-(a) hydrogen spectrum and mass spectrum (W11)
Fig. 3. Fig. 4. be respectively the amino nicotinic acid nitrile of 4-(4-hydroxy 3-methoxybenzene base)-6-phenyl-2-(b) hydrogen spectrum and mass spectrum (W12)
Fig. 5. the impact of tested material W12 on the growth of people's cancer of the stomach SGC-7901 Nude Mice
Five, embodiment
Embodiment 1.
The amino nicotinic acid nitrile of 4-(4-hydroxyl-3,5-Dimethoxyphenyl)-6-phenyl-2-(a) (W11)
By syringic aldehyde (2 mmol), with methyl phenyl ketone (2 mmol), propane dinitrile (2 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane, then adds ammonium acetate (4 mmol), 120 ℃ of reaction 20 min of microwave (300 W) boosting.In reaction mixture, add frozen water, product is separated out, then can obtain product through recrystallization, productive rate 84%.IR?(KBr)?v/cm
-1:?3471,?3395,?3358,?3065,?2953,?2111,?1630,?1573,?1588,?1514,?1464,?1379,?1250,?1211,?1109,?770,?699;?
1H?NMR?(300?MHz,?DMSO-d
6)?δ/ppm:?8.88?(s,?1H,?OH),?8.12-8.15?(m,?2H,?ArH),?7.45-7.56?(m,?3H,?ArH),?7.32?(s,?1H,?H5),?7.00?(s,?2H,?ArH),?6.91?(s,?2H,?NH
2),?3.86?(s,?6H,?2×OCH
3);?
13C?NMR?(75.5?MHz,?DMSO-d
6)?δ/ppm:?160.9,?158.3,?155.0,?147.9,?137.7,?137.3,?130.0,?128.5,?127.2,?126.6,?117.5,?109.1,?106.3,?86.5,?56.2;?MS?(ESI)?m/z:?348.3?[M+H]
+,?370.3?[M+Na]
+;?Anal.?Calcd?for?C
20H
17N
3O
3:?C,?69.15;?H,?4.93;?N,?12.10;?found:?C,?69.03;?H,?4.98;?N,?12.17.
Embodiment 2.
The amino nicotinic acid nitrile of 4-(4-hydroxy 3-methoxybenzene base)-6-phenyl-2-(b) (W12)
By Vanillin (2 mmol), with methyl phenyl ketone (2 mmol), propane dinitrile (2 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane, then adds ammonium acetate (4 mmol), 120 ℃ of reaction 20 min of microwave (300 W) boosting.In reaction mixture, add frozen water, product is separated out, then can obtain product through recrystallization, productive rate 82%.IR?(KBr)?v/cm
-1:?3486,?3401,?3308,?3196,?2209,?1632,?1577,?1551,?1519,?1469,?1278,?1220,?1126,?764;?
1H?NMR?(300?MHz,?DMSO-d
6)?δ/ppm:?9.53?(s,?1H,?OH),?8.11-8.14?(m,?2H,?ArH),?7.42-7.56?(m,?3H,?ArH),?7.24-7.29?(m,?2H,?H5,?ArH),?7.15?(dd,?1H,?ArH,?J?=?2.1,?8.1?Hz),?6.85-6.96?(m,?3H,?ArH,?NH
2),?3.87?(s,?3H,?OCH
3);?
13C?NMR?(75.5?MHz,?DMSO-d
6)?δ/ppm:?161.0,?158.3,?154.9,?148.2,?147.5,?137.7,?129.9,?128.6,?127.7,?121.4,?117.5,?115.5,?112.6,?109.0,?86.4,?55.8;?MS?(ESI)?m/z:?318.1?[M+H]
+,?340.3?[M+Na]
+,?356.0?[M+K]
+;?Anal.?Calcd?for?C
19H
15N
3O
2:?C,?71.91;?H,?4.76;?N,?13.24;?found:?C,?71.83;?H,?4.70;?N,?13.31.
Embodiment 3 is relevant for (W11) and pharmacological experiment (W12)
One, the screening of anti tumor activity in vitro
1.1 tested material
Tested material is the embodiment of the present invention 1 and the prepared compound of embodiment 2.
A(W11) be the compound of the embodiment of the present invention 1 preparation, the amino nicotinic acid nitrile of Chinese 4-(4-hydroxyl-3,5-Dimethoxyphenyl)-6-phenyl-2-by name; B(W12) be the compound of the embodiment of the present invention 2 preparations, the amino nicotinic acid nitrile of Chinese 4-(4-hydroxyl-3,5-Dimethoxyphenyl)-6-phenyl-2-by name.Positive drug is Zorubicin, purchased from Sigma company.
1.2 subject cell strains
Select people's cancer of the stomach SGC7901, people's liver cancer HepG2, human leukemia cell line HKB, human pancreas cancer cell strain KP4, human lung carcinoma cell line NCI-H292, NCI-H727.
1.3 experimental technique
Get in one bottle, cell in good condition exponential phase of growth, add 0.25 trypsin digestion cell, add in perfect medium and pancreatin after, repeatedly blow evenly, be prepared into 4 * 10
-4the cell suspension of individual cell/ml.Above-mentioned cell suspension, by 100 μ L/ holes, is joined in 96 porocyte culture plates, put constant temperature CO
2incubator is cultivated 24 hours, changes liquid, and new substratum 180 μ L are added in every hole, and what add different concns is subject to reagent 20 μ L, continues to cultivate 24-72 hour.Then every hole adds the MTT 20 μ L of 5 mg/ml concentration, continues to cultivate 4 hours in incubator, sucks supernatant liquor, add DMSO, 150 μ L, jolting mixes, the OD value of measuring every hole at 570 nm wavelength places by multi-functional microplate reader, calculates respectively the cell inhibitory rate under each concentration.Tested material arranges 6 concentration, and each concentration is established 3 repetitions, uses IC
50software for calculation calculates the IC of tested material
50.
Cell inhibitory rate %=(negative control group OD value-administration group OD value)/negative control group OD value * 100%.
1.4 test-results
Table one, tested material W11 and W12 extracorporeal anti-tumor function
Note: the above results is the mean value of three revision tests.
Two, the experimental therapy effect of W12 to people's cancer of the stomach Nude Mice
2.1 tested material
W12(b) be the compound of the embodiment of the present invention 2 preparations, Chinese is called the amino nicotinic acid nitrile of 4-(4-hydroxyl-3,5-Dimethoxyphenyl)-6-phenyl-2-, uses the solvent of the proportional arrangement of DMSO and sterilized water 1:1, is made into the solution of 16 mg/ml.
Positive drug is paclitaxel injection (specification: 30 mg/5ml), by the dosage preparation of 10 mg/kg, get 0.5 ml sample and add 2.5 ml physiological saline, concussion shakes up, and being mixed with concentration is 1.0 mg/ml solution.
2.2 transplanted tumor
This experiment adopts people's cancer of the stomach SGC-7901 Model in Nude Mice, and this model is by every mouse forelimb armpit subcutaneous vaccination 1 * 10
7individual SGC-7901 cell, grows and forms for 7 days.
2.3 animal
Male BALB/c nude mouse, in age in age in days 7-8 week, body weight 18-22 g, is provided by Yangzhou University's medical science Correlation Centre, credit number SCXK (Soviet Union) 2000-001.Every treated animal is established 10 of negative control group, 6 of administration groups.
2.4 test method
The SGC-7901 stomach cancer cell of taking the logarithm vegetative period, is mixed with 1 * 10 with the nutrient solution containing Metrigel
8the cell suspension of/ml, under aseptic condition, is inoculated in nude mouse right side armpit by 0.1 ml/ mouse subcutaneous.Observe the growing state of Nude Mice every day, when enough large, by vernier caliper measurement transplanted tumor size, treat tumor growth to 100～200 mm
3after by animal random packet.By measuring weekly size and the body weight of tumour for 3 times.Oral administration, 5 times weekly, totally 3 weeks; Paclitaxel injection intravenously administrable 20 mg/kg, 2 times weekly, every of each 0.4 ml, totally 3 weeks; Negative control group is given equivalent physiological saline simultaneously.Observe and record diet and activity situation and the growth of xenografted situation of nude mice every day.With heavy (the FBW)/first body weight of opisthosoma (IBW), carry out drug toxicity evaluation, heavy (the FBW)/first body weight of opisthosoma (IBW) >=0.8 is non-toxic reaction, and < 0.8 is toxic reaction.
2.5 detect index and method of calculation
(1) gross tumor volume (tumor volume, TV), calculation formula is:
TV?=?1/2×a×b
2
Wherein a, b represent respectively the length of tumour and wide.
(2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV?=?TV
t/TV
0。
TV wherein
0(d during for minute cage administration
0) gross tumor volume, the gross tumor volume of T when measuring each time.
(3) the relative proliferation rate T/C(% of tumour), calculation formula is:
T/C（%）=?RTV
t/RTV
c×100%
RTV
t: the relative knurl volume for the treatment of group; RTV
c: the relative knurl volume of control group.
Test-results is usingd the relative proliferation rate T/C(% of tumour) as the evaluation index of anti-tumor activity.
2.6 statistical method
Experimental data represents with mean value and standard deviation, statistical method employing t-check.
2.7 test-results are shown in Fig. 5.
Claims (7)
1. a compound, is characterized in that the structural formula of this compound is
（I）。
2. the acceptable salt of compound according to claim 1 is: hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt, acetate, trifluoroacetate, maleate, fumarate, Citrate trianion, oxalate, succinate, tartrate, malate, mandelate, methane sulfonates, tosilate, sodium salt, sylvite, calcium salt and ammonium salt, ethylenediamine salt, ethanolamine salt, N, N-bis-alkylidene group ethanolamine salts, triethanolamine salt or alkaline amino acid salt.
3. a pharmaceutical composition, is characterized in that it contains compound claimed in claim 1, and more than one pharmaceutical carriers or vehicle.
4. pharmaceutical composition according to claim 3, is characterized in that: this pharmaceutical composition is tablet, capsule, powder, granule, injection, nanometer formulation or emulsion.
5. according to the application of compound in preparing antitumor drug described in claim 1-2.
6. the application of compound according to claim 5 in preparing antitumor drug, is characterized in that described tumour is: leukemia, lung cancer, colorectal carcinoma, kidney, prostate cancer, ovarian cancer, the cancer of the brain, mammary cancer, carcinoma of the pancreas, cervical cancer, cancer of the stomach, liver cancer, sarcoma or melanoma.
7. the preparation method of compound according to claim 1, is characterized in that realizing as follows:
By Vanillin 2 mmol, with methyl phenyl ketone 2 mmol, propane dinitrile 2 mmol are dissolved in 1, in 4-dioxane, then add ammonium acetate 4 mmol, 120 ℃ of reaction 20 min of microwave 300 W boosting, in reaction mixture, add frozen water, product is separated out, then can obtain target product through recrystallization.
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| CN103977002B (en) * | 2014-05-30 | 2016-10-05 | 中国药科大学 | 2-amino nicotinic acid nitrile compounds of induction autophagy and application thereof |
| CN105237473B (en) * | 2015-10-09 | 2017-12-26 | 浙江大学 | The 4,5,6 multifunctional amino nicotinic acid nitrile derivatives of dough 2 and preparation method |
| CN111606848A (en) * | 2020-06-05 | 2020-09-01 | 广西民族大学 | Preparation method of fluorodiphenyl substituted pyridine compound |
Citations (2)
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|---|---|---|---|---|
| JP2785894B2 (en) * | 1988-08-09 | 1998-08-13 | 株式会社トクヤマ | Monoclonal antibody, method for producing the same, and diagnostic reagent |
| CN101362719A (en) * | 2007-08-06 | 2009-02-11 | 北京师范大学 | Chinolines derivates and composition containing thereof |
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| JP3223159B2 (en) * | 1988-08-09 | 2001-10-29 | 株式会社トクヤマ | Method for producing monoclonal antibody |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2785894B2 (en) * | 1988-08-09 | 1998-08-13 | 株式会社トクヤマ | Monoclonal antibody, method for producing the same, and diagnostic reagent |
| CN101362719A (en) * | 2007-08-06 | 2009-02-11 | 北京师范大学 | Chinolines derivates and composition containing thereof |
Non-Patent Citations (3)
| Title |
|---|
| JP特开平11-28087A 1999.02.02 |
| Xiao-Hui Yang，等.2-Amino-4-（4-hydroxy-3，5-dimethoxyphenyl）-6-phenylnicotinonitrile.《Acta Crystallographica, Section E: Structure Reports Online》.2010,第66卷(第11期),在第o2746页左栏. * |
| 张帆,等.4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其抗肿瘤活性研究.《中国药物化学杂志》.2011,第21卷(第5期),第352-357页. * |
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