阅读说明：本技术 一种苯并[b]氮杂䓬-查尔酮杂合物及其制备方法和用途 (Benzo [ b ] azepine-chalcone heterozygote and preparation method and application thereof ) 是由 邓胜松 杨瑞 姚日生 喻明军 于 2021-01-14 设计创作，主要内容包括：本发明公开了一种苯并[b]氮杂-查尔酮杂合物及其制备方法和用途,涉及药物化学技术领域,本发明采用药物拼合原理,将具有一定抗肿瘤活性的天然查尔酮母体结构(1,3-二苯基丙烯酮)保留,同时引入具有特殊的结构类型和电子云分布的苯并[b]氮杂结构,获得一种新型的苯并[b]氮杂-查尔酮杂合物；药理学研究表明,该类化合物可以显著抑制人胃癌细胞HGC-27的活性且活性明显高于阳性对照顺铂,同时对人正常的胃粘膜细胞GES-1具有较低的毒性且明显低于阳性对照顺铂。(The invention discloses a benzo [ b ]]Aza derivatives The invention relates to a chalcone heterozygote and a preparation method and application thereof, relating to the technical field of pharmaceutical chemistry, and the invention adopts the drug combination principle to reserve the natural chalcone parent structure (1, 3-diphenyl propenone) with certain antitumor activity and simultaneously introduce benzo [ b ] with special structure type and electron cloud distribution]Aza derivatives Structure, a novel benzo [ b ] is obtained]Aza derivatives -chalcone hybrids; pharmacological research shows that the compounds can be remarkably usedThe activity of human gastric cancer cell HGC-27 is inhibited, the activity is obviously higher than that of positive control cisplatin, and meanwhile, the activity has lower toxicity to human normal gastric mucosal cell GES-1 and is obviously lower than that of the positive control cisplatin.)

1. Benzo [ b ]]Aza derivatives-a chalcone hybrid or a pharmaceutically acceptable salt thereof, wherein: said benzo [ b]Aza derivatives-chalcone hybrids have the following structural formula:

in the formula: r₁Selected from hydrogen, alkyl; r₂Is selected from-OCH₃、-CH(CH₃)₂、-CH₂CH₂CH₃、-CH₂CH₃；R₃Selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy.

2. Benzo [ b ] according to claim 1]Aza derivatives-a chalcone hybrid or a pharmaceutically acceptable salt thereof, wherein: the salt is alkali metal salt, alkaline earth metal salt, amino acid salt, basic compound salt containing amino, inorganic acid salt or organic acid salt.

3. Benzo [ b ] according to claim 2]Aza derivatives-a chalcone hybrid or a pharmaceutically acceptable salt thereof, wherein: the salt is potassium salt, sodium salt, ammonium salt, hydrochloride, sulfate, oxalate, citrate, acetate, propionate, perchlorate, lactate, benzene sulfonate, p-toluene sulfonate, maleate or succinate.

4. Benzo [ b ] according to claim 1]Aza derivatives-a process for the preparation of a chalcone hybrid or a pharmaceutically acceptable salt thereof, characterized in that: taking aromatic amine as an initial raw material, carrying out N-alkylation reaction with 4-ethyl bromobutyrate to obtain an intermediate 1, carrying out carbonylation reaction on the intermediate 1 and methyl chloroformate to obtain an intermediate 2, carrying out hydrolysis reaction on the intermediate 2 to obtain an intermediate 3, carrying out Friedel-crafts acylation reaction on the intermediate 3 to obtain an intermediate 4, carrying out Claise-Schmidt reaction on the intermediate 4 and benzaldehyde with different substituents to obtain a target compound, carrying out hydrolysis decarboxylation reaction on the intermediate 4 to obtain an intermediate 5, carrying out carbonylation reaction on the intermediate 5 and fatty acyl chloride to obtain an intermediate 6, and carrying out Claise-Schmidt reaction on the intermediate 6 and benzaldehyde with different substituents to obtain a target compound;

the reaction equation is as follows:

5. the method of claim 4, wherein: the aromatic amine is selected from aniline or aniline containing alkyl hydrocarbon.

6. The method of claim 4, wherein: the fatty acyl chloride is selected from butyryl chloride, propionyl chloride or isobutyryl chloride.

7. The method of claim 4, wherein: the differently substituted benzaldehydes are selected from benzaldehydes or benzaldehydes containing halogen, alkyl, haloalkyl, alkoxy, haloalkoxy.

8. Benzo [ b ] according to any one of claims 1 to 3]Aza derivatives-the use of chalcone hybrids or pharmaceutically acceptable salts thereof for the preparation of an anti-tumor medicament.

9. Use according to claim 8, characterized in that: the tumor is gastric cancer.

The technical field is as follows:

the invention relates to the technical field of pharmaceutical chemistry, in particular toAnd a benzo [ b ]]Aza derivatives-chalcone hybrids and methods of preparation and use thereof.

Background art:

gastric cancer is a common tumor of the digestive system and is one of the most common malignant tumors worldwide. At present, surgical treatment is mainly adopted for treating early gastric cancer, but most of gastric cancers are difficult to diagnose due to early symptoms similar to gastritis, and can be diagnosed only when the disease progresses to middle and late stages, at the moment, the traditional surgical treatment effect is limited, only chemical drug treatment can be adopted, but the existing drugs for treating gastric cancer clinically have the defects of high toxicity, low selectivity, poor curative effect and the like, and the research and development of novel anti-tumor drugs with strong selectivity, low toxic and side effects and good curative effect are urgently needed to improve the cure rate of patients with middle and late gastric cancer.

Chalcone is a kind of polyphenol flavone substances widely existing in liquorice, angelica keiskei and other natural plants, the parent structure of the chalcone is 1, 3-diphenyl propenone, and the chalcone is formed by connecting two benzene rings through alpha, beta-unsaturated carbonyl formed by three carbon atoms and a double bond (as shown in formula 1, the benzene ring connected with carbonyl substitution is generally defined as ring A, and the other benzene ring is named as ring B), and belongs to alpha, beta-unsaturated ketone with high activity. Chalcones exhibit a wide range of biological activities, such as anti-tumor, anti-oxidant, anti-inflammatory, etc., especially in the anti-tumor field.

In recent years, researchers at home and abroad have conducted a large amount of screening studies on chalcone compounds in natural plants such as licorice and angelica keiskei, and found that 2 chalcone compounds in licorice, isoliquiritigenin [ Hsu Y L, Kuo P L, Lin C.isoliquiritigenin antigens and cell cycle extract P53-dependent pathway in HepG2 cells [ J ]. Life Sci,2005,77(3):279 and 292 ] licochalcone A (licohalcone A) [ Xiu-ying, Xessia, and, et al.licochallc A inhibitors of microstructure nuclear reaction and of chalcone polysaccharide derivative and of polysaccharide derivative in Japanese Kokai, and that 2 chalcone compounds in licorice, Kaishi, Ak J, Shi 4, chalcone J, and Keishikari J, Akahi, Kaishi, Kaishikari, and Keishikari-3, takashi, Suzuki.4-Hydroxydericin from Angelica keiskei roots antigens, caspase-dependent apoptosis cell death in HL60 human leukaemia cells [ J ]. Journal of oleo science,2011,60(2):71-7 ] and Xanthanol [ Pan L, Becker H, Gerhauer C.Xantho aloe antigens in cultured 40-16human collagen cell by activation of the death receptor and octondrial pathway [ J ]. Moltr Nultr Nu foods, 2005,49:837 ] have significant anti-tumor activity, 2. the compounds show significant anti-tumor activity, as well as poor anti-tumor activity, as shown by the natural chalcone synthesis, but show poor anti-tumor activity, as shown by the formula, and poor anti-tumor activity, as shown by the natural chalcone synthesis, and the like.

Benzazepine compoundsAlso known as benzazepine seven-membered rings, refers to the parent structure formed by the fusion of a benzene ring and a nitrogen-containing seven-membered ring, as is common for benzo [ b]Aza derivatives1, 5-benzodiazepinesEtc., as shown in formula 3. The benzazepine is prepared by special structure type and electron cloud distributionThe compounds show wide physiological activity and medicinal value, such as: anti-tumor, anti-bacterial, anti-hypertension, anti-inflammatory and the like, and get wide attention and attention of scientists in different fields. In the field of antitumor, benzazepinesThe compounds are often designed as inhibitors of tumor closely related kinases (such as PLKI, VEGF-R2, CDKs, Cyclins, etc.) to participate in antitumor studies, as shown in formula 4, and therefore, we will benzo [ b [ -b ]]Aza derivativesThe fragment is introduced into the design of chalcone derivatives to improve the antitumor activity and selectivity of chalcone.

The invention content is as follows:

the technical problem to be solved by the invention is to provide benzo [ b]Aza derivatives-chalcone heterozygotes and preparation method thereof, pharmacological test shows that the benzo [ b ] is]Aza derivativesChalcone hybrids have good antitumor activity.

The technical problem to be solved by the invention is realized by adopting the following technical scheme:

the invention provides a benzo [ b ]]Aza derivatives-chalcone hybrids or pharmaceutically acceptable salts thereof, of the formula:

in the formula:

R₁selected from hydrogen, alkyl;

R₂is selected from-OCH₃、-CH(CH₃)₂、-CH₂CH₂CH₃、-CH₂CH₃；

R₃Selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy.

Preferably, said benzo [ b]Aza derivatives-chalcone hybrids are compounds of the following structure:

the salt is alkali metal salt, alkaline earth metal salt, amino acid salt, basic compound salt containing amino, inorganic acid salt or organic acid salt.

Preferably, the salt is a potassium salt, a sodium salt, an ammonium salt, a hydrochloride salt, a sulfate salt, an oxalate salt, a citrate salt, an acetate salt, a propionate salt, a perchlorate salt, a lactate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a maleate salt or a succinate salt.

It is another object of the present invention to provide said benzo [ b]Aza derivativesA process for preparing the heterocomplex of chalcone and its pharmacologically acceptable salt includes such steps as N-alkylating reaction of arylamine with 4-bromoethylbutyrate to obtain intermediate 1, carbonylating reaction of intermediate 1 with methyl chloroformate to obtain intermediate 2, hydrolyzing reaction of intermediate 2 to obtain intermediate 3, Friedel-crafts acylation reaction of intermediate 3 to obtain intermediate 4, Claise-Schmidt reaction of intermediate 4 and different substituted benzaldehydes to obtain target compound, and hydrolyzing and decarboxylating reaction of intermediate 4 to obtain intermediateAnd (3) carrying out carbonylation reaction on the intermediate 5 and fatty acyl chloride to obtain an intermediate 6, and carrying out Claise-Schmidt reaction on the intermediate 6 and different substituted benzaldehydes to obtain the target compound.

The reaction equation is as follows:

the aromatic amine is selected from aniline or aniline containing alkyl hydrocarbon.

The fatty acyl chloride is selected from butyryl chloride, propionyl chloride or isobutyryl chloride.

The differently substituted benzaldehydes are selected from benzaldehydes or benzaldehydes containing halogen, alkyl, haloalkyl, alkoxy, haloalkoxy.

It is a third object of the present invention to provide said benzo [ b]Aza derivatives-the use of chalcone hybrids or pharmaceutically acceptable salts thereof for the preparation of an anti-tumor medicament.

Preferably, the tumor is gastric cancer.

The invention has the beneficial effects that: the invention adopts the principle of drug combination, reserves the parent structure of natural chalcone (1, 3-diphenyl propenone) with certain anti-tumor activity, and introduces benzo [ b ] with special structure type and electron cloud distribution]Aza derivativesStructure, a novel benzo [ b ] is obtained]Aza derivatives-chalcone hybrids; pharmacological research shows that the compound can obviously inhibit the activity of human gastric cancer cell HGC-27 and the activity is obviously higher than that of positive control cisplatin, and simultaneously the compound has lower toxicity to human normal gastric mucosa cell GES-1 and is obviously lower than that of the positive control cisplatin, thereby showing that the novel compound has better inhibition activity on gastric cancer cells andand selectivity, and has the potential of developing high-efficiency and low-toxicity medicaments for treating gastric cancer.

Description of the drawings:

FIGS. 1-20 are hydrogen and mass spectra of compounds 1-10.

The specific implementation mode is as follows:

in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.

Example 1

(E) -1-methoxycarbonyl-4- (4-chlorobenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivativesPreparation of (Compound 1):

the method comprises the following steps: synthesis of ethyl 4- (anilino) butyrate

4-aniline (0.011mol), triethylamine (5eq, 0.055mol) and toluene (3.3v) were added to a 50ml single-neck flask, heated to 95 ℃, ethyl 4-bromobutyrate (1.2eq) was slowly added dropwise into the flask, and after completion of the addition, the reaction solution was stirred at 95 ℃ for 2 h. The reaction mixture was filtered to remove triethylamine hydrobromide, and then concentrated under vacuum to give 1.824g of ethyl 4- (anilino) butyrate as a brown yellow oily liquid in 80% yield.

Step two: synthesis of ethyl 4- (N-methoxycarbonylanilino) butyrate

The above ethyl 4- (anilino) butyrate (0.0088mol, 1.824g) and Na were added₂CO₃(1.2eq, 0.01056mol) and toluene (10v) were added to a 50ml single-hole flask, cooled to 0 ℃ to 5 ℃, methyl chloroformate (1.4eq, 0.01232mol) was slowly added dropwise at a temperature of 10 ℃ or lower, and after dropping, the reaction mixture was stirred at 0 ℃ to 10 ℃ for 1 hour. The reaction mixture was extracted twice with water (100ml), and the organic layer was dried under vacuum to give 2.101g of ethyl 4- (N-methoxycarbonylanilino) butyrate as a brown yellow oily liquid in a yield of 89.7%

Step three: synthesis of 4- (N-methoxycarbonylanilino) butyric acid

Ethyl 4- (N-methoxycarbonylanilino) butyrate (0.0079mol, 2.101g) was added with water (10v), methanol (8v) and NaOH (2eq, 0.01584mol), and stirred at reflux temperature for 2.5 h. The reaction solution was concentrated, followed by extraction twice with ethyl acetate (50ml), temperature control, pH adjustment with 5% dilute hydrochloric acid, followed by extraction twice with dichloromethane (100ml), and the organic layer was concentrated under vacuum to give 1.779g of 4- (N-methoxycarbonylanilino) butyric acid as a tan oily liquid with a yield of 94.9%.

Step four: 1-methoxycarbonyl-2, 3,4, 5-tetrahydro-5H-benzazepineSynthesis of (E) -5-ketones

The above 4- (N-methoxycarbonylanilino) butyric acid (0.0075mol, 1.779g), anhydrous dichloromethane (5v) and DMF (0.1v) were charged in a 100ml single-neck flask, cooled to 0 ℃ to 5 ℃, thionyl chloride (1.5eq, 0.01125mol) was slowly added dropwise while maintaining the temperature, and after dropping, the reaction solution was allowed to warm up to room temperature and stirred for 1.5 hours. The reaction was concentrated in vacuo to give an oily intermediate, which was dissolved in dichloromethane (5v) and used directly in the next step. Anhydrous dichloromethane (10v) and anhydrous AlCl₃(4eq, 0.03mol) is added into a 50ml single-neck flask, heated to 35 ℃ to 40 ℃, the dichloromethane solution of the acyl chloride in the previous step is slowly dripped into the single-neck flask, and stirred for 2 to 3 hours at 35 ℃ to 40 ℃ after dripping. Cooling the reaction liquid to 10-20 ℃, dropwise adding pre-cooled 5% dilute hydrochloric acid (5v), continuously stirring for 15min after dropwise adding, standing for 30min, separating an organic layer, drying by anhydrous sodium sulfate, and concentrating under a vacuum environment to obtain a brown yellow oily liquid 1-methoxycarbonyl-2, 3,4, 5-tetrahydro-5H-benzazepine0.822g of (E) -5-ketone was obtained, and the yield was 50%.

Step five: (E) -1-methoxycarbonyl-4- (4-chlorobenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivativesSynthesis of (2)

Mixing the brown yellow oily liquid 1-methoxycarbonyl-2, 3,4, 5-tetrahydro-5H-benzazepine-5-ketone (0.00375mol, 0.822g), 4-chlorobenzaldehyde (1.2eq, 0.0045mmol), ethanol (6v) and potassium hydroxide (2eq, 0.009mol) were added into a 25ml single-neck flask, stirred at room temperature for 6H, the reaction solution was directly filtered to obtain a crude solid, and then the crude solid was recrystallized to obtain (E) -1-methoxycarbonyl-4- (4-chlorobenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] as a white solid]Aza derivatives0.999g, yield 78%. mp 175-177 ℃;¹HNMR(600MHz,DMSO-d6)δ7.70-7.64(m,3H),7.61-7.58(m,2H),7.56-7.50(m,3H),7.39(d,J＝7.8Hz,1H),3.95(s,2H),3.53(d,J＝37.0Hz,3H),2.71(s,2H)；HRMS:m/z Calc for C₁₉H₁₆ClNO₃[M+H]⁺：342.0891,found:342.0886.

example 2

(E) -1-methoxycarbonyl-4- (4-methoxybenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 2);

the same procedure was followed as for the preparation of Compound 1 except that 4-methoxybenzaldehyde was used instead of 4-chlorobenzaldehyde. The product was a white solid. mp 173-175 ℃;¹HNMR(600MHz,DMSO-d6)δ7.68-7.62(m,3H),7.57(d,J＝8.5Hz,2H),7.50(t,J＝7.5Hz,1H),7.37(d,J＝7.8Hz,1H),7.05(d,J＝8.4Hz,2H),3.96(s,2H),3.81(s,3H),3.48(s,3H),2.75(s,2H).HRMS:m/z Calc for C₂₀H₁₉NO₄[M+H]⁺：338.1387,found:338.1396.

example 3

(E) -1-methoxycarbonyl-4- (4-fluorobenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 3)

The same procedure was followed as for the preparation of Compound 1 except that 4-chlorobenzaldehyde was replaced with 4-fluorobenzaldehyde. The product was a white solid. mp 145-147 deg.C;¹HNMR(600MHz,DMSO-d6)δ7.67(ddd,J＝21.4,11.0,4.0Hz,5H),7.52(t,J＝7.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.33(t,J＝8.6Hz,2H),3.95(s,2H),3.49(s,3H),2.72(s,2H).HRMS:m/z Calc for C₁₉H₁₆FNO₃[M+H]⁺：326.1187,found:326.1185.

example 4

(E) -1-methoxycarbonyl-4- (4- (dimethylamino) benzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 4);

the same procedure was followed as for the preparation of Compound 1 except that 4- (N, N-dimethyl) benzaldehyde was used instead of 4-chlorobenzaldehyde. The product was a yellow solid. mp 158-160 ℃;¹HNMR(600MHz,DMSO-d6)δ7.61(dd,J＝18.2,10.8Hz,3H),7.49(t,J＝9.5Hz,3H),7.34(d,J＝7.6Hz,1H),6.78(d,J＝8.4Hz,2H),3.96(s,2H),3.47(s,3H),2.99(s,6H),2.77(s,2H).HRMS:m/z Calc for C₂₁H₂₂N₂O₃[M+H]⁺：351.1703,found:351.1707.

example 5

(E) -1-methoxycarbonyl-4- (4- (tert-butyl) benzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 5);

the same procedure was followed as for the preparation of Compound 1 except that 4- (4- (tert-butyl)) benzaldehyde was used instead of 4-chlorobenzaldehyde. The product was a white solid. mp 156-158 ℃;¹HNMR(600MHz,DMSO-d6)δ7.69-7.64(m,3H),7.54-7.49(m,5H),7.38(d,J＝7.8Hz,1H),3.97(s,2H),3.49(s,3H),2.74(s,2H),1.31(s,9H).HRMS:m/z Calc for C₂₃H₂₅NO₃[M+H]⁺：364.1907,found:364.1912.

example 6

(E) -1-methoxycarbonyl-4- (3, 4-dimethoxybenzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 6);

the same procedure was followed as for the preparation of Compound 1 except that 3, 4-dimethoxybenzaldehyde was used in place of 4-chlorobenzaldehyde. The product was a pale yellow solid. mp 175-177 ℃;¹HNMR(600MHz,DMSO-d6)δ7.66(dd,J＝14.4,8.6Hz,3H),7.51(t,J＝7.4Hz,1H),7.37(d,J＝7.7Hz,1H),7.21(d,J＝8.0Hz,1H),7.15(s,1H),7.07(d,J＝8.3Hz,1H),3.97(s,2H),3.81(s,6H),3.48(s,3H),2.77(s,2H).HRMS:m/z Calc for C₂₁H₂₁NO₅[M+H]⁺：368.1492,found:368.1493.

example 7

(E) -1-methoxycarbonyl-4- (4- (methylsulfonyl) benzylidene) -5-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives(Compound 7);

the same procedure was followed as for the preparation of Compound 1 except that 4-methylsulfonylbenzaldehyde was used in place of 4-chlorobenzaldehyde. The product was a white solid. mp 204-206 ℃;¹HNMR(600MHz,DMSO-d6)δ8.02(d,J＝8.3Hz,2H),7.80(d,J＝8.3Hz,2H),7.69(ddd,J＝9.1,8.4,4.8Hz,3H),7.53(td,J＝7.6,0.7Hz,1H),7.40(d,J＝7.7Hz,1H),3.96(s,2H),3.50(s,3H),3.27(s,3H),2.72(s,2H).HRMS:m/z Calc for C₂₀H₁₉NO₅S[M+H]⁺：386.1057,found:386.1692.

example 8

(E) -1-butyryl-4- (4- (dimethylamino) benzylidene) -1,2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-5-one (Compound 8)

Intermediate 1-methoxycarbonyl-2, 3,4, 5-tetrahydro-5H-benzazepineSynthesis of (E) -5-keto ester prepared according to the procedure of example 1.

Step one, 1,2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-synthesis of 5-ketones:

the 1-methoxycarbonyl-2, 3,4, 5-tetrahydro-5H-benzazepine-5-ketone (0.33g, 1.5mmol), potassium hydroxide (0.17g, 3mmol, 2eq) and methanol (40v, 10ml) were addedHeating and refluxing the mixture in a 50ml single-neck flask for 6H, concentrating the reaction solution in a vacuum environment, adding water (50ml), extracting the mixture twice with ethyl acetate (50ml), drying the mixture by anhydrous sodium sulfate, concentrating the oily liquid in the vacuum environment, and separating the oily liquid by column chromatography to obtain a light yellow solid 1,2,3, 4-tetrahydro-5H-benzo [ b ] b]Aza derivatives-5-ketone, yield 72%.

Step two, 1-butyryl-1, 2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-synthesis of 5-ketones:

mixing the above 1,2,3, 4-tetrahydro-5H-benzo [ b ]]Aza derivatives-5-ketone (1mmol, 0.162g), anhydrous dichloromethane (50v, 8ml) and triethylamine (1.5eq, 0.21ml) were added to a 25ml single-neck flask, cooled to 0-5 ℃, butyryl chloride (1.2mmol, 1.2eq, 0.127g) was added dropwise at a temperature controlled below 10 ℃, and after completion of the addition, stirring was carried out at room temperature for 2 h. Adding water (50ml), extracting twice with dichloromethane (50ml), combining organic layers, drying over anhydrous sodium sulfate, and concentrating under vacuum to obtain oily liquid 1-butyryl-1, 2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-5-ketone, yield 83%.

Step three, (E) -1-butyryl-4- (4- (dimethylamino) benzylidene) -1,2,3, 4-tetrahydro-5H-benzo [ b ]]Aza derivatives-synthesis of 5-ketones:

mixing the above 1-butyryl-1, 2,3, 4-tetrahydro-5H-benzo [ b ]]Aza derivatives-5-ketone (1mmol, 0.231g), 4- (N, N-dimethyl) benzaldehyde (1.2eq, 1.2mmol, 0.179g), ethanol(50v, 12.5ml) and potassium hydroxide (2eq, 2mmol, 0.112) were added to a 25ml single-neck flask, stirred at room temperature for 6H, the reaction solution was directly filtered to give a crude solid product, which was then recrystallized to give the purified target compound (E) -1-butyryl-4- (4- (dimethylamino) benzylidene) -1,2,3, 4-tetrahydro-5H-benzo [ b ] (S-H-B)]Aza derivatives-5-ketone, yellow solid, yield 46%. mp 142-144 ℃;¹HNMR(600MHz,DMSO-d6)δ7.69(dd,J＝16.0,7.5Hz,2H),7.60-7.54(m,2H),7.49(d,J＝8.3Hz,2H),7.40(d,J＝7.5Hz,1H),6.78(d,J＝8.4Hz,2H),4.87(s,1H),3.22(dd,J＝35.9,7.9Hz,2H),2.99(s,6H),2.30(s,1H),2.01-1.90(m,1H),1.67-1.56(m,1H),1.30(dd,J＝14.1,6.9Hz,2H),0.60(t,J＝7.2Hz,3H).HRMS:m/z Calc for C₂₃H₂₆N₂O₂[M+H]⁺：363.2067,found:363.2041.

example 9

(E) -1-propionyl-4- (4- (dimethylamino) benzylidene) -1,2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-5-one (Compound 9)

The same procedure was followed as for the preparation of Compound 8, substituting butyryl chloride with propionyl chloride. The product was a pale yellow solid with a yield of 38%. mp 198-200 ℃;¹HNMR(600MHz,DMSO-d6)δ7.69(dd,J＝12.6,7.3Hz,2H),7.57(d,J＝9.1Hz,2H),7.49(d,J＝8.4Hz,2H),7.43(d,J＝7.6Hz,1H),6.78(d,J＝8.5Hz,2H),4.84(s,1H),3.26(s,1H),3.19(d,J＝11.7Hz,1H),2.99(s,6H),2.30(s,1H),2.00(d,J＝6.8Hz,1H),1.61(d,J＝7.3Hz,1H),0.79(t,J＝7.3Hz,3H).HRMS:m/z Calc for C₂₂H₂₄N₂O₂[M+H]⁺：349.1911,found:349.1893.

example 10

(E) -1-isobutyryl-4- (4- (dimethylamino)Yl) benzylidene) -1,2,3, 4-tetrahydro-5H-benzo [ b]Aza derivatives-5-one (Compound 10)

The same procedure was followed as for the preparation of Compound 8 except that isobutyryl chloride was used instead of butyryl chloride. The product was an orange solid with a yield of 58%. mp 202-204 ℃;¹HNMR(600MHz,DMSO-d6)δ7.70(t,J＝8.2Hz,2H),7.61-7.56(m,2H),7.49(d,J＝8.6Hz,2H),7.42(d,J＝7.5Hz,1H),6.79(d,J＝8.6Hz,2H),4.83(td,J＝12.5,5.6Hz,1H),3.24(dd,J＝12.3,6.5Hz,1H),3.20(dd,J＝14.7,5.2Hz,1H),2.99(s,6H),2.31(td,J＝13.9,6.5Hz,1H),2.16(dt,J＝13.2,6.5Hz,1H),0.93(d,J＝6.5Hz,3H),0.61(d,J＝6.6Hz,3H).HRMS:m/z Calc for C₂₃H₂₆N₂O₂[M+H]⁺：363.2067,found:363.2046.

pharmacological experiments and results of the above compounds 1-10:

test of inhibitory Activity of human gastric cancer cell HGC-27 and human Normal gastric mucosal cell GES-1: the MTT method is adopted to detect the inhibitory activity of the compounds 1-10 on human gastric cancer cell HGC-27 and human normal gastric mucosal cell GES-1, and the commercial medicine cisplatin is used as a positive control. The main experimental steps are that human gastric cancer cells HGC-27 and human normal gastric mucosal cells GES-1 in logarithmic growth phase are transplanted into a transparent 96-well plate by 5000 cells per well, the culture is carried out for 12h in a cell incubator, 2 mu L of the test compound solutions with different concentrations are respectively added into each well, the culture is continued for 48h in the cell incubator, then 10 mu L of 5mg/ml MTT solution is respectively added into each well, the culture is continued for 4h in the cell incubator, then cell culture solution is discarded, 200 mu L of DMSO is added into each well, the gentle shaking is carried out for 15min, and the absorbance of the cells is measured by a microplate reader at 490nm wavelength. The survival rate of cancer cells was calculated for each group: percent survival [ (% absorbance of experimental group-absorbance of blank group)/(absorbance of control group-absorbance of blank group)]x 100%, and then importing the data into GrCalculating to obtain IC in aphPad Prism software₅₀Values, all experiments were repeated three times under the same conditions and the final results are expressed as mean ± SD.

TABLE 1 inhibitory Activity of Compounds 1-10 against human gastric cancer cell HGC-27 and human Normal gastric mucosal cell GES-1

^aData are presented as themeans±SDs of three independent experiments.

^bSelectivity Index(SI)＝(IC₅₀GES-1)/(IC₅₀HGC-27).

As shown in Table 1, it can be seen that most of the compounds have good inhibitory activity (IC) against human gastric cancer cell HGC-27₅₀0.78-11.15 μ M), and has low toxicity to human normal gastric mucosal cell GES-1 (IC)₅₀20-40 μ M), compound 4 having optimal inhibitory activity (IC) on human gastric carcinoma cell HGC-27₅₀0.78 μ M), and has low toxicity to human normal gastric mucosal cell GES-1 (IC)₅₀0.78 mu M and SI 29.19), has the best selectivity, has high selectivity and high activity on gastric cancer cells, and is expected to be used as a lead compound for developing clinical medicaments for treating gastric cancer.

The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.