CN103739513B - 4-methoxyl group-1,3-phenyl-diformyl aminated compounds and application thereof - Google Patents

4-methoxyl group-1,3-phenyl-diformyl aminated compounds and application thereof Download PDF

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CN103739513B
CN103739513B CN201410019630.3A CN201410019630A CN103739513B CN 103739513 B CN103739513 B CN 103739513B CN 201410019630 A CN201410019630 A CN 201410019630A CN 103739513 B CN103739513 B CN 103739513B
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methoxyl group
benzenedicarboxamide
phenyl
platelet aggregation
target compound
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CN103739513A (en
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刘秀杰
李爱祥
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Tianjin University of Technology
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Abstract

One group of 4-methoxyl group-1,3-phenyl-diformyl aminated compounds, comprise 4-methoxyl group-N, N '-two (3,4-Dimethoxyphenethyl)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (the chloro-4-trifluoromethyl of 2-)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (4-n-butylphenyl)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (2,4 difluorobenzene base)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (3-isopropyl phenyl)-1,3-benzenedicarboxamide; 4-methoxyl group-N, N '-two (the chloro-2-fluorophenyl of 3-)-1,3-benzenedicarboxamide and 4-methoxyl group-N, N '-two (3,4-difluorophenyl)-1,3-benzenedicarboxamide.These seven kinds of compounds have platelet aggregation inhibitory activity, open up new approach for developing new medicament for resisting platelet aggregation.

Description

4-methoxyl group-1,3-phenyl-diformyl aminated compounds and application thereof
Technical field
The present invention relates to high antiplatelet and assemble pharmaceutical field, particularly 4-methoxyl group-1,3-phenyl-diformyl aminated compounds and application thereof.
Background technology
Platelet aggregation is a key link in normal coagulation mechanism, and hematoblastic adhesion, gathering and release reaction cause thrombosis.Medicament for resisting platelet aggregation refers to and can suppress hematoblastic adhesion and aggregation capability, prevents thrombotic medicine, therefore plays a significant role in treatment thrombus disease.Oral anti-diabetic agent thing is the long-term preventive therapy of the most normal prescription at present.
In recent years, in order to find to upgrade platelet aggregation-against new drug that is more effective and more wide spectrum, the present invention is to 4-methoxyl group-N, and N '-di-substituted-phenyl-1,3-phenyl-diformyl aminated compounds has done further research.Find that there is seven compounds, there is very high platelet aggregation inhibitory activity, all there is the prospect being developed as new medicament for resisting platelet aggregation.The pertinent literature that there is no at present about these seven compounds is reported.
Summary of the invention
The object of the invention is for above-mentioned technical Analysis, 4-methoxyl group-1 is provided, 3-phenyl-diformyl aminated compounds and application thereof, this compounds has platelet aggregation inhibitory activity, opens up new approach for developing new medicament for resisting platelet aggregation and enriching clinical application kind.
Technical scheme of the present invention:
One group of 4-methoxyl group-1,3-phenyl-diformyl aminated compounds, comprise 4-methoxyl group-N, N '-two (3,4-Dimethoxyphenethyl)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (the chloro-4-trifluoromethyl of 2-)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (4-n-butylphenyl)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (2,4 difluorobenzene base)-1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (3-isopropyl phenyl)-1,3-benzenedicarboxamide; 4-methoxyl group-N, N '-two (the chloro-2-fluorophenyl of 3-)-1,3-benzenedicarboxamide and 4-methoxyl group-N, N '-two (3,4-difluorophenyl)-1,3-benzenedicarboxamide.
A kind of described 4-methoxyl group-N, the preparation method of N '-di-substituted-phenyl-1,3-phenyl-diformyl aminated compounds, step is as follows:
1) by arylamine and 4-methoxyl group-1,3-phthalyl chloride mixes, building-up reactions is carried out under the condition added or do not add solvent, except target compound crude product obtained after desolventizing, described arylamine is 3, the chloro-4-5-trifluoromethylaniline of 4-dimethoxy-phenylethylamine, 2-, 4-n-butyl aniline, 2, the chloro-2-fluoroaniline of 4-difluoroaniline, 3-isopropyl aniline, 3-or 3,4-difluoroaniline, arylamine and 4-methoxyl group-1, the mol ratio of 3-phthalyl chloride is 7.5-12.5:3.5-6.5, and solvent is ethyl acetate;
2) crude product recrystallization: be solvent by adding ethanol after the drying of above-mentioned target compound crude product, is heated to boiling, is cooled to filtering and standing after room temperature, can obtains target compound sterling.
A kind of described 4-methoxyl group-N, the application of N '-di-substituted-phenyl-1,3-phenyl-diformyl aminated compounds, for the preparation of anticoagulant medicine.
Advantage of the present invention is: these seven kinds of 4-methoxyl group-N, and N '-di-substituted-phenyl-1,3-phenyl-diformyl aminated compounds has platelet aggregation inhibitory activity, opens up new approach for developing new medicament for resisting platelet aggregation and enriching clinical application kind; Its preparation method technique is simple, easy to implement, yield can reach 40-99%, is suitable for large-scale production.
Embodiment
Strong and all have inhibiting wide spectrum anticoagulant to multiple inductor in order to find curative effect, in conjunction with the understanding to medicament for resisting platelet aggregation, according to reported in literature and applicant laboratory research work achievement for many years, synthesize multiple aryl amide compound, and the test of In Vitro Anti platelet aggregation activity primary dcreening operation pharmacological research has been carried out to the target compound obtained.Find that wherein seven have 4-methoxyl group-N, the compound of N '-di-substituted-phenyl-1,3-phenyl-diformyl amine structure has very high platelet aggregation inhibitory activity, has the prospect being developed as new medicament for resisting platelet aggregation.The structure of target compound is confirmed by infrared spectra and nuclear magnetic resonance spectrum.
embodiment 1:
4-methoxyl group-N, N '-two (3,4-Dimethoxyphenethyl)-1,3-benzenedicarboxamide (C 29h 34o 7n 2) preparation, step is as follows:
1) by 3,4-dimethoxy-phenylethylamine 1.43g (7.89mmol) and 0.92g(3.95mol) 4-methoxyl group-1,3-phthalyl chloride mix, at room temperature carry out building-up reactions, the reaction times is 72h, obtained target compound crude product;
2) target compound crude product recrystallization: add ethanol by after the drying of above-mentioned target compound crude product, the amount ratio of ethanol and crude product is 25ml:1g, is heated to boiling, is cooled to filtering and standing after room temperature, can obtains white crystalline target compound sterling 1.45g, yield 61.7%; Mp:202-204 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN477.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN477 structure is confirmed: IR(KBr) cm -1: 33765.0 (NH), 1641.4 (C=O), 1516.94,1464.1 (Ph), 2940.9 (-OCH 3); 1h-NMR (Acetone): 7.97 (s, 1H ,-NH-), 7.78 (s, 1H ,-NH-), 8.48 (d, 1H, benzene-H), 6.67-6.91 (m, 8H ,-NHC 6h 4-), 3.76 (s, 3H ,-OCH 3), 2.79 (t, 2H ,-CH 2), 3.62 (m, 2H ,-CH 2).
embodiment 2:
4-methoxyl group-N, N '-two (the chloro-4-trifluoromethyl of 2-)-1,3-benzenedicarboxamide (C 23h 14o 3n 2f 6cl 2) preparation, step is as follows:
1) by chloro-for 2-4-5-trifluoromethylaniline 2.0g (10.3mmol) and 1.20g(5.2mmol) 4-methoxyl group-1,3-phthalyl chloride mix, at room temperature carry out building-up reactions, the reaction times is 72h, obtained target compound crude product;
2) white crystalline target compound sterling 1.95g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 60.9%; Mp:179-181 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN478.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN478 structure is confirmed: IR(KBr) cm -1: 3421.2; (3312.1 υ NH); (1685.9 υ C=O); 1595.8,1542.7,1500.7; (1477.3 υ C=C); 1324.8 (υ CF3), 1261.9 (υ C-N), 1081.1 (υ C-O-C); 1h-NMR (CDCl 3): 4.24 (s, 3H ,-OCH3), 8.74 (d, 1H, H-2), 8.68 (d, 1H, H-5), 8.89 (dd, 1H, H-6), 7.70 (m, 3H ,-C 6h 4-), 7.29 (m, 3H ,-C 6h 4-), 10.75 (s, 1H ,-CONH-);
embodiment 3:
4-methoxyl group-N, N '-two (4-n-butylphenyl)-1,3-benzenedicarboxamide (C 29h 24o 3n 2) preparation, step is as follows:
1) by 4-n-butyl aniline 1.78g (11.9mmol) and 1.39g(5.95mmol) 4-methoxyl group-1,3-phthalyl chloride mix, at room temperature carry out building-up reactions, the reaction times is 48h, obtained target compound crude product;
2) white crystalline target compound sterling 1.3g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 67.5%; Mp:254-257 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN479.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN479 structure is confirmed: IR(KBr) cm -1: 3240.1 (-NH), 2959.0 (-CH 3), 1591.3,1507.4,1485.2,1461.8 (Ph), 2927.0 (-CH 2); 1h-NMR (Acetone): 9.72 (s, 1H ,-NH-), 8.73 (s, 1H,-NH-), 7.93 (d, 1H, benzene-H), 8.28 (dd, 1H, benzene-H), 7.21 (m, 4H ,-NHC 6h 4-), 7.59 (m, 4H ,-NHC 6h 4-), 4.17 (s, 3H ,-OCH 3), 0.95 (-CH 2), 1.38 (-CH 2), 1.62 (-CH 2), 2.63 (-CH 2);
embodiment 4:
4-methoxyl group-N, N '-two (2,4 difluorobenzene base)-1,3-benzenedicarboxamide (C 21h 14o 3n 2f 4) preparation, step is as follows:
1) by 2,4 difluorobenzene amine 1.2g (9.29mmol) and 1.09g(4.65mmol) 4-methoxyl group-1,3-phthalyl chloride mix, at room temperature carry out building-up reactions, the reaction times is 24h, obtained target compound crude product;
2) white crystalline target compound sterling 1.6g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 69.87%; Mp:186-188 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN480.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN480 structure is confirmed: IR(KBr) cm -1: 3320.2,3247.8 (υ NH), 1688.6, (1651.5 υ C=O), 1604.6,1559.4,1507.8,1427.4 (υ C=C), 1267.4 (υ C-N), 1233.0, (1216.6 υ C-O-C), 1119.0 (υ CF), 964.9,855.1 (υ CH); 1h-NMR (CDCl 3): 4.19 (s, 3H ,-OCH 3), 8.79 (s, 1H, H-2), 8.25 (dd, 1H, H-6), 8.04 (d, 1H, H-5), 7.28 (m, 6H, 2 ×-C 6h 3-), 10.17 (s, 2H ,-CONH-);
embodiment 5:
4-methoxyl group-N, N '-two (3-isopropyl phenyl)-1,3-benzenedicarboxamide (C 27h 27o 3n 2) preparation, step is as follows:
1) by 3-isopropyl aniline 1.4g (10.4mmol) and 1.21g(5.2mmol) 4-methoxyl group-1,3-phthalyl chloride mix, at room temperature carry out building-up reactions, the reaction times is 18 h, obtained target compound crude product;
2) white crystalline target compound sterling 1.7g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 65.13%; Mp: ﹥ 300 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN481.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN481 structure is confirmed: IR(KBr) cm -1: 3248.3 (υ NH), 1647.4 (υ c=o), 1610.2,1548.9,1487.9,1463.9 (Ph), 2958.7 (-CH 3); 1h-NMR (CDCl 3): 8.43 (d, 2H, 2 ×-NH-), 9.72 (d, 2H, 2 ×-NH-), 7.28 (d, 1H, benzene-H), 8.21 (m, 4H ,-NHC 6h 4-), 8.75 (m, 4H ,-NHC 6h 4-), 4.10 (s, 3H ,-OCH 3), 2.92 (-CH), 1.28 (-CH 3× 4);
embodiment 6:
4-methoxyl group-N, N '-two (the chloro-2-fluorophenyl of 3-)-1,3-benzenedicarboxamide (C 21h 14o 3n 2f 2cl 2) preparation, step is as follows:
1) chloro-for 3-2-fluoroaniline 1.5 g (10.3 mmol) and 1.21 g (5.2 mmol) 4-methoxyl group-1,3-phthalyl chloride are mixed, at room temperature carry out building-up reactions, the reaction times is 48h, obtained target compound crude product;
2) white crystalline target compound sterling 1.2g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 44.28%; Mp: ﹥ 300 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN483.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN483 structure is confirmed: IR (KBr) cm -1: 3338.2,3226.9 (υ NH), 1719.3,1676.4 (υ C=O), 1611.3,1551.6,1494.8,1458.2 (υ C=C), 1303.9 (υ C-N), 1234.3,1011.4 (υ C-O-C); 1h-NMR (DMSO-d 6) δ (ppm): 4.17 (s, 3H ,-OCH3), 7.28 (s, 1H, H-2), 8.22 (dd, 1H, H-6), 8.96 (d, 1H, H-5), 7.13 (m, 6H, 2 ×-C 6h 3-), 10.27 (s, 2H ,-CONH-);
embodiment 7:
4-methoxyl group-N, N '-two (3,4-difluorophenyl)-1,3-benzenedicarboxamide (C 21h 14o 3n 2f 4) preparation, step is as follows:
1) by 3,4-difluoroaniline 1.60g (12.4 mmol) be dissolved in 20ml ethyl acetate again with 1g(6.2 mmol) 4-methoxyl group-1,3-phthalyl chloride mixes, and at room temperature carries out building-up reactions, reaction times is 24h, except target compound crude product obtained after desolventizing;
2) white crystalline target compound sterling 2.13g is obtained by embodiment 1 same procedure by after target compound crude product recrystallization, yield 70.06%; Mp:226-228 oc.
The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN484.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN484 structure is confirmed: IR(KBr) cm -1: 3356.4 (υ NH), 1678.6,1656.8 (υ C=O), 1617.4,1552.5,1470.9,1428.1 (υ C=C), 1332.1,1304.4 (υ C-N), 1160.6 (υ CF); 1h-NMR (DMSO): 4.20 (s, 3H ,-OCH 3), 8.72 (s, 1H, H-2), 8.28 (dd, 1H, H-6), 7.82 (d, 1H, H-5), 7.28 (m, 6H, 2 ×-C 6h 3-), 9.80 (s, 2H ,-CONH-);
The mensuration of In Vitro Anti platelet aggregation activity:
The collagen-induced In Vitro Anti Platelet Aggregation in Rabbits activity of seven compounds is recorded in table 1 according to Born turbidimetry.
Table 1
Compound number Dosage (10 ﹣6 mol/l） MA Inhibiting rate
PN477 1.3 26.53±7.93 27.97%
PN478 1.3 23.70±5.10 33.24%
PN479 1.3 22.45±7.95 28.73%
PN480 1.3 22.2±7.9 36.14%
PN481 1.3 13.95±0.3 53.5%
PN483 1.3 11.65±1.65 32.85%
PN484 1.3 13.05±0.25 28.10%
ASP 1.3 31.13±9.63 16.47%
Pirodomast 1.3 27.45±6.45 26.01%
The detected result of table 1 shows: the platelet aggregation inhibitory activity of four compounds of gained is all apparently higher than positive control drug Pirodomast and acetylsalicylic acid.
The above, it is only preferred embodiment of the present invention, not any pro forma restriction is done to the present invention, every above embodiment is done according to technical spirit of the present invention any simple modification, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.

Claims (2)

1. a 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene diamide compound, is characterized in that: described compound is 4-methoxyl group-N, N '-two (3-isopropyl phenyl)-1,3-benzenedicarboxamide.
2. the application of 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene diamide compound as claimed in claim 1, is characterized in that: described compound is for the preparation of anticoagulant medicine.
CN201410019630.3A 2014-01-16 2014-01-16 4-methoxyl group-1,3-phenyl-diformyl aminated compounds and application thereof Expired - Fee Related CN103739513B (en)

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