CN103553985B - 4-methoxy-N,N-bisubstituted phenyl-1,3-benzene bisulfonamide compound and application thereof - Google Patents

4-methoxy-N,N-bisubstituted phenyl-1,3-benzene bisulfonamide compound and application thereof Download PDF

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CN103553985B
CN103553985B CN201310569165.6A CN201310569165A CN103553985B CN 103553985 B CN103553985 B CN 103553985B CN 201310569165 A CN201310569165 A CN 201310569165A CN 103553985 B CN103553985 B CN 103553985B
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benzene
compound
methoxyl group
platelet aggregation
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CN103553985A (en
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刘秀杰
张庆响
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INNOCHEM (BEIJING) TECHNOLOGY CO., LTD.
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Tianjin University of Technology
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Abstract

The invention discloses a 4-methoxy-N,N-bisubstituted phenyl-1,3-benzene bisulfonamide compound and an application thereof. The preparation method comprises the following steps: synthesizing a crude target product, namely adding an arylamine compound and 4-methoxy1,3-benzene bisulfonyl chloride into a solvent a and uniformly mixing, reacting for 4-120 hours at minus 5 to 80 DEG C, and distilling to remove the solvent so as to obtain the crude target product; and recrystallizing the crude target product, drying the crude target product, subsequently adding a solvent b, heating till being boiled, cooling down to be the room temperature, filtering and standing so as to obtain a pure target product for preparing a medicament for inhibiting platelet aggregation. The 4-methoxy-N,N-bisubstituted phenyl-1,3-benzene bisulfonamide compound has the advantages that the compound has a high platelet aggregation prevention activity, the preparation method is simple in process and easy to implement, the yield can be 25-99%, and good foundation is made for further study and development of medicaments and applications of the medicaments for platelet aggregation prevention.

Description

A kind of 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides and application thereof
Technical field
The present invention relates to medicament for resisting platelet aggregation, particularly a kind of 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides and application thereof.
Background technology
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.
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-benzene Bis-sulfonamides has done further research.Found that, wherein four compounds, have very high platelet aggregation inhibitory activity, all have the prospect being developed as new medicament for resisting platelet aggregation.4-methoxyl group-the N that the present invention relates to, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides comprises: 4-methoxyl group-N, N '-two (4-luorobenzyls)-1,3-benzene disulfonic acid amide, 4-methoxyl group-N, N '-two (2-luorobenzyl)-1,3-benzene disulfonic acid amide, 4-methoxyl group-N, N '-two (4-fluorobenzene ethyls)-1,3-benzene disulfonic acid amide and 4-methoxyl group-N, N '-two (2,3-3,5-dimethylphenyl)-1,3-benzene disulfonic acid amide.There is no four 4-methoxyl group-N about right of the present invention at present, the patent report of N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides; Also pertinent literature for the present invention report is had no.
Summary of the invention
The object of the present invention is to provide new a kind of 4-methoxyl group-N with medicament for resisting platelet aggregation prospect, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides, described compound has higher platelet aggregation inhibitory activity, has the prospect being developed as new medicament for resisting platelet aggregation.
Technical scheme of the present invention:
A kind of 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides, comprise 4-methoxyl group-N, N '-two (4-luorobenzyl)-1,3-benzene disulfonic acid amide, 4-methoxyl group-N, N '-two (2-luorobenzyls)-1,3-benzene disulfonic acid amide, 4-methoxyl group-N, N '-two (4-fluorobenzene ethyl)-1,3-benzene disulfonic acid amide and 4-methoxyl group-N, N '-two (2,3-3,5-dimethylphenyl)-1,3-benzene disulfonic acid amide.
A kind of described 4-methoxyl group-N, the preparation method of N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides, step is as follows:
1) target compound crude product is synthesized: aromatic amine compound and 4-methoxyl group-1,3-benzene-disulfo-chloride being added in solvent a and to mix, at-5 to 80 DEG C of temperature, react 4-120h, distillation removes desolventizing and obtains target compound crude product;
2) crude product recrystallization: add solvent b by 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.
Described aromatic amine compound is NSC 158269, adjacent flunamine, to fluorophenethylamine or 23 dimethyl aniline, the mol ratio of aromatic amine compound and 4-methoxyl group-1,3-benzene-disulfo-chloride is 2:1.
Described solvent a is ethyl acetate, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, tetrachloromethane or acetone, solvent b is tetrahydrofuran (THF), dioxane, dioxane, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, acetone, glacial acetic acid or pyridine, the amount ratio of solvent a, solvent b and 4-methoxyl group-1,3-benzene-disulfo-chloride is 10ml:20-40 ml: 0.75 g.
A kind of described 4-methoxyl group-N, the application of N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides, for the preparation of anticoagulant medicine.
Advantage of the present invention is: this 4-methoxyl group-N, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides has very strong platelet aggregation inhibitory activity, its preparation method technique is simple, easy to implement, yield can reach 25-99%, for furtheing investigate further from now on and developing new medicament for resisting platelet aggregation and good basis is laid in application.
Embodiment
According to reported in literature and present invention applicant laboratory research work achievement for many years, the applicant has designed and synthesized four sulfamide compounds, and carries out the test of In Vitro Anti platelet aggregation activity primary dcreening operation pharmacological research to the target compound obtained.Found that each compound all has high platelet aggregation inhibitory activity, there is 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:
A kind of 4-methoxyl group-N, N '-two (4-luorobenzyl)-1,3-benzene disulfonic acid amide (C 21n 2o 5s 2f 2h 20) preparation method, step is as follows:
1) by 0.63g (5mmol) NSC 158269 and 0.75 g(2.5mmol) 4-methoxyl group-1,3-benzene-disulfo-chloride to add in 10ml ethyl acetate and to mix, at 0 DEG C of temperature, react 24h, and distillation obtains target compound crude product except desolventizing;
2) be placed on after the drying of above-mentioned target compound crude product in single port bottle, add 25ml acetone, be heated to boiling, be cooled to filtering and standing after room temperature, target compound sterling can be obtained.With obtaining transparence target compound crystallization 0.98 g after acetone recrystallization.Yield: 82.7 %, mp:164.5-166.8C.The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN463.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN463 structure is confirmed: IR (KBr, cm -1): 3267.1,1586.7,1502.3,1348.5,1170.3,850.1; 1h-NMR (CDCl 3) δ: 8.37 (d, 1H ,-C 6h 3), 7.99 (dd, 1H ,-C 6h 3), 7.23 (q, 2H ,-C 6h 4), 7.16 (q, 2H ,-C 6h 4), 7.01 (t, 2H ,-C 6h 4), 6.94 (t, 2H ,-C 6h 4), 5.17 (t, 1H ,-NH), 4.83 (t, 1H ,-NH), 4.15 (t, 4H ,-CH 2), 3.96 (s, 3H ,-OCH 3).
Embodiment 2:
A kind of 4-methoxyl group-N, N '-two (2-luorobenzyl)-1,3-benzene disulfonic acid amide (C 21n 2o 5s 2f 2h 20) preparation method, step is as follows:
1) by 0.63g (5mmol) adjacent flunamine and 0.75 g(2.5mmol) 4-methoxyl group-1,3-benzene-disulfo-chloride to add in 10ml methylene dichloride and to mix, at 0 DEG C of temperature, react 30h, and distillation obtains target compound crude product except desolventizing;
2) be placed on after the drying of above-mentioned target compound crude product in single port bottle, add 30ml dehydrated alcohol, be heated to boiling, be cooled to filtering and standing after room temperature, target compound sterling can be obtained.With obtaining white object thing crystallization 0.8 g after dehydrated alcohol recrystallization.Yield: 65.89%, mp:169.1-171.2 oc.The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN466.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN466 structure is confirmed: IR (KBr, cm -1): 3271.1,1601.4,1565.9,1356.7,1150.6,763.2; 1h-NMR (CDCl 3) δ: 8.15 (d, 1H ,-C 6h 3), 7.80 (dd, 1H ,-C 6h 3), 6.95-7.35 (m, 8H ,-C 6h 4), 6.69 (d, 1H ,-C 6h 3), 5.69 (t, 1H ,-NH), 5.11 (t, 1H ,-NH), 4.32 (d, 2H ,-CH 2c 6h 4), 4.28 (d, 2H ,-CH 2c 6h 4), 3.87 (s, 3H ,-OCH 3).
Embodiment 3:
A kind of 4-methoxyl group-N, N '-two (4-fluorobenzene ethyl)-1,3-benzene disulfonic acid amide (C 23n 2o 5s 2f 2h 24)) preparation method, step is as follows:
1) by 0.7g (5mmol) to fluorophenethylamine and 0.75 g(2.5mmol) 4-methoxyl group-1,3-benzene-disulfo-chloride to add in 10ml acetone and to mix, at 0 DEG C of temperature, react 24h, distillation obtains target compound crude product except desolventizing;
2) be placed on after the drying of above-mentioned target compound crude product in single port bottle, add 20ml methyl alcohol, be heated to boiling, be cooled to filtering and standing after room temperature, target compound sterling can be obtained.With obtaining white object thing crystallization 0.65 g after recrystallizing methanol.Yield: 52.0%, mp:151.6-153.1 oc.The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN468.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN468 structure is confirmed: IR(KBr) cm -1: 3190.62,1605.7,1586.2,1488.8,1108.12,817.0,1259.5,1059.5; 1h-NMR (CDCl 3): 8.46 (s, 1H ,-C 6h 3), 7.98 (dd, 1H ,-C 6h 3), 7.37 (d, 1H ,-C 6h 3), 7.25-7.34 (m, 8H ,-C 6h 4), 5.04 (t, 1H ,-NH), 4.78 (t, 1H ,-NH), 3.68 (s, 3H ,-OCH 3), 3.40 (m, 4H, 2 ×-NHCH 2), 2.78 (dd, 4H, 2 ×-CH 2c 6h 4).
Embodiment 4:
A kind of 4-methoxyl group-N, N '-two (2,3-3,5-dimethylphenyl)-1,3-benzene disulfonic acid amide (C 23n 2o 5s 2h 26) preparation method, step is as follows:
1) by 0.61g (5mmol) 2,3-xylidine and 0.75 g(2.5mmol) 4-methoxyl group-1,3-benzene-disulfo-chloride to add in 10ml tetrahydrofuran (THF) and mixes, at 25 DEG C of temperature, react 36h, and distillation obtains target compound crude product except desolventizing;
2) be placed on after the drying of above-mentioned target compound crude product in single port bottle, add 40ml tetrahydrofuran (THF), be heated to boiling, be cooled to filtering and standing after room temperature, target compound sterling can be obtained.With obtaining white powder target compound solid 0.6 g after tetrahydrofuran (THF) recrystallization.Yield: 50.42%, mp:210.7-212.9 oc.The group of this compound in Platelet Aggregation in Rabbits reaction experiment is numbered PN476.
By infrared spectra (IR) and nuclear magnetic resonance spectrum ( 1h-NMR) PN476 structure is confirmed: IR(KBr) cm -1: 3450.71,1586.85,1487.32,1317.45,1168.12,566.98; 1h-NMR (CDCl 3): 8.26 (d, 1H ,-C 6h 3), 7.98 (dd, 1H ,-C 6h 3), 6.91-7.08(m, 6H ,-NHC 6h 3-), 6.82(d, 1H ,-C 6h 3), 6.72 (s, 1H ,-NH-), 6.28 (s, 1H ,-NH-), 4.08 (s, 3H ,-OCH 3), 2.22-2.28 (t, 12H, 4 ×-CH 3).
By the 4-methoxyl group-N of above-mentioned preparation, N '-di-substituted-phenyl-1,3-benzene Bis-sulfonamides is for the preparation of anticoagulant medicine.
Record the collagen-induced In Vitro Anti platelet aggregation activity of four new compounds according to Born turbidimetry, measurement result is in table 1.
The restraining effect that table 1 Pirodomast derivative reacts collagen-induced rat platelet aggregation
Table 1 shows: the platelet aggregation inhibitory activity of four compounds of gained is all 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 Bis-sulfonamides, it is characterized in that, described compound is: compound 4-methoxyl group-N, N '-two (4-luorobenzyl)-1,3-benzene disulfonic acid amide (code name: PN463), 4-methoxyl group-N, N '-two (2-luorobenzyl)-1,3-benzene disulfonic acid amide (code name: PN466) and 4-methoxyl group-N, N '-two (2,3-3,5-dimethylphenyl)-1,3-benzene disulfonic acid amide (code name: PN476).
2. compound 4-methoxyl group-N according to claim 1, N '-two (4-luorobenzyl)-1,3-benzene disulfonic acid amide, 4-methoxyl group-N, N '-two (2-luorobenzyl)-1,3-benzene disulfonic acid amide and 4-methoxyl group-N, N '-two (2,3-3,5-dimethylphenyl)-1, the 3-application of benzene disulfonic acid amide in the medicine preparing platelet aggregation-against.
CN201310569165.6A 2013-11-15 2013-11-15 4-methoxy-N,N-bisubstituted phenyl-1,3-benzene bisulfonamide compound and application thereof Active CN103553985B (en)

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Publication number Priority date Publication date Assignee Title
CN101058549A (en) * 2006-04-19 2007-10-24 天津大学 4-methoxy-1,3-phenyl disubstituted amide derivative
EP2570417A1 (en) * 2010-05-13 2013-03-20 Tianjin Institute Of Pharmaceutical Research Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof
CN103012189A (en) * 2012-12-20 2013-04-03 天津理工大学 Amide compound with anti-platelet aggregation function, and preparation and application of amide compound
CN103373939A (en) * 2012-04-13 2013-10-30 天津理工大学 4-methoxy-N, N'-bisubstituted phenyl-1, 3-benzene diamide compounds as well as preparation method and application thereof

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CN1986525B (en) * 2006-12-12 2010-11-17 天津理工大学 4-methoxy-1,3-phenyl disulfamide derivative and its application

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101058549A (en) * 2006-04-19 2007-10-24 天津大学 4-methoxy-1,3-phenyl disubstituted amide derivative
EP2570417A1 (en) * 2010-05-13 2013-03-20 Tianjin Institute Of Pharmaceutical Research Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof
CN103373939A (en) * 2012-04-13 2013-10-30 天津理工大学 4-methoxy-N, N'-bisubstituted phenyl-1, 3-benzene diamide compounds as well as preparation method and application thereof
CN103012189A (en) * 2012-12-20 2013-04-03 天津理工大学 Amide compound with anti-platelet aggregation function, and preparation and application of amide compound

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