CN1173958C - Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application - Google Patents
Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application Download PDFInfo
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- CN1173958C CN1173958C CNB001142399A CN00114239A CN1173958C CN 1173958 C CN1173958 C CN 1173958C CN B001142399 A CNB001142399 A CN B001142399A CN 00114239 A CN00114239 A CN 00114239A CN 1173958 C CN1173958 C CN 1173958C
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Abstract
The present invention discloses a novel compound shown in the structural formula (I), a method for preparing the compound and an application of the compound to the preparation of platelet aggregation inhibiting agents, medicines for treating thrombus, medicines for treating thrombolysis, medicines for treating apoplexy and medicines for treating migraine.
Description
The present invention relates to a kind of compound of novelty, its preparation method and its application in preparation anticoagulant, treatment antithrombotic reagent, treatment thrombolytic drug, treatment apoplexy medicine and treatment migraine remedy.
Antiplatelet drug can reduce thrombocyte and build up and blood viscosity.At present the most frequently used is acetylsalicylic acid and Ticlid (ticlopidine HCI).
The object of the present invention is to provide a kind of new compound with pharmaceutical use.It can anticoagulant, and antithrombotic forms.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
Another object of the present invention is to provide the application of above-claimed cpd in preparation anticoagulant, treatment antithrombotic reagent, treatment thrombolytic drug, treatment apoplexy medicine and treatment migraine remedy.
Compound of the present invention is forulic acid Tetramethylpyrazine (a forulic acid 2), and its structural formula is
Compound of the present invention can prepare with following method:
(1) Vanillin, propanedioic acid are mixed in organic solvent, reflux is poured into after the cooling in concentrated hydrochloric acid and the trash ice solution, leaves standstill, again with the crystal recrystallization of separating out;
(2) Sodium Nitrite, second alcohol and water are mixed solution I, with sulfuric acid, second alcohol and water mix solution II.Solution II is added drop-wise in the solution I, obtains ethyl nitrite gas, then the feeding of ethyl nitrite gas has been added in the reactor of butanone, hydrochloric acid, keeping temperature of reaction is 40～55 ℃, after having led to gas, underpressure distillation gets the biacetyl monoxime crystal to remove the ethanol that dereaction produces;
(3) biacetyl monoxime, ammonium chloride and acetic acid are mixed, stir adding zinc powder in the time of 10～15 ℃ down.After adding zinc powder, 85 ℃ of insulations 30 minutes, after the cooling, being neutralized to pH value with alkali was 7～8, then water distillation distillation.With the distillate cooling, crystallization is filtered, and gets the Tetramethylpyrazine crystal;
(4) Tetramethylpyrazine and acetone are mixed, after the heated and stirred dissolving, add forulic acid again, reflux is filtered drying.
Wherein the mol ratio of Vanillin and propanedioic acid is 1: 1 in the first step reaction, and organic solvent is a pyridine, and reflux temperature is 90～95 ℃, and return time is 1 hour; Butanone in the reaction of second step: hydrochloric acid (12mol/L): Sodium Nitrite: ethanol (I): water (I): sulfuric acid (18mol/L): ethanol (II): water (II)=1.000: 0.023: 1.520: 0.630: 2.800: 0.630: 1.320: 1.600 (weight ratio); Acetate concentration is 75% in the three-step reaction, biacetyl monoxime: ammonium chloride: acetic acid (75%): zinc powder=1.00: 0.16: 3.20: 0.88: 0.22 (weight ratio); The mol ratio of Tetramethylpyrazine and forulic acid is 1: 1 in the four-step reaction, and the used alkali that neutralizes is sodium hydroxide, and reflux temperature is 60 ℃, and return time is 1 hour.
Migraine is because the interior calcium contents of thrombocyte increases, and has strengthened hematoblastic aggregation capability, impels thrombocyte to discharge serotonin and brings out; And apoplexy is because platelet aggregation causes elevation of blood pressure, causes hemorrhage causing at last.Compound of the present invention not only has the obvious suppression effect to the platelet aggregation of ADP, collagen, thrombin induction, and accumulative thrombocyte there is unzipping, thrombosis there is the obvious suppression effect, and can make established thrombolysis, and compound of the present invention also has analgesic activity.Compound of the present invention can be used for preparing anticoagulant, treatment antithrombotic reagent, treatment thrombolytic drug, treatment apoplexy medicine and treatment migraine remedy.
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1
The preparation of The compounds of this invention
(1) Vanillin 7.7g, propanedioic acid 5.2g are mixed in the 7ml pyridine, heating refluxed 1 hour at 92 ℃, pour into after the cooling in 20ml concentrated hydrochloric acid and the trash ice solution, leave standstill, again with 95% ethanol with the crystal recrystallization of separating out, obtain product 8.6g, fusing point is 169～173 ℃, and yield is 87.8%;
(2) Sodium Nitrite 15.2g, ethanol 6.3g and water 28.0g are mixed solution I, with sulfuric acid 13.2g, ethanol 6.3g and water 16.0g mix solution II.Solution II is added drop-wise in the solution I, obtain ethyl nitrite gas, then ethyl nitrite gas is fed and added in the reactor of butanone 10.0g, hydrochloric acid 0.23g, keeping temperature of reaction is 50 ℃, after having led to gas, underpressure distillation gets biacetyl monoxime crystal 11.5g to remove the ethanol that dereaction produces, fusing point is 75.5～79 ℃, and yield is 82.0%;
(3) biacetyl monoxime 10.0g, ammonium chloride 1.6g and 75% acetic acid 32.0g are mixed, stir adding zinc powder in the time of 10 ℃ down.After adding zinc powder, 85 ℃ of insulations 30 minutes, after the cooling, being neutralized to pH value with sodium hydroxide solution was 7, then water distillation distillation.With the distillate cooling, crystallization is filtered, and gets Tetramethylpyrazine crystal 4 .7g, and fusing point is 75.8～77.0 ℃, and yield is 35%;
(4) Tetramethylpyrazine 2.8g and acetone 45ml are mixed, after the heated and stirred dissolving, add forulic acid 4.0g again, 60 ℃ were refluxed 1 hour, filtered, and drying gets The compounds of this invention 3.5g, and fusing point is 160～164 ℃, and yield is 51.4%.
IR (KBr), cm
-1: 2926.4 (υ
C-H), 1667.0～2000 (the general frequencies of aromatic hydrocarbons), 1596.7,1515.4,1580.0,1472.0 (υ
C=CSkeleton), 1401.0 (δ
-OH), 1273.0 (υ
85 =C-O-C), 1205.3 (υ
C-O), 1032.1 (υ
5 =C-O-C), 976.3 (δ
-N=C-,=N-C=), 846.2,686.9 (δ
C-H).MS，m/z(％)：
1H-NMR(DMSO)：δ，ppm：7.31(d，1H，C
2-H)，6.86(d，1H，C
5-H)，7.13(dd，1H，C
6-H)，7.60(dd，1H，C
7-H)，6.37(d，1H，C
8-H)，3.90(s，3H，OCH
3)，2.40(d，3H，N＝C-CH
3)。
13C-NMR(DMSO)：
Carbon ppm
1 127.3
2 115.9
3 149.9
4 148.7
5 115.8
6 123.8
7 148.6
8 111.1
9 168.6
OCH
3 56.2
N＝
*C 145.9
N＝C-C
* 29.9
Embodiment 2
Anti-ADP hyperamization platelet focusing experiment
Get 0.2ml PPP blood plasma, put into test tube, insert blood pool instrument (MPG-3E blood pool instrument, the Shanghai electric equipment of this grand doctor company limited) and detect the hole, show " 100 "; Extract PPP pipe, get 0.2mlPRP blood plasma equally, and put down gently, show platelet count, when showing " 00 ", add ADP10ul, after 5 minutes, show that aggregation rate is 23% (19 minutes time show that MA is 25%) into little splash bar.Equally, when showing " 00 ", add the The compounds of this invention 5ul (concentration is 0.025g/ml) that embodiment 1 makes, add ADP10ul again, after 5 minutes, show that aggregation rate is 12% (1 minute and 45 seconds time show that MA is 16%).Show that compound of the present invention has anti-ADP hyperamization platelet congregation.
Embodiment 3
The antithrombin experiment
Get 0.2mlPPP blood plasma, put into test tube, and put down gently, add TT reagent 0.1ml, begin test, show that the TT value is 16.9 seconds into little splash bar.Get 0.2mlPPP blood plasma equally, put into test tube, and put down gently, add the The compounds of this invention 5ul (concentration is 0.025g/ml) that embodiment 1 makes, add TT reagent 0.1ml again, begin test, show that the TT value is 36.4 seconds into little splash bar.Show that compound of the present invention has the antithrombin effect.
Claims (5)
1, structural formula (I) compound
The preparation method, may further comprise the steps:
(1) Vanillin, propanedioic acid are mixed in organic solvent, reflux is poured into after the cooling in concentrated hydrochloric acid and the trash ice solution, leaves standstill, again with the crystal recrystallization of separating out;
(2) Sodium Nitrite, second alcohol and water are mixed solution I, with sulfuric acid, second alcohol and water mix solution II, solution II is added drop-wise in the solution I, obtain ethyl nitrite gas, then ethyl nitrite gas is fed and added in the reactor of butanone, hydrochloric acid, keeping temperature of reaction is 40～55 ℃, led to gas after, underpressure distillation gets the biacetyl monoxime crystal to remove the ethanol that dereaction produces;
(3) biacetyl monoxime, ammonium chloride and acetic acid are mixed, stir and in the time of 10～15 ℃, add zinc powder down, add zinc powder after, 85 ℃ of insulations 30 minutes, after the cooling, being neutralized to pH value with alkali is 7～8, and distillate is cooled off in water distillation distillation then, crystallization is filtered, and gets tetramethyl-and adjoins the piperazine crystal;
(4) Tetramethylpyrazine and acetone are mixed, after the heated and stirred dissolving, add forulic acid again, reflux is filtered drying.
2, preparation method as claimed in claim 1 is characterized in that the mol ratio of Vanillin and propanedioic acid is 1: 1 in the first step reaction, and organic solvent is a pyridine, and reflux temperature is 90～95 ℃, and return time is 1 hour.
3, preparation method as claimed in claim 1 is characterized in that butanone in the reaction of second step: hydrochloric acid (12mol/L): inferior stone acid sodium: ethanol (I): water (I): sulfuric acid (18mol/L): ethanol (II): water (II)=1.000: 0.023: 1.520: 0.630: 2.800: 0.630: 1.320: 1.600 (weight ratio).
4, preparation method as claimed in claim 1 is characterized in that in the three-step reaction, and acetate concentration is 75%, and biacetyl monoxime: chlorination is pressed: acetic acid (75%): zinc powder=1.00: 0.16: 3.20: 0.88: 0.22 (weight ratio).
5, preparation method as claimed in claim 1 is characterized in that the mol ratio of Tetramethylpyrazine and forulic acid is 1: 1 in the four-step reaction, and the used alkali that neutralizes is sodium hydroxide, and reflux temperature is 60 ℃, and return time is 1 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001142399A CN1173958C (en) | 2000-04-30 | 2000-04-30 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001142399A CN1173958C (en) | 2000-04-30 | 2000-04-30 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1274722A CN1274722A (en) | 2000-11-29 |
| CN1173958C true CN1173958C (en) | 2004-11-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001142399A Expired - Fee Related CN1173958C (en) | 2000-04-30 | 2000-04-30 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
Country Status (1)
| Country | Link |
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| CN (1) | CN1173958C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060787B (en) * | 2010-11-23 | 2013-06-12 | 广东药学院 | Tetramethylpyrazine ferulate crystals for suppressing platelet aggregation and thrombosis and preparation method thereof |
| CN103664804B (en) * | 2013-11-12 | 2016-01-20 | 安徽中医药大学 | Pirodomast analogue, preparation method and application thereof |
| CN104341359B (en) * | 2014-11-11 | 2017-01-11 | 武汉武药制药有限公司 | Preparation method of tetramethyl-pyrazine |
| CN110156701B (en) * | 2019-06-25 | 2020-10-16 | 吴赣药业（苏州）有限公司 | Synthesis method of 2,3,5, 6-tetramethylpyrazine |
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2000
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| Publication number | Publication date |
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| CN1274722A (en) | 2000-11-29 |
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