CN101811974A - 4-(3-(dimethoxy) propoxy)-3, 5-dimethoxy benzoic acid, and preparation method and medical purpose thereof - Google Patents
4-(3-(dimethoxy) propoxy)-3, 5-dimethoxy benzoic acid, and preparation method and medical purpose thereof Download PDFInfo
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- CN101811974A CN101811974A CN 201010151142 CN201010151142A CN101811974A CN 101811974 A CN101811974 A CN 101811974A CN 201010151142 CN201010151142 CN 201010151142 CN 201010151142 A CN201010151142 A CN 201010151142A CN 101811974 A CN101811974 A CN 101811974A
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Abstract
The invention relates to the field of medical chemistry, in particular to a preparation method and medical purpose of 4-(3-(dimethoxy) propoxy)-3, 5-dimethoxy benzoic acid (I). Proved by pharmacological tests, the compound (I) of the invention has curing effect on cardiovascular and cerebrovascular diseases caused by platelet aggregation.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a 4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid compound and salt thereof, it has therapeutic action to the cardiovascular and cerebrovascular diseases that platelet aggregation causes.
Background technology
Cardiovascular and cerebrovascular diseases is common disease, the frequently-occurring disease of serious harm human health, and along with the astogeny of social population, sickness rate rises day by day.According to statistics, the whole world has 1,600 ten thousand people to die from all kinds of cardiovascular and cerebrovascular diseases every year, is the No.1 killer who threatens human health.
Thromboembolism be cause cardiovascular and cerebrovascular diseases important factor it-, coronary artery disease and corresponding ischemic complication thereof can cause the various clinical syndromes, as apoplexy, myocardial infarction or peripheral arterial disease, the thrombus artery-clogging of main diseases because of forming in artery exactly causes severe ischemic.With coronary artery thrombosis and cerebral thrombosis is that the thrombotic disease of core also has very high M ﹠ M in China, and therefore, anti-hemostasis suppository has also just become one of current the most popular research topic in cardiovascular disorder field.
Ozagrel and Dazoxiben are the TXA of high selectivity
2Synthetase inhibitors, has very high antiplatelet aggregative activity (referring to Iizuka.K, Akahane.K, Momose.D, et al.Highyl selective inhibitors of thromboxanesynthetase.1.Imidazole Derivatives.J.Med.Chem.1981,24 (10): 1139-1148).Can suppress cerebral thrombosis and cerebral vasospasm.(referring to Song Bo, it is refined etc. that Jiang Congqing, behaviour pass, the clinical study of Sodium Ozagrel treatment unstable angina pectoris, Chinese omni-doctor's magazine, 2006,5 (4): 255-256 to be mainly used in acute cerebral infarction, coronary heart disease and anginal treatment clinically; Wu Jinying, the 42 routine clinical observations of Sodium Ozagrel treatment acute cerebral infarction).The structural formula of ozagrel and Dazoxiben is as follows:
Clinical needs are medicament for resisting platelet aggregation more effectively.
Summary of the invention
The invention discloses a 4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid compound, I is as follows for its structural formula:
The present invention also comprises the pharmacy acceptable salt of formula I compound, and these salt are formula I compound and metal, alkaline-earth metal, amino acid, contain the salt that amino basic cpd, mineral acid or organic acid form.The preferably sodium salt of formula I compound, sylvite, calcium salt, magnesium salts, arginic acid salt, hydrochloride, vitriol, phosphoric acid salt, maleate, fumarate, citrate, mesylate, tosilate or tartrate.
Formula I compound of the present invention can prepare with following method:
More preferred manufacturing procedure is as follows:
In three-necked bottle, add Ethyl syringate, N, N-dimethylamino chloropropane hydrochloride, salt of wormwood, N, dinethylformamide (DMF) is made solvent, react 7h down in 90 ℃, TLC detects to reaction complete substantially, and cooling is filtered, in filtrate, add entry, use ethyl acetate extraction then three times, the combined ethyl acetate layer, wash three times with water after, through anhydrous sodium sulfate drying, after the reclaim under reduced pressure ethyl acetate lark liquid, through the silicagel column wash-out separate 4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid ethyl ester weak yellow liquid.
In round-bottomed flask, add 4-(3-(dimethylamino) propoxy-)-3 successively, 5-dimethoxybenzoic acid ethyl ester, NaOH, ethanol, water, hydrolysis reaction 4h, TLC[developping agent: V (CHCl
3): V (methyl alcohol)=4: 1] detection reaction is complete substantially, regulate about pH to 2 with concentrated hydrochloric acid, decompression and solvent recovery adds the 15mL dehydrated alcohol to doing, heating in water bath 10min, suction filtration cools off while hot, and the adularescent precipitation is separated out, filter, filter cake dehydrated alcohol recrystallization gets 4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid hydrochloride white crystal.
The invention also discloses a kind of pharmaceutical composition, wherein contain the formula I compound and the pharmaceutically acceptable carrier for the treatment of significant quantity, this pharmaceutical composition can also be pharmacy acceptable salt and the pharmaceutically acceptable carrier that contains the formula I compound for the treatment of significant quantity.Described pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when formula I compound of the present invention was used for the treatment of, the human dosage range was 0.5mg～2000mg/ days.Also can be according to the difference and the disease severity of formulation, using dosage exceeds this scope.
Pharmacological testing proves that formula I compound or pharmaceutically acceptable salt thereof of the present invention has the effect of the cardiovascular and cerebrovascular diseases for the treatment of or preventing to cause because of platelet aggregation, particularly treats diseases such as ischemic heart disease, myocardial infarction, cerebral apoplexy, cerebral infarction disease.
Be the pharmacodynamics test and the result of formula I compound of the present invention below:
Medicine: positive drug: Sodium Ozagrel
Be subjected to the reagent thing: formula I compound of the present invention
Dosage: Sodium Ozagrel, human dosage 120mg/60kg/d, rabbit consumption (120mg ÷ 60kg) * 3=6mg/kg.Sodium Ozagrel rabbit administration volume is 2mL/kg, and the administration concentration of rabbit is 3.00mg/mL, and volumetric molar concentration is 11.99mmol/L, volumetric molar concentrations such as given the test agent and Sodium Ozagrel.
Compound method: take by weighing Sodium Ozagrel 75mg, add 25mL physiological saline, final concentration 11.99mmol/L.Melbourne invention formula I compound such as take by weighing, add 15mL physiological saline earlier, ultrasonic dissolution adds NaOH solution 20～25 μ L of 1mol/L again, and solution is clarified fully, adds physiological saline again and is diluted to required volume.
Experimental technique:
To clean the level male rabbit (2.0～2.5kg) random packet, 6 every group, give compound (I) respectively, Sodium Ozagrel and physiological saline, administration volume are 2mL/kg.Anaesthetize after the auricular vein administration, the carotid artery intubate is got blood, 3.8% Sodium Citrate (1: 9) anti-freezing, with the centrifugal 10min of 800r/min, with the preparation platelet rich plasma (platelet-rich plasma, PRP), afterwards again with the centrifugal 10min of 3000r/min, the preparation platelet poor plasma (platelet-poor plasma, PPP), aggregation inducing agent ADP (final concentration 30 μ mol/L).Every pipe 270 μ l PRP incubation 5min add ADP then and induce gathering, measure the thrombocyte MA with LG-PABER-1 type platelet aggregation instrument.
Calculate the thrombocyte inhibiting rate by following formula: inhibiting rate (%)=[(blank group MA-administration group MA)/blank group MA] * 100%, the result is organized a t check, data see Table.
Table 1. compound (I) is to the influence of platelet aggregation
| Group | Thrombocyte MA (%) | Assemble inhibiting rate (%) |
| Blank group Sodium Ozagrel formula I compound | ??38.0±6.3??28.6±3.8??1.7±1.3 ** | ??24.7??95.4 |
Table 1 shows: the platelet aggregation-against experimental result shows in the body of formula I compound of the present invention, and their platelet aggregation inhibitory activity is respectively 3.9 times of ozagrel positive drug, demonstrates excellent development and is worth.
Embodiment
Embodiment 1
4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid hydrochloride synthetic
1,4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid ethyl ester synthetic
Reaction formula
Reactions steps
In three-necked bottle, add Ethyl syringate (3.0g, 0.013mol), N, N-dimethylamino chloropropane hydrochloride (2.5g, 0.016mol), salt of wormwood (4.1g, 0.030mol), DMF (50mL) reacts 7h down in 90 ℃, TLC (developping agent: ethyl acetate) detect to reacting complete substantially, cooling filters to get filtrate, add water 50mL, with ethyl acetate (3 * 50mL) extractions, the combined ethyl acetate layer, water (after 3 * 25mL) washings, through anhydrous sodium sulfate drying, the yellow liquid of reclaim under reduced pressure ethyl acetate, separate through the silicagel column wash-out, ethyl acetate is an eluent, collects product, gets 4-(3-(dimethylamino) propoxy-)-3 behind the decompression and solvent recovery, 5-dimethoxybenzoic acid ethyl ester weak yellow liquid 3.1g, yield 75.1%.
1H-NMR(CDCl
3，300MHz)δ：7.30(s，2H，Ar-H)，4.38(q，J＝7.2Hz，2H，CH
3 CH 2 O)，4.10(t，J＝6.3Hz，2H，CH
2CH
2 CH 2 O)，3.90(s，6H，-OCH3)，2.61(t，J＝7.5Hz，2H，N
CH 2 CH
2CH
2O)，2.33{s，6H，-N(CH
3)
2}，1.98(m，2H，NCH
2 CH 2 CH
2O)，4.38(t，J＝7.2Hz，3H，
CH 3 CH
2O)；
13C-NMR(CDCl
3，75.5MHz)δ：166.2，153.1，141.3，125.5，106.8，71.7，61.1，56.4，56.2，45.2，28.0，14.4；IR(KBr，cm
-1)υ：2953.9，2816.1，2788.0，2763.9，1704.3，1588.8，1501.3，1474.9，1415.1，1370.7，1331.2，1257.9，1234.7，1186.2，1130.8，1036.7，916.6，867.4，762.7，721.5；ESI-Mass(
+c)m/z?for?C
16H
25NO
5：312.06(M
++H).
2,4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid hydrochloride synthetic
Reaction formula
Reactions steps
In round-bottomed flask, add 4-(3-(dimethylamino) propoxy-)-3 successively, 5-dimethoxybenzoic acid ethyl ester (3.0g, 0.0096mol), NaOH (0.5g, 0.013mol), ethanol (15mL), pure water (10mL), hydrolysis 4h, TLC[developping agent: V (CHCl
3): V (methyl alcohol)=4: 1] detection reaction is complete substantially, regulates about pH to 2 with 12mol/L hydrochloric acid, and decompression and solvent recovery is done to clean, add the 15mL dehydrated alcohol, heating in water bath 10min, suction filtration while hot, cooling, the adularescent precipitation is separated out, and filters, filter cake dehydrated alcohol recrystallization, drying gets 4-(3-(dimethylamino) propoxy-)-3,5-dimethoxybenzoic acid hydrochloride white solid 2.4g, yield 78.0%, m.p.249.6～251.0 ℃.
1H-NMR(D
2O，300MHz)δ：7.25(s，2H，Ar-H)，4.10(s，2H，CH
2CH
2 CH 2 O)，3.84(s，6H，-OCH
3)，3.37(t，J＝6.6Hz，2H，N
CH 2 CH
2CH
2O)，2.90{s，6H，-N(CH
3)
2}，2.10(m，2H，NCH
2 CH 2 CH
2O)；
13C-NMR(D
2O，75.5MHz)δ：169.2，152.3，139.8，125.7，107.0，71.5，56.8，56.3，43.4，24.9；IR(KBr，cm
-1)υ：2966.7，2687.3，1699.3，1590.8，1504.7，1466.6，1415.1，1380.0，1317.1，1178.9，1129.6，1055.2，934.0，867.9，768.9；ESI-Mass(
+c)m/z?for?C
14H
21NO
5：(M
++H)284.10.
Claims (6)
1. the compound of structural formula (I) or its pharmacy acceptable salt:
2. the preparation method of the compound of claim 1 comprises:
3. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is sodium salt, sylvite, calcium salt, magnesium salts, arginic acid salt, hydrochloride, vitriol, phosphoric acid salt, maleate, fumarate, citrate, mesylate, tosilate or the tartrate of the compound of claim 1.
4. pharmaceutical composition wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
5. the compound of claim 1 or its pharmacy acceptable salt are used to prepare the purposes of the cardiovascular and cerebrovascular diseases medicament for the treatment of or preventing to be caused by platelet aggregation.
6. the purposes of claim 5, wherein the cardiovascular and cerebrovascular diseases that is caused by platelet aggregation is ischemic heart disease, myocardial infarction, cerebral apoplexy or cerebral infarction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010151142 CN101811974B (en) | 2010-04-15 | 2010-04-15 | 4-(3-(dimethoxy) propoxy)-3, 5-dimethoxy benzoic acid, and preparation method and medical purpose thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010151142 CN101811974B (en) | 2010-04-15 | 2010-04-15 | 4-(3-(dimethoxy) propoxy)-3, 5-dimethoxy benzoic acid, and preparation method and medical purpose thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101811974A true CN101811974A (en) | 2010-08-25 |
| CN101811974B CN101811974B (en) | 2012-12-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113893242A (en) * | 2021-10-12 | 2022-01-07 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636500A (en) * | 1978-12-13 | 1987-01-13 | Pfizer Inc. | N-(phenoxyalkyl)imidazoles as selective inhibitors of the thromboxane synthetase enzyme and pharmaceutical compositions thereof |
| CN1376667A (en) * | 2002-04-09 | 2002-10-30 | 胥淑蓉 | Medical compound with antalgic, inflammation relieving and thrombocyte decoagulating actions |
-
2010
- 2010-04-15 CN CN 201010151142 patent/CN101811974B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636500A (en) * | 1978-12-13 | 1987-01-13 | Pfizer Inc. | N-(phenoxyalkyl)imidazoles as selective inhibitors of the thromboxane synthetase enzyme and pharmaceutical compositions thereof |
| CN1376667A (en) * | 2002-04-09 | 2002-10-30 | 胥淑蓉 | Medical compound with antalgic, inflammation relieving and thrombocyte decoagulating actions |
Non-Patent Citations (1)
| Title |
|---|
| 《中国药学杂志》 19960531 周远鹏等 益母草碱、丁香酰胍醇及丁香酸氨基醇酯类化合物抗血小板聚集活性及其与结构的关系 271-274 1-6 第31卷, 第5期 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113893242A (en) * | 2021-10-12 | 2022-01-07 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
| CN113893242B (en) * | 2021-10-12 | 2023-10-13 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
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| Publication number | Publication date |
|---|---|
| CN101811974B (en) | 2012-12-12 |
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Address after: 230088 F8 Floor, Venture Center, Hefei High-tech Zone, Anhui Province Patentee after: Hefei Medical and Pharmaceutical Co., Ltd. Address before: 230088 F8 Floor, Venture Center, Hefei High-tech Zone, Anhui Province Patentee before: Hefei Yigong Medicine Co., Ltd. |