CN102267977B - Thio and seleno homologue of 3-substituted benzo [c] furanone, preparation method and medical application thereof - Google Patents
Thio and seleno homologue of 3-substituted benzo [c] furanone, preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, and specifically relates to a thio and seleno homologue (I) of 3-substituted benzo [c] furanone. The compounds can be used for preparing medicaments preventing and treating heart and cerebral ischemia diseases, antiplatelet medicaments, antithrombotic medicaments, medicaments against cerebral ischemia, hypolipidemic medicaments, antiatherosclerosis medicaments, medicaments resisting diabetes and its complications, medicaments treating metabolic syndrome or antitumor medicaments. The invention also relates to a preparation method of the compounds as well as medical combinations containing the compounds.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to sulfo-, seleno homologue that a kind of 3-replaces benzo [c] furanone.This compounds can be used for preparation prevention and treats ischemic cardiovascular and cerebral vascular disease and improve cardiovascular and cerebrovascular circulation disturbances medicine, antiplatelet drug, antithrombotic reagent, anti-cerebral ischemia drugs, blood lipid-lowering medicine, Antiatherosclerosis medicine, anti-diabetic and complication medicine thereof, treatment metabolic syndrome medicine or antitumor drug.The drug regimen that the invention still further relates to the preparation method of this compounds and contain them.
Background technology
Biologically active pdgf plays very important effect extremely in the generation of cardiovascular and cerebrovascular diseases and development.In normal blood circulation, thrombocyte is in quiescent condition.When blood vessel endothelium injury or under some physiological and pathological stimulating factor effect, the priming reactions such as thrombocyte adheres to, gathering.
The Angiotensin II of patients with hypertension platelet surface (Ang II) acceptor has strong impulse platelet aggregation and release action, can cause platelet activation, vascular endothelial cell is impaired and thrombotic complications (Hypertension, 1993,22,853).
Hyperlipidemia and atherosclerotic's blood high viscosity and the oxidation of low-density lipoprotein can activated blood platelets, then adhesion and aggregation when flowing through artery congee sample piece spot place, discharge a series of activity and cause polymers matter, and then under the effect of Fibrinogen and Ca2+, there is aggreation, thereby form thrombus (Trends Cardiovasc.Med., 2004,14,18).
For congestive heart failure patients, the vascular endothelial cell damage that anoxic causes and cytokine profiles discharge and all can cause biologically active pdgf abnormal, make the probability that thrombotic complications occurs increase (N.Engl.J.Med.2001,345,1689).
The platelet activation degree of Patients with Ischemic Cerebrovascular Disease obviously increases, and causes thrombocyte and assembles in brain arteries, causes thrombosis, and arterial occlusion, finally causes cerebral tissue organ necrosis.Platelet activation degree and infarct volume be proportionate (Blood, 2008,112,3555).
In addition the platelet function abnormality of, suffering from the patients such as coronary heart disease, irregular pulse, diseases associated with inflammation, diabetes all has ubiquity and runs through the feature of the whole course of disease.Therefore, platelet aggregation-against treatment becomes the important means of cardiovascular and cerebrovascular diseases.
Benzo [c] Furanones compound; be called again phthalide analog compound; at vegitabilia's aboundresources; the main effective constituent of many conventional herbal medicine (as Radix Angelicae Sinensis, Ligusticum wallichii, celery etc.); it has the multiple biological activity (J.Nat.Prod. such as anti-inflammatory, antibacterial, antitumor, antiviral, anti-oxidant and cardiovascular protection; 2007,70,891).Wherein, 3-normal-butyl benzo [c] furanone (being called again NBP) is identical with the structure of the left-handed Butylphthalide extracting in celery seed, is the raceme of its synthetic, ratifies listing in China in November, 2004.Clinical study result shows, NBP and Radix Salviae Miltiorrhizae Injection intravenous drip combined utilization are improved effect to the damage of the central functions of patients with acute ischemic cerebral stroke, can promote patient's functional rehabilitation.Animal pharmacodynamic study prompting; a plurality of pathology links of NBP cerebral infarction induced brain injury capable of blocking; there is stronger anti-cerebral ischemia and cerebral protection; especially can obviously improve ATP and phosphocreatine level in ischemic mouse brain; obviously dwindle the infarct size of focal cerebral ischemia in rats; alleviate cerebral edema; improve microcirculation and the volume of blood flow of brain energy metabolism and ischemic brain area; suppress nerve cell apoptosis; and there is certain anti-cerebral thrombosis and antiplatelet aggregative activity (J.Neurol.Sci.; 2007,260,106).Separately there is document to show; butylphthalide is by affecting arachidonic acid (AA) metabolism; selectivity suppresses the multiple pathophysiological process of AA and meta-bolites mediation thereof, can remove capillary blood vessel spasm, anticoagulant; suppress the synthetic of thromboxane A2; remove free radical etc., thereby by multipath, the pathologic, physiologic evolution that too many levels blocking-up cerebral ischemia causes; neuroprotective unit, repairs neural function.(J.Cardiovasc.Pharmacol.，2004，43，876；Acta?Pharmacol.Sin.，1998，19，117)。
NBP
Yet NBP anti thrombotic action is weaker than acetylsalicylic acid, often it is combined clinically to use (cardiovascular and cerebrovascular disease control, 2009,9,29) with certain antithrombotic reagent.Therefore,, in order to strengthen the antithrombotic effect of NBP, need research and development to there is the novel cpd of new constitutional features and the new mechanism of action.
Summary of the invention
The invention discloses sulfo-, seleno homologue or its enantiomorph, diastereomer and pharmacy acceptable salt thereof that a kind of 3-replaces benzo [c] furanone, pharmacological evaluation proves, it is active that this compounds has good anticoagulant, therefore, they can be used for the abnormal relative disease of prevention and treatment and biologically active pdgf, and this class disease comprises ischemic cerebrovascular, hyperlipidemia, atherosclerosis, hypertension, congested heart rate exhaustion, coronary heart disease, diabetes and complication, metabolic syndrome etc.
The compounds of this invention structure is as shown in general formula I, and it has enantiomorph and diastereo-isomerism body structure.
Wherein:
When X represents sulphur atom, R represents C
4-C
10straight chained alkyl, C
3-C
10branched-chain alkyl or (CH
2)
nphenyl, wherein n represents the integer of 0-6;
When X represents selenium atom, R represents C
1-C
10straight chained alkyl, C
3-C
10branched-chain alkyl or (CH
2)
nphenyl, wherein n represents the integer of 0-6.
Specifically, compound or its enantiomorph, diastereomer and pharmacy acceptable salt thereof described in general formula I, is characterized in that in described general formula I:
X represents sulphur atom or selenium atom;
R represents C
4-C
8straight chained alkyl, C
3-C
8branched-chain alkyl or benzyl.
Enter-walk ground, compound is preferably from following compounds described in general formula I:
3-normal-butyl benzo [c] thienone;
3-n-pentyl benzo [c] thienone;
3-isopentyl benzo [c] thienone;
3-n-hexyl benzo [c] thienone;
3-n-heptyl benzo [c] thienone;
3-n-octyl benzo [c] thienone;
3-benzyl benzo [c] thienone;
3-ethyl benzo [c] selenophen ketone;
3-n-propyl benzo [c] selenophen ketone;
3-normal-butyl benzo [c] selenophen ketone;
3-n-pentyl benzo [c] selenophen ketone;
3-isopentyl benzo [c] selenophen ketone;
3-n-hexyl benzo [c] selenophen ketone;
3-n-heptyl benzo [c] selenophen ketone;
3-n-octyl benzo [c] selenophen ketone;
3-benzyl benzo [c] selenophen ketone.
Specifically, described in general formula I compound further preferably from following compounds:
3-normal-butyl benzo [c] thienone (compound number: I
1, lower same);
3-n-pentyl benzo [c] thienone (I
2);
3-isopentyl benzo [c] thienone (I
3);
3-n-hexyl benzo [c] thienone (I
4);
3-n-heptyl benzo [c] thienone (I
5);
3-n-propyl benzo [c] selenophen ketone (I
6);
3-normal-butyl benzo [c] selenophen ketone (I
7);
3-n-pentyl benzo [c] selenophen ketone (I
8);
3-isopentyl benzo [c] selenophen ketone (I
9);
3-n-hexyl benzo [c] selenophen ketone (I
10);
3-n-heptyl benzo [c] selenophen ketone (I
11).
The enantiomorph of preferred compound of the present invention, diastereomer and pharmacy acceptable salt thereof have formed intact part of the present invention.
The preparation method who another object of the present invention is to provide compound described in general formula I of the present invention, is characterized by and be, comprises the steps:
A), when X is sulphur atom, the preparation method that the 3-shown in general formula I replaces the sulfo-homologue of benzo [c] furanone comprises the steps:
Take Tetra hydro Phthalic anhydride as starting raw material, with nine hydrated sodium sulfide mix and blend 5h, add water and dilute hydrochloric acid and obtain benzo [c] thiophene-1,3-diketone (II), II reacts and makes compound (III) with corresponding Grignard reagent (RMgBr), and III finally makes target compound (I) under hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, the definition of R as previously mentioned;
B), when X is selenium atom, the preparation that the 3-shown in general formula I replaces the seleno homologue of benzo [c] furanone comprises the steps:
Take phthalyl chloride as starting raw material, added in the mixed solution of selenium powder and lithium aluminum hydride and stir 5h, add water and dilute hydrochloric acid and obtain benzo [c] selenophen-1,3-diketone (IV); IV reacts to obtain compound (V) with corresponding Grignard reagent (RMgBr), and V is finally converted into target compound (I) under hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, the definition of R as previously mentioned;
Prepare formula V compound and be characterised in that, Grignard reagent (RMgBr) and benzo [c] selenophen-1, the mol ratio of 3-diketone (IV) charging capacity is 2-3; The temperature of reaction adopting is 25-70 ℃; Prepare target compound (I) and be characterised in that, the mol ratio of hydroiodic acid HI and compound (III) or (V) charging capacity is 3-5; The temperature of reaction adopting is 100-125 ℃.
These compounds can be according to conventional isolation technique purifying in addition, if need available conventional isolation technique to be separated into their isomer.
It is a kind of containing the compound of Formula I of effective dose or the pharmaceutical composition of its enantiomorph, diastereomer and pharmacy acceptable salt thereof and carrier that a further object of the present invention is to provide.
A further object of the present invention is to provide the application of compound of Formula I of the present invention in preparation prevention or treatment and platelet aggregation diseases related medicine, in particular for preparation, prevents and treats ischemic cardiovascular and cerebral vascular disease and improve cardiovascular and cerebrovascular circulation disturbances medicine, antiplatelet drug, antithrombotic reagent, anti-cerebral ischemia drugs, blood lipid-lowering medicine, Antiatherosclerosis medicine, anti-diabetic and complication medicine thereof, treatment metabolic syndrome medicine or antitumor drug.
Compared with prior art, beneficial effect of the present invention is: sulphur and selenium and oxygen are congeners, optionally a certain Sauerstoffatom in compound molecule is replaced with sulphur or selenium atom, conventionally can improve the lipotropy of molecule, and cause electrostatic variation in molecule; The medicine that contains sulphur or selenium atom is compared with general medicine, has the specific selectivity of better cytolemma penetrance and target protein; In addition, the introducing of sulphur or selenium atom also may make molecule have antioxygenation and neuroprotective.
The compounds of this invention is as follows to the pharmacological experimental method of platelet aggregation activity and result:
Experimental technique: get 2 of rabbit, use lignocaine toponarcosis, the separated arteria carotis communis of performing the operation is got blood, take the anti-freezing in 1: 9 of 3.8% Sodium Citrate, with the centrifugal 10min of 500r/min, prepare platelet rich plasma (PRP), remainder is centrifugal with 3000r/min again, prepare platelet poor plasma (PPP), by turbidimetry, carry out platelet aggregation test.Measure in pipe and add PRP 240 μ L and the tested medicine 30 μ L of different concns, temperature is incubated 5min, take respectively 30 μ L adenosine diphosphate (ADP) sodium salts (ADP) (final concentration is 10 μ mol/L) and 30 μ L arachidonic acids (AA) (final concentration is 1mmol/L) is inductor, MA in observed and recorded 5min.With physiological saline (NS), compare, calculate the inhibiting rate (%) of each test-compound:
Inhibiting rate (%)=[the interior MA of MA-testing sample group 5min in control group 5min]/[MA in control group 5min] * 100%.
Test result: listed the Platelet Aggregation in Rabbits activity data of part of compounds to ADP and AA induction in table 1, positive control drug is n butylphthalide (NBP).
Table 1. part of compounds of the present invention to the inhibition of the Platelet Aggregation in Rabbits of ADP and AA induction active (n=4,
)
*P＜0.05，
**P＜0.01?vs?Control?group；
#P＜0.05，
##P＜0.01，
###P＜0.001?vs?NBP?group.
αtest-compound concentration is 100 μ M;
Above pharmacology data shows, the 3-the present invention relates to replaces the anticoagulant that the sulphur, seleno homologue of benzo [c] furanone can be in various degree, wherein, and Compound I
1, I
2, I
4, I
5, I
10and I
11nBP compares with positive control drug, can better anticoagulant.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative completely, they are only used for the present invention to specifically describe, and not should be understood to limitation of the present invention.
Embodiment 1
Benzo [c] thiophene-1,3-diketone synthetic
In dry round-bottomed flask, add 15.0g (0.1mol) Tetra hydro Phthalic anhydride and 30.0g (0.125mol) nine hydrated sodium sulfides, mechanical stirring 5h under room temperature, has a large amount of hydrogen sulfide to produce in whole process and reaction system becomes liquid gradually.React the complete 200mL distilled water that slowly adds, under room temperature, continue to stir 0.5 hour.In this reaction system, add 100mL 5% dilute hydrochloric acid, have a large amount of white solids to separate out, standing over night.Filter and collect the solid of separating out, washing, dry, obtains white powder title compound 14.9g, yield 92%, m.p.112-114 ℃.ESI-MS：m/z?187[M+Na]
+；
1H?NMR(300MHz，CDCl
3，δ)：7.74-7.79(m，2H，ArH)，7.92-7.95(m，2H，ArH).
Synthesizing of 3-hydroxyl-3-ethyl benzo [c] thienone
In dry three-necked bottle, put into 4.84g (0.20mol) magnesium powder and 20mL anhydrous diethyl ether, add a small amount of monobromethane with initiation reaction, then continue to drip monobromethane until the completely dissolve of magnesium powder, the total amount that adds of monobromethane is 21.8g (0.20mol), backflow 1h, cooling stand-by.To 250mL, containing 16.4g (0.10mol) benzo [c] thiophene-1, in the anhydrous ether solution of 3-diketone, dropwise add this Grignard reagent, drip and finish, reflux 1h, cooling stirring at room 8h.In this mixture, carefully add 150mL saturated ammonium chloride solution cancellation reaction, then add 5% dilute hydrochloric acid to adjust pH 2-3, separate organic phase, water is used extracted with diethyl ether three times again, merges organic phase, boils off solvent after anhydrous sodium sulfate drying.Rapid column chromatography (petrol ether/ethyl acetate: 10/1, V/V) obtain yellow powder shape title compound 10.8g, yield 56%, m.p.92-94 ℃.ESI-MS：m/z?193[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：1.03(t，3H，CH
3，J＝7.1Hz)，2.07-2.12(m，1H，CH)，2.31-2.39(m，1H，CH)，3.53(brs，1H，OH)，7.47(m，1H，ArH)，7.59-7.64(m，2H，ArH)，7.83(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-ethyl benzo [c] thienone
5.0g (25.7mmol) 3-hydroxyl-3-ethyl benzo [c] thienone is dissolved in 10mL Glacial acetic acid, adds 5mL 57% hydroiodic acid HI solution, be warming up to 125 ℃ and stir 0.5-1h.In cooling backward reaction mixture, add 150mL 5% sodium sulfite solution, water layer extracted with diethyl ether three times, merge organic phase, boil off solvent after anhydrous sodium sulfate drying.Rapid column chromatography (petrol ether/ethyl acetate: 50/1, V/V) obtain faint yellow oily title compound 2.11g, yield 46%.ESI-MS?m/z：201[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：1.05(t，3H，CH
3，J＝7.2Hz)，1.84-1.95(m，1H，CH)，2.30-2.38(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.52(d，1H，ArH，J＝7.5Hz)，7.64(m，1H，ArH)，7.80(d，1H，ArH，J＝7.5Hz).
Embodiment 2
Synthesizing of 3-hydroxyl-3-n-propyl benzo [c] thienone
Press the similar approach of embodiment 1, use 3.50g (21.3mmol) benzo [c] thiophene-1,3-diketone, 5.31g (42.7mmol) n-propyl bromide and 1.09g (42.7mmol) magnesium powder react, obtain yellow powder shape title compound 2.26g, yield 51%, m.p.78-80 ℃.ESI-MS：m/z?207[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：1.03(t，3H，CH
3，J＝7.1Hz)，1.45-1.57(m，2H，CH
2)，2.03-2.10(m，1H，CH)，2.22-2.33(m，1H，CH)，3.51-3.60(br?s，1H，OH)，7.42(m，1H，ArH)，7.52-7.67(m，2H，ArH)，7.80(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-n-propyl benzo [c] thienone
Press the similar approach of embodiment 1, use 2.51g (12.0mmol) 3-hydroxyl-3-n-propyl benzo [c] thienone and 2mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 1.29g, yield 56%.ESI-MS?m/z：193[M+H]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.99(t，3H，CH
3，J＝7.5Hz)，1.43-1.61(m，2H，CH
2)，1.73-1.84(m，1H，CH)，2.20-2.30(m，1H，CH)，4.84(m，1H，SCH)，7.45(m，1H，ArH)，7.52(d，1H，ArH，J＝7.5Hz)，7.65(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 3
Synthesizing of 3-hydroxyl-3-normal-butyl benzo [c] thienone
Press the similar approach of embodiment 1, use 6.55g (39.9mmol) benzo [c] thiophene-1,3-diketone, 10.9g (79.9mmol) bromination of n-butane and 1.92g (79.9mmol) magnesium powder react, obtain yellow powder shape title compound 5.41g, yield 61%, m.p.65-67 ℃.ESI-MS：m/z?221[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.91(t，3H，CH
3，J＝7.1Hz)，1.12-1.73(m，4H，2×CH
2)，2.07-2.17(m，1H，CH)，2.35-2.45(m，1H，CH)，3.58(br?s，1H，OH)，7.48(m，1H，ArH)，7.62-7.68(m，2H，ArH)，7.80(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-normal-butyl benzo [c] thienone
Press the similar approach of embodiment 1, use 4.20g (18.9mmol) 3-hydroxyl-3-normal-butyl benzo [c] thienone and 4mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 2.64g, yield 67%.ESI-MS?m/z：207[M+H]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.92(t，3H，CH
3，J＝7.2Hz)，1.35-1.56(m，4H，2×CH
2)，1.74-1.87(m，1H，CH)，2.26-2.35(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.53(d，1H，ArH，J＝7.5Hz)，7.65(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 4
Synthesizing of 3-hydroxyl-3-n-pentyl benzo [c] thienone
Press the similar approach of embodiment 1, use 5.54g (33.8mmol) benzo [c] thiophene-1,3-diketone, 10.2g (67.6mmol) bromo pentane and 1.62g (67.6mmol) magnesium powder react, obtain yellow powder shape title compound 5.10g, yield 64%, m.p.61-63 ℃.ESI-MS：m/z?235[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.90(t，3H，CH
3，J＝6.9Hz)，1.22-1.67(m，6H，3×CH
2)，2.06-2.15(m，1H，CH)，2.34-2.45(m，1H，CH)，3.60(br?s，1H，OH)，7.45(m，1H，ArH)，7.52-7.68(m，2H，ArH)，7.80(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-n-pentyl benzo [c] thienone
Press the similar approach of embodiment 1, use 3.24g (13.7mmol) 3-hydroxyl-3-n-pentyl benzo [c] thienone and 3mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 1.96g, yield 65%.ESI-MS：m/z?221[M+H]
+；243[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.89(t，3H，CH
3，J＝6.9Hz)，1.32-1.57(m，6H，3×CH
2)，1.75-1.85(m，1H，CH)，2.23-2.33(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.52(d，1H，ArH，J＝7.5Hz)，7.62(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 5
Synthesizing of 3-hydroxyl-3-isopentyl benzo [c] thienone
Press the similar approach of embodiment 1, use 4.52g (27.6mmol) benzo [c] thiophene-1,3-diketone, 9.09g (55.1mmol) bromo iso-pentane and 1.32g (55.1mmol) magnesium powder react, and obtain yellow oily title compound 3.97g, yield 61%.ESI-MS：m/z?235[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.90(m，6H，2×CH
3)，1.23-1.52(m，3H，CH
2，CH)，2.07-2.12(m，1H，CH)，2.34-2.44(m，1H，CH)，3.55(br?s，1H，OH)，7.47(m，1H，ArH)，7.53-7.63(m，2H，ArH)，7.78(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-isopentyl benzo [c] thienone
Press the similar approach of embodiment 1, use 3.04g (12.9mmol) 3-hydroxyl-3-isopentyl benzo [c] thienone and 3mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 1.95g, yield 69%.ESI-MS：m/z?221[M+H]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.90(m，6H，2×CH
3)，1.22-1.30(m，2H，CH
2)，1.48(m，1H，CH)，1.74-1.87(m，1H，CH)，2.24-2.35(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.53(d，1H，ArH，J＝7.5Hz)，7.63(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 6
Synthesizing of 3-hydroxyl-3-n-hexyl benzo [c] thienone
Press the similar approach of embodiment 1, use 7.34g (44.7mmol) benzo [c] thiophene-1,3-diketone, 14.7g (89.5mmol) bromo normal hexane and 2.15g (89.5mmol) magnesium powder react, obtain yellow powder shape title compound 7.27g, yield 65%, m.p.56-58 ℃.ESI-MS：m/z?249[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.89(t，3H，CH
3，J＝7.1Hz)，1.32-1.57(m，8H，4×CH
2)，2.00-2.04(m，1H，CH)，2.30-2.42(m，1H，CH)，3.58(br?s，1H，OH)，7.46(m，1H，ArH)，7.52-7.63(m，2H，ArH)，7.80(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-n-hexyl benzo [c] thienone
Press the similar approach of embodiment 1, use 6.45g (25.8mmol) 3-hydroxyl-3-n-hexyl benzo [c] thienone and 6mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 3.56g, yield 59%.ESI-MS：m/z?235[M+H]
+；257[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.90(t，3H，CH
3，J＝7.2Hz)，1.30-1.58(m，8H，4×CH
2)，1.74-1.86(m，1H，CH)，2.23-2.34(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.52(d，1H，ArH，J＝7.5Hz)，7.62(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 7
Synthesizing of 3-hydroxyl-3-n-heptyl benzo [c] thienone
Press the similar approach of embodiment 1, use 6.50g (39.6mmol) benzo [c] thiophene-1,3-diketone, 14.2g (79.3mmol) bromo heptane and 1.90g (79.3mmol) magnesium powder react, obtain yellow oily title compound 4.70g, yield 45%, m.p.65-67 ℃.ESI-MS：m/z?263[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.90(t，3H，CH
3，J＝7.2Hz)，1.31-1.60(m，10H，5×CH
2)，2.02-2.05(m，1H，CH)，2.30-2.44(m，1H，CH)，3.56(br?s，1H，OH)，7.45(m，1H，ArH)，7.52-7.62(m，2H，ArH)，7.77(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-n-heptyl benzo [c] thienone
Press the similar approach of embodiment 1, use 4.45g (16.8mmol) 3-hydroxyl-3-n-hexyl benzo [c] thienone and 4mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 2.05g, yield 49%.ESI-MS：m/z?249[M+H]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.85(t，3H，CH
3，J＝7.2Hz)，1.27-1.58(m，10H，5×CH
2)，1.74-1.86(m，1H，CH)，2.23-2.34(m，1H，CH)，4.83(m，1H，SCH)，7.45(m，1H，ArH)，7.52(d，1H，ArH，J＝7.5Hz)，7.62(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 8
Synthesizing of 3-hydroxyl-3-benzyl benzo [c] thienone
Press the similar approach of embodiment 1, use 3.53g (21.5mmol) benzo [c] thiophene-1,3-diketone, 5.44g (43,0mmol) benzyl chloride and 1.03g (43.0mmol) magnesium powder reacts, obtain yellow powder shape title compound 4.24g, yield 77%, m.p.126-128 ℃.ESI-MS：m/z?255[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：3.48-3.69(m，2H，CH
2)，7.26-7.36(m，5H，ArH)，7.48(m，1H，ArH)，7.62(m，2H，ArH)，7.68(d，1H，ArH，J＝8.1Hz).
Synthesizing of 3-benzyl benzo [c] thienone
Press the similar approach of embodiment 1, use 4.05g (15.8mmol) 3-hydroxyl-3-benzyl benzo [c] thienone and 4mL 57% hydroiodic acid HI solution reaction, obtain pale yellow powder shape title compound 2.35g, yield 62%, m.p.118-120 ℃.ESI-MS：m/z?241[M+H]
+；
1H?NMR(CDCl
3，300Hz，δ)：3.02-3.09(m，1H，CH)，3.53-3.59(m，1H，CH)，5.07(m，1H，SCH)，7.24-7.36(m，5H，ArH)，7.47(m，2H，ArH)，7.62(m，1H，ArH)，7.80(d，1H，ArH，J＝8.1Hz).
Embodiment 9
Benzo [c] selenophen-1,3-diketone synthetic
Containing adding selenium powder 10.4g (0.13mol) and lithium aluminum hydride 5.0g (0.13mol) in the 250mL round-bottomed flask of anhydrous tetrahydro furan 50mL, stir 0.5h at 0 ℃.In reaction system, add phthalyl chloride 26.4g (0.13mol), stirring at room 5h.Reaction finishes carefully to add 150mL water, is extracted with ethyl acetate three times, merges organic phase, boils off solvent after anhydrous sodium sulfate drying.Rapid column chromatography (petrol ether/ethyl acetate: 20/1, V/V), obtain yellow powder shape title compound 14.5g, yield 53%, m.p.125-126 ℃.ESI-MS：m/z?235[M+Na]
+；
1H?NMR(300MHz，CDCl
3，δ)：7.75-7.79(m，2H，ArH)，795-7.99(m，2H，ArH).
Synthesizing of 3-hydroxyl-3-n-propyl benzo [c] selenophen ketone
In dry three-necked bottle, put into 0.55g (22.8mmol) magnesium powder and 5mL anhydrous diethyl ether, add a small amount of n-propyl bromide with initiation reaction, then continue to add n-propyl bromide until the completely dissolve of magnesium powder, the total amount that adds of n-propyl bromide is 2.75g (22.8mmol), reflux 1h, cooling stand-by.To in this Grignard reagent, dropwise add 50mL to contain 2.4g (11.4mmol) benzo [c] thiophene-1, in the anhydrous ether solution of 3-diketone, drip and finish, reflux 1h, cooling stirring at room 8h.In this mixture, carefully add 50mL saturated ammonium chloride solution cancellation reaction, then add 5% dilute hydrochloric acid to adjust pH 2-3, separate organic phase, water is used extracted with diethyl ether three times again, merges organic phase, boils off solvent after anhydrous sodium sulfate drying.Rapid column chromatography (petrol ether/ethyl acetate: 20/1, V/V) obtain yellow oily title compound 1.05g, yield 36%.ESI-MS：m/z?255[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.99(t，3H，CH
3，J＝7.5Hz)，1.43-1.61(m，2H，CH
2)，2.10-2.19(m，1H，CH)，2.39-2.50(m，1H，CH)，7.45(m，1H，ArH)，7.52-7.65(m，2H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-n-propyl benzo [c] selenophen ketone
0.52g (2.0mmol) 3-hydroxyl-3-n-propyl benzo [c] thienone is dissolved in 5mL Glacial acetic acid, and 0.5mL adds 57% hydroiodic acid HI solution, is warming up to 125 ℃ and stirs 0.5-1h.In cooling backward reaction mixture, add 15mL 5% sodium sulfite solution, water layer extracted with diethyl ether three times, merge organic phase, boil off solvent after anhydrous sodium sulfate drying.Rapid column chromatography (petrol ether/ethyl acetate: 50/1, V/V) obtain faint yellow oily title compound 0.42g, yield 86%.ESI-MS?m/z：241[M+H]
+；263[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：1.01(t，3H，CH
3，J＝7.5Hz)，1.40-1.69(m，2H，CH
2)，1.83-1.96(m，1H，CH)，2.37-2.49(m，1H，CH)，5.11(m，1H，SeCH)，7.39(t，1H，ArH，J＝7.2Hz)，7.52-7.63(m，2H，ArH)，7.76(d，1H，ArH，J＝7.8Hz).
Embodiment 10
Synthesizing of 3-hydroxyl-3-normal-butyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 2.55g (12.1mmol) benzo [c] selenophen-1,3-diketone, 3.32g (24.2mmol) bromination of n-butane and 0.58g (24.2mmol) magnesium powder react, and obtain yellow oily title compound 1.33g, yield 41%.ESI-MS：m/z?269[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：1.06(t，3H，CH
3，J＝7.1Hz)，1.41-1.61(m，2H，2×CH
2)，2.10-2.18(m，1H，CH)，2.39-2.50(m，1H，CH)，7.35(m，1H，ArH)，7.51-7.65(m，2H，ArH)，7.80(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-normal-butyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 0.42g (1.6mmol) 3-hydroxyl-3-normal-butyl benzo [c] selenophen ketone and 0.5mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 0.30g, yield 77%.ESI-MS?m/z：277[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.99(t，3H，CH
3，J＝7.2Hz)，1.35-1.56(m，4H，2×CH
2)，1.74-1.87(m，1H，CH)，2.26-2.35(m，1H，CH)，5.10(m，1H，SeCH)，7.45(m，1H，ArH)，7.53(d，1H，ArH，J＝7.5Hz)，7.65(m，1H，ArH)，7.79(d，1H，ArH，J＝7.5Hz).
Embodiment 11
Synthesizing of 3-hydroxyl-3-n-pentyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 1.54g (7.3mmol) benzo [c] selenophen-1,3-diketone, 2.20g (14.6mmol) bromo pentane and 0.35g (14.6mmol) magnesium powder react, and obtain yellow oily title compound 0.71g, yield 34%.ESI-MS：m/z?283[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.98(t，3H，CH
3，J＝6.9Hz)，1.32-1.67(m，6H，3×CH
2)，2.16-2.23(m，1H，CH)，2.40-2.52(m，1H，CH)，7.45(m，1H，ArH)，7.52-7.68(m，2H，ArH)，7.80(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-n-pentyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 0.45g (1.6mmol) 3-hydroxyl-3-n-pentyl benzo [c] selenophen ketone and 0.4mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 0.32g, yield 75%.ESI-MS：m/z?269[M+H]
+；291[M+N]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.90(t，3H，CH
3，J＝6.6Hz)，1.34-1.60(m，6H，3×CH
2)，1.84-1.96(m，1H，CH)，2.40-2.48(m，1H，CH)，5.11(m，1H，SeCH)，7.39(m，1H，ArH)，7.52-7.63(m，2H，ArH)，7.76(d，1H，ArH，J＝7.5Hz).
Embodiment 12
Synthesizing of 3-hydroxyl-3-isopentyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 3.25g (15.4mmol) benzo [c] selenophen-1,3-diketone, 4.65g (30.8mmol) bromo iso-pentane and 0.74g (30.8mmol) magnesium powder react, and obtain yellow oily title compound 1.79g, yield 41%.ESI-MS：m/z?283[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.90(m，6H，2×CH
3)，1.20-1.72(m，3H，CH
2，CH)，2.17-2.22(m，1H，CH)，2.39-2.53(m，1H，CH)，7.47(m，1H，ArH)，7.53-7.63(m，2H，ArH)，7.78(d，1H，ArH，J＝7.5Hz).
Synthesizing of 3-isopentyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 0.34g (1.1mmol) 3-hydroxyl-3-isopentyl benzo [c] selenophen ketone and 3mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 0.24g, yield 79%.ESI-MS：m/z?269[M+H]
+；291[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.89(m，6H，2×CH
3)，1.25-1.70(m，3H，CH
2，CH)，1.84-1.97(m，1H，CH)，2.41-2.53(m，1H，CH)，5.11(m，1H，SeCH)，7.39(m，1H，ArH)，7.53-7.63(m，2H，ArH)，7.77(d，1H，ArH，J＝7.5Hz).
Embodiment 13
Synthesizing of 3-hydroxyl-3-n-hexyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 3.75g (1.78mmol) benzo [c] selenophen-1,3-diketone, 5.86g (3.55mmol) bromo normal hexane and 0.85g (3.55mmol) magnesium powder react, obtain yellow oily title compound 1.85g, yield 35%, m.p.65-67 ℃.ESI-MS：m/z?297[M-H]
-；
1H?NMR(CDCl
3，300Hz，δ)：0.89(t，3H，CH
3，J＝7.1Hz)，1.32-1.57(m，8H，4×CH
2)，2.19-2.24(m，1H，CH)，2.40-2.52(m，1H，CH)，7.46(m，1H，ArH)，7.52-7.63(m，2H，ArH)，7.80(d，1H，ArH，J＝7.8Hz).
Synthesizing of 3-n-hexyl benzo [c] selenophen ketone
Press the similar approach of embodiment 9, use 0.45g (1.5mmol) 3-hydroxyl-3-n-hexyl benzo [c] selenophen ketone and 6mL57% hydroiodic acid HI solution reaction, obtain faint yellow oily title compound 0.29g, yield 69%.ESI-MS：m/z?283[M+H]
+；305[M+Na]
+；
1H?NMR(CDCl
3，300Hz，δ)：0.87(t，3H，CH
3，J＝7.2Hz)，1.25-1.65(m，8H，4×CH
2)，1.84-1.96(m，1H，CH)，2.44-2.48(m，1H，CH)，5.10(m，1H，SeCH)，7.39(m，1H，ArH)，7.52-7.62(m，2H，ArH)，7.76(d，1H，ArH，J＝7.8Hz).
Claims (8)
1. the compound shown in general formula I or its enantiomorph, diastereomer and pharmacy acceptable salt thereof:
Wherein:
When X represents sulphur atom, R represents C
4-C
10straight chained alkyl, C
3-C
10branched-chain alkyl or (CH
2)
nphenyl, wherein n represents the integer of 0-6;
When X represents selenium atom, R represents C
1-C
10straight chained alkyl, C
3-C
10branched-chain alkyl or (CH
2)
nphenyl, wherein n represents the integer of 0-6;
Shown compound is selected from:
3-normal-butyl benzo [c] thienone;
3-n-pentyl benzo [c] thienone;
3-n-hexyl benzo [c] thienone;
3-n-heptyl benzo [c] thienone;
3-n-hexyl benzo [c] selenophen ketone;
3-n-heptyl benzo [c] selenophen ketone.
2. the preparation method of compound of Formula I claimed in claim 1, is characterized in that:
A), when X is sulphur atom, the preparation method of compound shown in general formula I comprises the steps:
Take Tetra hydro Phthalic anhydride as starting raw material, with nine hydrated sodium sulfide mix and blend 5h, add water and dilute hydrochloric acid and obtain benzo [c] thiophene-1,3-diketone II, II reacts and makes compound III with corresponding Grignard reagent RMgBr, and III finally makes target compound I under hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, the definition of R as previously mentioned;
B), when X is selenium atom, the preparation of compound shown in general formula I comprises the steps:
Take phthalyl chloride as starting raw material, added in the mixed solution of selenium powder and lithium aluminum hydride and stir 5h, add water and dilute hydrochloric acid and obtain benzo [c] selenophen-1,3-diketone IV; IV reacts to obtain compound V with corresponding Grignard reagent RMgBr, and V is finally converted into target compound I under hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, the definition of R as previously mentioned.
3. method according to claim 2, preparation formula V compound is characterised in that, Grignard reagent RMgBr and benzo [c] selenophen-1, the mol ratio of 3-diketone IV charging capacity is 2-3; The temperature of reaction adopting is 25-70 ℃.
4. method according to claim 2, prepares compound of Formula I and is characterised in that, the mol ratio of hydroiodic acid HI and compound III or V charging capacity is 3-5; The temperature of reaction adopting is 100-125 ℃.
5. a pharmaceutical composition, wherein contains compound of Formula I claimed in claim 1 or its enantiomorph and diastereomer or its pharmacy acceptable salt and the carrier for the treatment of significant quantity.
6. the compound of Formula I of claim 1 or its pharmacy acceptable salt purposes in the medicine of preparation prevention or the treatment disease relevant with platelet aggregation.
7. the purposes of claim 6, it is characterized in that, compound of Formula I or its pharmacy acceptable salt can be used for preparation prevention and treat ischemic cardiovascular and cerebral vascular disease and improve cardiovascular and cerebrovascular circulation disturbances medicine, antiplatelet drug, antithrombotic reagent, blood lipid-lowering medicine, Antiatherosclerosis medicine.
8. the purposes of claim 7, is characterized in that, compound of Formula I or its pharmacy acceptable salt can be used for preparation prevention and treatment ischemic cardiovascular and cerebral vascular disease medicine is anti-cerebral ischemia drugs.
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| CN109824649A (en) * | 2019-03-11 | 2019-05-31 | 南京红杉生物科技有限公司 | Homocysteinic acid thiolactone hydrochloride and its preparation method and application |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1787815A (en) * | 2003-05-14 | 2006-06-14 | 帝斯曼知识产权资产管理有限公司 | Use of phthalide derivatives for the treatment and prevention of diabetes mellitus |
| CN1807421A (en) * | 2006-01-25 | 2006-07-26 | 中国科学院上海有机化学研究所 | High optical activity chiral phthalide analog compound and synthesis method |
| CN101455661A (en) * | 2008-11-19 | 2009-06-17 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
-
2011
- 2011-05-06 CN CN201110115922.3A patent/CN102267977B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1787815A (en) * | 2003-05-14 | 2006-06-14 | 帝斯曼知识产权资产管理有限公司 | Use of phthalide derivatives for the treatment and prevention of diabetes mellitus |
| CN1807421A (en) * | 2006-01-25 | 2006-07-26 | 中国科学院上海有机化学研究所 | High optical activity chiral phthalide analog compound and synthesis method |
| CN101455661A (en) * | 2008-11-19 | 2009-06-17 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
Non-Patent Citations (4)
| Title |
|---|
| John J. Beck et.al..The Structural Diversity of Phthalides from the Apiaceae.《J. Nat. Prod.》.2007,第70卷(第5期),891-900. |
| John J. Beck et.al..The Structural Diversity of Phthalides from the Apiaceae.《J. Nat. Prod.》.2007,第70卷(第5期),第893页figure 2. |
| The Structural Diversity of Phthalides from the Apiaceae;John J. Beck et.al.;《J. Nat. Prod.》;20070504;第70卷(第5期);891-900 * |
| The Structural Diversity of Phthalides from the Apiaceae;John J. Beck et.al.;《J. Nat. Prod.》;20070504;第70卷(第5期);第893页figure 2 * |
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