CN102267977A - 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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- 0 O=C(c1ccccc11)O*1=O Chemical compound O=C(c1ccccc11)O*1=O 0.000 description 3
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Abstract
Relating to the fields of pharmaceutical chemistry and pharmacotherapeutics, the invention 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 the 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 the preparation prevention and treats ischemic cardiovascular and cerebral vascular disease and improve heart and brain cycle penalty 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 important effect unusually in the generation of cardiovascular and cerebrovascular diseases and development.Thrombocyte is in quiescent condition in the normal blood circulation.When blood vessel endothelium injury or under some physiological and pathological stimulating factor effect, 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).
But hyperlipidemia and atherosclerotic's the blood high viscosity and the oxidation activated blood platelet of low-density lipoprotein, 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+, aggreation takes place, thereby forms thrombus (Trends Cardiovasc.Med., 2004,14,18).
For congestive heart failure patients, the vascular endothelial cell damage that anoxic causes and the various kinds of cell factor discharge and all can cause biologically active pdgf unusual, make the probability that thrombotic complications takes place increase (N.Engl.J.Med.2001,345,1689).
Ischemic cerebrovascular patient's platelet activation degree obviously increases, and causes thrombocyte and assembles in the brain arteries, causes thrombosis, and arterial occlusion causes the cerebral tissue organ necrosis at last.Platelet activation degree and infarct stove long-pending be proportionate (Blood, 2008,112,3555).
In addition, the platelet function abnormality of suffering from patients such as coronary heart disease, irregular pulse, diseases associated with inflammation, diabetes all has ubiquity and runs through the characteristics of the whole course of disease.Therefore, the important means of platelet aggregation-against treatment becoming cardiovascular and cerebrovascular diseases.
Benzo [c] Furanones compound; be called phthalide analog compound again; at vegitabilia's aboundresources; be the main effective constituent of many herbal medicine commonly used (as Radix Angelicae Sinensis, Ligusticum wallichii, celery etc.); it has multiple biological activity (J.Nat.Prod. such as anti-inflammatory, antibiotic, antitumor, antiviral, anti-oxidant and cardiovascular protection; 2007,70,891).Wherein, the structure of the left-handed Butylphthalide that extracts in 3-normal-butyl benzo [c] furanone (being called NBP again) and the celery seed is identical, is the raceme of its synthetic, in China in November, 2004 approval listing.Clinical study is the result show, NBP and Radix Salviae Miltiorrhizae Injection intravenous drip combined utilization have the improvement effect to the damage of acute ischemic cerebral apoplexy patient's nervus centralis function, can promote patient's functional rehabilitation.Animal pharmacodynamic study prompting; a plurality of pathology links of brain injury due to the NBP cerebral infarction capable of blocking; have stronger anti-cerebral ischemia and cerebral protection; especially can obviously improve ATP and phosphocreatine level in the ischemic mouse brain; obviously dwindle the infarct size of rat local cerebral ischemia; alleviate cerebral edema; improve the microcirculation and the volume of blood flow in brain energy metabolism and ischemic brain district; suppress nerve cell apoptosis; and have certain anti-cerebral thrombosis and antiplatelet aggregative activity (J.Neurol.Sci.; 2007,260,106).Other has document to show; butylphthalide is by influencing arachidonic acid (AA) metabolism; selectivity suppresses the multiple pathophysiological process of AA and meta-bolites mediation thereof, can remove the 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; neural function is repaired by neuroprotective unit.(J.Cardiovasc.Pharmacol.，2004，43，876；Acta?Pharmacol.Sin.，1998，19，117)。
NBP
Yet the NBP anti thrombotic action is weaker than acetylsalicylic acid, often itself and certain antithrombotic reagent is united use (cardiovascular and cerebrovascular disease control, 2009,9,29) clinically.Therefore, in order to strengthen the antithrombotic effect of NBP, need research and development to have the novel cpd of the 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, this compounds has good anticoagulant activity, therefore, they can be used for preventing and treatment and the unusual relative disease of biologically active pdgf, and this class disease comprises ischemic cerebrovascular, hyperlipidemia, atherosclerosis, hypertension, congested heart rate depletion, coronary heart disease, diabetes and complication, metabolic syndrome etc.
The The compounds of this invention structure is shown in general formula I, and it has enantiomorph and diastereo-isomerism body structure.
Wherein:
When X represented sulphur atom, R represented 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 represented selenium atom, R represented 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, the described compound of general formula I or its enantiomorph, diastereomer and pharmacy acceptable salt thereof is characterized in that in the 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-go on foot ground, the described compound of general formula I is preferably from following compounds:
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, the described compound of general formula I is further preferably from following compounds:
3-normal-butyl benzo [c] thienone (compound number: I
1, down together);
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 constituted intact part of the present invention.
Another object of the present invention is to provide the preparation method of the described compound of general formula I of the present invention, it is characterized by and be, comprise the steps:
A) when X is sulphur atom, the preparation method that the 3-shown in the general formula I replaces the sulfo-homologue of benzo [c] furanone comprises the steps:
With the Tetra hydro Phthalic anhydride is starting raw material, mix stirring 5h with nine hydrated sodium sulfides, add water and dilute hydrochloric acid and obtain benzo [c] thiophene-1,3-diketone (II), II makes compound (III) with corresponding Grignard reagent (RMgBr) reaction, and III makes target compound (I) at last under the hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, R's is described as defined above;
B) when X is selenium atom, the preparation that the 3-shown in the general formula I replaces the seleno homologue of benzo [c] furanone comprises the steps:
With the phthalyl chloride is starting raw material, stirs 5h in the mixed solution with its adding selenium powder and lithium aluminum hydride, adds water and dilute hydrochloric acid and obtains benzo [c] selenophen-1,3-diketone (IV); IV and corresponding Grignard reagent (RMgBr) react compound (V), V is converted into target compound (I) at last under the hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, R's is described as defined above;
Preparation formula V compound is characterised in that, Grignard reagent (RMgBr) and benzo [c] selenophen-1, and the mol ratio of 3-diketone (IV) charging capacity is 2-3; The temperature of reaction that adopts is 25-70 ℃; The preparation target compound (I) be characterised in that, hydroiodic acid HI and compound (III) or (V) mol ratio of charging capacity be 3-5; The temperature of reaction that adopts is 100-125 ℃.
These compounds can be according to conventional isolation technique purifying in addition, and available if desired conventional isolation technique is separated into their isomer.
Further purpose of the present invention is to provide a kind of compound of Formula I of effective dosage or pharmaceutical composition of its enantiomorph, diastereomer and pharmacy acceptable salt thereof and carrier of containing.
A further object of the present invention provides 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 preparing prevention and treating ischemic cardiovascular and cerebral vascular disease and improve heart and brain cycle penalty 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 the compound molecule are replaced with sulphur or selenium atom, can improve the lipotropy of molecule usually, and cause electrostatic variation in the 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 and the result of platelet aggregation activity:
Experimental technique: get 2 of rabbit, use lignocaine toponarcosis, operation separates arteria carotis communis and gets blood, take the anti-freezing in 1: 9 of 3.8% Sodium Citrate, with the centrifugal 10min of 500r/min, preparation platelet rich plasma (PRP), remainder is centrifugal with 3000r/min again, preparation platelet poor plasma (PPP) carries out platelet aggregation test by turbidimetry.Adding PRP 240 μ L and different concns are subjected to reagent thing 30 μ L in the mensuration pipe, temperature is incubated 5min, be inductor with 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) respectively, MA in the observed and recorded 5min.(NS) compares with physiological saline, calculates the inhibiting rate (%) of each test-compound:
Inhibiting rate (%)=[MA in MA in the control group 5min-testing sample group 5min]/[MA in the control group 5min] * 100%.
Test result: listed part of compounds in the table 1 to ADP and AA inductive rabbit platelet aggregation activity data, positive control drug is normal-butyl phthalide (NBP).
Table 1. part of compounds of the present invention to the inhibition activity of ADP and AA inductive rabbit platelet aggregation (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-that 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 fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1
Benzo [c] thiophene-1,3-diketone synthetic
Add 15.0g (0.1mol) Tetra hydro Phthalic anhydride and 30.0g (0.125mol) nine hydrated sodium sulfides in the exsiccant round-bottomed flask, mechanical stirring 5h under the room temperature has a large amount of hydrogen sulfide to produce in the whole process and reaction system becomes liquid gradually.Reaction finishes and slowly adds 200mL distilled water, continues under the room temperature 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, drying obtain 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 the exsiccant three-necked bottle, put into 4.84g (0.20mol) magnesium powder and 20mL anhydrous diethyl ether, add small amount of bromine ethane with initiation reaction, continue dripping bromine ethane then until the completely dissolve of magnesium powder, the adding total amount of monobromethane is 21.8g (0.20mol), backflow 1h cools off stand-by.Contain 16.4g (0.10mol) benzo [c] thiophene-1 to 250mL, dropwise add this Grignard reagent in the anhydrous ether solution of 3-diketone, drip and finish, reflux 1h, cooling stirring at room 8h.The cancellation of the careful 150mL of adding saturated ammonium chloride solution is reacted in this mixture, adds 5% dilute hydrochloric acid then and transfers pH 2-3, tells organic phase, and water is used extracted with diethyl ether three times again, merges organic phase, boils off solvent behind the 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 the 10mL Glacial acetic acid, adds 5mL 57% hydroiodic acid HI solution, be warming up to 125 ℃ and stir 0.5-1h.The cooling back adds 150mL 5% sodium sulfite solution in reaction mixture, water layer extracted with diethyl ether three times merge organic phase, boil off solvent behind the 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, and 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, and 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, and 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, and 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, and 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
Add selenium powder 10.4g (0.13mol) and lithium aluminum hydride 5.0g (0.13mol) in containing the 250mL round-bottomed flask of anhydrous tetrahydro furan 50mL, 0 ℃ is stirred 0.5h down.In reaction system, add phthalyl chloride 26.4g (0.13mol), stirring at room 5h.Reaction finishes the careful 150mL of adding water, uses ethyl acetate extraction three times, merges organic phase, boils off solvent behind the 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 the exsiccant 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, continue to add n-propyl bromide then until the completely dissolve of magnesium powder, the adding total amount of n-propyl bromide is 2.75g (22.8mmol), reflux 1h cools off stand-by.Contain 2.4g (11.4mmol) benzo [c] thiophene-1 with dropwise adding 50mL in this Grignard reagent, in the anhydrous ether solution of 3-diketone, drip and finish, reflux 1h, cooling stirring at room 8h.The cancellation of the careful 50mL of adding saturated ammonium chloride solution is reacted in this mixture, adds 5% dilute hydrochloric acid then and transfers pH 2-3, tells organic phase, and water is used extracted with diethyl ether three times again, merges organic phase, boils off solvent behind the 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 the 5mL Glacial acetic acid, and 0.5mL adds 57% hydroiodic acid HI solution, is warming up to 125 ℃ and stirs 0.5-1h.The cooling back adds 15mL 5% sodium sulfite solution in reaction mixture, water layer extracted with diethyl ether three times merge organic phase, boil off solvent behind the 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, and 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 (10)
1. the compound shown in the general formula I or its enantiomorph, diastereomer and pharmacy acceptable salt thereof:
Wherein:
When X represented sulphur atom, R represented 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 represented selenium atom, R represented C
1-C
10Straight chained alkyl, C
3-C
10Branched-chain alkyl or (CH
2)
nPhenyl, wherein n represents the integer of 0-6.
2. compound of Formula I according to claim 1 or its enantiomorph, diastereomer and pharmacy acceptable salt thereof is characterized in that:
X represents sulphur atom or selenium atom;
R represents C
4-C
8Straight chained alkyl, C
3-C
8Branched-chain alkyl or benzyl.
3. compound of Formula I according to claim 1 is characterized in that, described compound is selected from:
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.
4. compound of Formula I according to claim 1 is characterized in that, described compound is further certainly preferred:
3-normal-butyl benzo [c] thienone;
3-n-pentyl benzo [c] thienone;
3-n-hexyl benzo [c] thienone;
3-n-pentyl benzo [c] selenophen ketone;
3-n-hexyl benzo [c] selenophen ketone;
3-n-heptyl benzo [c] selenophen ketone.
5. the preparation method of the described compound of Formula I of claim 1 is characterized in that:
A) when X is sulphur atom, the preparation method of compound shown in the general formula I comprises the steps:
With the Tetra hydro Phthalic anhydride is starting raw material, mix stirring 5h with nine hydrated sodium sulfides, add water and dilute hydrochloric acid and obtain benzo [c] thiophene-1,3-diketone (II), II makes compound (III) with corresponding Grignard reagent (RMgBr) reaction, and III makes target compound (I) at last under the hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, R's is described as defined above;
B) when X is selenium atom, the preparation of compound shown in the general formula I comprises the steps:
With the phthalyl chloride is starting raw material, stirs 5h in the mixed solution with its adding selenium powder and lithium aluminum hydride, adds water and dilute hydrochloric acid and obtains benzo [c] selenophen-1,3-diketone (IV); IV and corresponding Grignard reagent (RMgBr) react compound (V), V is converted into target compound (I) at last under the hydroiodic acid HI effect; Synthetic route is as follows:
Wherein, R's is described as defined above.
6. method according to claim 5, 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 that adopts is 25-70 ℃.
7. method according to claim 5, the preparation compound of Formula I be characterised in that, hydroiodic acid HI and compound (III) or (V) mol ratio of charging capacity be 3-5; The temperature of reaction that adopts is 100-125 ℃.
8. a pharmaceutical composition wherein contains the described compound of Formula I of the claim 1 for the treatment of significant quantity or its enantiomorph and diastereomer or its pharmacy acceptable salt and carrier.
9. the compound of Formula I of claim 1 or its pharmacy acceptable salt purposes in the medicine of preparation prevention or treatment and platelet aggregation diseases associated.
10. the purposes of claim 9, it is characterized in that compound of Formula I or its pharmacy acceptable salt can be used for the preparation prevention and treat ischemic cardiovascular and cerebral vascular disease and improve heart and brain cycle penalty 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.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739574A (en) * | 2013-12-30 | 2014-04-23 | 浙江工业大学 | Synthetic method of substitutive 5H-furan-2-ketone compound |
| 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 |
| CN112386592A (en) * | 2019-08-13 | 2021-02-23 | 江苏晶立信医药科技有限公司 | Beta-cyclodextrin of 3-n-pentylbenzo [ c ] thiophenone or its derivative clathrate, its preparation method and use |
| CN113754622A (en) * | 2021-10-25 | 2021-12-07 | 大理大学 | Lipid-lowering application of dibenzofuran compound |
| CN115304579A (en) * | 2022-07-19 | 2022-11-08 | 河北海力香料股份有限公司 | Preparation method of 4,4' -biphenyl disulfuric anhydride |
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 |
|---|
| 《J. Nat. Prod.》 20070504 John J. Beck et.al. The Structural Diversity of Phthalides from the Apiaceae 891-900 5-7 第70卷, 第5期 * |
| CHUN-LING LIU ET AL: "dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP", 《JOURNAL OF THE NEUROLOGICAL SCIENCES》, vol. 260, 5 June 2007 (2007-06-05) * |
| JOHN J. BECK ET.AL.: "The Structural Diversity of Phthalides from the Apiaceae", 《J. NAT. PROD.》, vol. 70, no. 5, 4 May 2007 (2007-05-04), pages 891 - 900 * |
| 徐文方等: "《药物设计学》", 31 August 2007, article "第七章 基于生物电子等排体原理的药物设计", pages: 178-183 * |
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|---|---|---|---|---|
| CN103739574A (en) * | 2013-12-30 | 2014-04-23 | 浙江工业大学 | Synthetic method of substitutive 5H-furan-2-ketone compound |
| CN103739574B (en) * | 2013-12-30 | 2015-08-26 | 浙江工业大学 | A kind of synthetic method of 5H-furans-2-ketone compounds of replacement |
| 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 |
| CN112386592A (en) * | 2019-08-13 | 2021-02-23 | 江苏晶立信医药科技有限公司 | Beta-cyclodextrin of 3-n-pentylbenzo [ c ] thiophenone or its derivative clathrate, its preparation method and use |
| CN113754622A (en) * | 2021-10-25 | 2021-12-07 | 大理大学 | Lipid-lowering application of dibenzofuran compound |
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| CN115304579B (en) * | 2022-07-19 | 2023-10-31 | 河北海力恒远新材料股份有限公司 | Preparation method of 4,4' -biphenyl dithioanhydride |
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