CN109503548B - Butylphthalide derivative and preparation method and application thereof - Google Patents

Butylphthalide derivative and preparation method and application thereof Download PDF

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CN109503548B
CN109503548B CN201811597400.XA CN201811597400A CN109503548B CN 109503548 B CN109503548 B CN 109503548B CN 201811597400 A CN201811597400 A CN 201811597400A CN 109503548 B CN109503548 B CN 109503548B
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butylphthalide
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CN109503548A (en
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王晓丽
尹健
毕永馨
尹文文
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a butylphthalide derivative and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry and pharmacotherapy. The invention relates to the application of butylphthalide derivatives in the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases, platelet aggregation inhibitor, antithrombotic agent, cerebral ischemia inhibitor, dementia inhibitor and atherosclerosis inhibitor. Pharmacological experiment results show that the butylphthalide derivative has excellent platelet aggregation resisting and antithrombotic activity, and can be clinically used for preparing medicines for preventing or treating diseases related to platelet aggregation.

Description

Butylphthalide derivative and preparation method and application thereof
Technical Field
The invention relates to a butylphthalide derivative and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry and pharmacotherapy.
Background
Cerebral ischemia is a rapidly developing injury to brain function resulting from an ischemic, obstructed blood supply to the brain. With the rapid aging of population, the incidence of cerebral ischemia is on a continuously increasing trend, and has become the first leading disability and the second leading death of the world, and the burden on society and families is further increased. The pathogenesis of cerebral ischemia is very complex and is a malignant cascade process with multiple factors, multiple mechanisms and multiple links. Over the years, the mechanisms involved in cerebral ischemia and reperfusion injury have been studied including excitotoxicity, ionic imbalance, oxidative stress, cortical diffusional depolarization, inflammatory responses, and the like. The existing clinical commonly used anti-cerebral ischemia drugs mainly comprise platelet aggregation resistant drugs, thrombolytic drugs, neuroprotective agents, free radical scavengers and the like, and although the drugs can play a certain role through different mechanisms, the drugs have single treatment target and larger toxic and side effects, and cannot achieve satisfactory curative effect when being used alone. Experts and scholars at home and abroad carry out extensive research on pathogenesis and prevention and treatment of cerebral ischemia and make great progress, but practical and effective clinical prevention and treatment measures are still lacked up to now. Therefore, how to adopt a new strategy to research and develop a novel high-efficiency medicine with multiple functions for preventing and treating cerebral ischemia is an important subject which is generally concerned by medical scientists all over the world currently.
NBP racemate (trade name "Enbip") synthesized in 2002 is a new national drug with independent intellectual property in the field of cerebrovascular diseases in China, and 9 domestic and international patents are obtained.
Hydrogen sulfide (Hydrogen sulfide, H)2S) has a wide range of biological effects as a newly discovered endogenous gas signaling molecule. Recent studies have shown that H2S has positive effect on cerebral ischemia-reperfusion injury, and the action mechanism of S is probably as follows: h2S can relax blood vessels and protect nerve cells by improving cerebral blood circulation; furthermore, H2S is an endogenous peroxynitrite scavenger, can block a key path for generating Reactive Oxygen Species (ROS), inhibits the generation of ROS from the source, or reacts with ROS to directly scavenge free radicals; h2S has antioxidant stress effects, and can raise intracellular glutathione level to protect nerve cells from the oxidative toxicity of glutamic acid in a dose-dependent manner. Thus, H2S plays an important role in cerebral ischemic injury.
Disclosure of Invention
The invention discloses a hydrogen sulfide donor type butylphthalide open-loop derivative, a preparation method and application thereof. Pharmacological experiments prove that the compounds have good platelet aggregation resistance and antithrombotic activity. Therefore, they are useful for the prevention and treatment of diseases associated with platelet aggregation, including myocardial infarction, angina pectoris, arrhythmia, coronary heart disease, cerebral ischemia, stroke, cerebral infarction, or ischemic neuro-recurrent disease.
The invention aims to provide a butylphthalide derivative, wherein a hydrogen sulfide molecule is introduced to a carboxyl group of a butylphthalide ring-opening chemical HPBA, and the chemical structural formula of the butylphthalide derivative is shown as a general formula I:
Figure GDA0002510442620000021
wherein:
r represents a hydrogen atom, C1-C8Straight or branched alkyl, NR1R2；
R1And R2Can be the same as orDifferent from each other and independently represent a hydrogen atom, C1-C8Straight or branched alkyl or R1And R2Together with the nitrogen atom to which they are attached form a 5-to 7-membered aliphatic or aromatic heterocyclic ring, which ring radical may be optionally mono-to fully substituted with the following same or different substituents including: c1-C8Straight or branched alkyl, C1-C8Straight or branched alkoxy, hydroxy or halogen;
one chiral center 1 in formula I represents S configuration or R configuration.
In one embodiment of the present invention, R is any one of a hydrogen atom, a methyl group, an ethyl group, a N-propyl group, an isopropyl group, a N-butyl group, an isobutyl group, a tert-butyl group, a N-pentyl group, an isopentyl group, a neopentyl group, a N-hexyl group, an isohexyl group, a dimethylamino group, a diethylamino group, a dipropylamino group, a di-N-butylamino group, a pyrrolyl group, a piperidinyl group, an imidazolyl group, a morphininyl group, a 4-hydroxypiperazinyl group, a 4-methylpiperidinyl group, an N-methylpiperazinyl group, or an N-hydroxyethylpiperazinyl.
In one embodiment of the present invention, the butylphthalide derivative is I1-I8Any one of:
Figure GDA0002510442620000031
in one embodiment of the invention, the butylphthalide derivative includes enantiomers and diastereomers of the compound, as well as addition salts thereof with a pharmaceutically acceptable acid.
In one embodiment of the invention, the pharmaceutically acceptable acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid.
The second object of the present invention is to provide a method for preparing the above butylphthalide derivative, which comprises:
(1) demethylating anethol trithione (ADT) under a certain temperature and alkaline condition to obtain a hydrogen sulfide donor ADTOH (compound 1);
(2) the (S) -or (R) -NBP is saponified and acidified in a solvent to prepare a lactone ring-opening product (S) or (R) -HPBA (compound 2), and then reacts with alkyl acyl chloride to form ester to obtain an ester compound (compound 3);
or reacting with chloroacetyl chloride to obtain ester compound (compound 4) containing chlorine substitution, and reacting with amine compound to obtain SN2, obtaining a nitrogen-containing compound (5 a-g);
(4) and (3) in a solvent, mixing the ester compound (compound 3) or the nitrogen-containing compound (compounds 5a-g) in the step (2), a hydrogen sulfide donor ADTOH and a condensing agent, and esterifying to obtain the target compound butylphthalide derivative.
In one embodiment of the present invention, the synthetic route of the method is as follows:
Figure GDA0002510442620000041
wherein the content of the first and second substances,
r' is selected from hydrogen atom, C1-C8A linear branched alkyl group; r' is selected from NR1R2；
R' is selected from NR1R2；R1And R2May be the same or different and each independently represents a hydrogen atom, C1-C8Straight or branched alkyl or R1And R2Together with the nitrogen atom to which they are attached form a 5-to 7-membered aliphatic or aromatic heterocyclic ring, which ring radical may be optionally mono-to pentasubstituted with the following substituents which may be the same or different, including: c1-C8Straight or branched alkyl, C1-C8Straight or branched alkoxy, hydroxy or halogen;
one chiral center 1 in formula I represents S configuration or R configuration.
In one embodiment of the present invention, the reaction conditions in step (1) are alkaline conditions, the reaction temperature is 200-300 ℃, and the base is potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or pyridine or triethylamine.
In one embodiment of the present invention, the reaction conditions in step (2) are firstly alkaline conditions, the reaction temperature is negative 20 ℃ to reflux, and the base is potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or pyridine or triethylamine; then, under acidic conditions, the acid is hydrochloric acid, citric acid, ascorbic acid and the like.
In one embodiment of the present invention, the solvent in step (2) is one or more of acetonitrile, ethyl acetate, acetone, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide or dioxane.
In one embodiment of the present invention, the reaction conditions in step (3) are alkaline conditions, the reaction temperature is from room temperature to reflux, and the base is potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or pyridine or triethylamine.
In one embodiment of the present invention, the solvent in the step (3) is one or more of acetonitrile, ethyl acetate, acetone, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide or dioxane.
In one embodiment of the present invention, the reaction conditions in step (4) are alkaline conditions, the reaction temperature is negative 20 ℃ to reflux, and the base is triethylamine, pyridine, 4-dimethylaminopyridine or N, N-diisopropylmethylamine.
In one embodiment of the present invention, the solvent in the step (4) is one or more of acetonitrile, ethyl acetate, acetone, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide or dioxane.
In one embodiment of the present invention, the condensing agent of step (4) is N, N' -dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1-hydroxybenzotriazole or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
In one embodiment of the present invention, the obtained intermediate compound or the target compound can be purified according to conventional separation techniques.
In one embodiment of the invention, the process further comprises converting the resulting butylphthalide derivative into an addition salt with a pharmaceutically acceptable acid.
In one embodiment of the present invention, the butylphthalide derivative can be used alone or in combination with a pharmaceutically acceptable carrier or diluent according to the standard pharmaceutical method.
The third purpose of the invention is to provide a pharmaceutical composition, which comprises the butylphthalide derivative.
In one embodiment of the present invention, the butylphthalide derivative in the pharmaceutical composition comprises an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the dosage form of the pharmaceutical composition comprises any one of injection, lyophilized powder for injection, controlled release injection, liposome injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
In one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutical carrier and/or a pharmaceutical excipient.
In one embodiment of the present invention, the drug carrier comprises any one of a microcapsule, a microsphere, a nanoparticle, and a liposome.
The fourth purpose of the invention is to provide the application of the butylphthalide derivative in preparing a medicament for preventing or treating diseases related to platelet aggregation.
The fifth purpose of the invention is to provide a pharmaceutical preparation for preventing or treating the ischemic cardiovascular and cerebrovascular diseases, which comprises the butylphthalide derivative or the pharmaceutical composition.
The sixth purpose of the invention is to provide a pharmaceutical preparation for improving cardio-cerebral circulatory disturbance, which comprises the butylphthalide derivative or the pharmaceutical composition.
The seventh object of the present invention is to provide an anti-platelet aggregation or anti-thrombosis pharmaceutical preparation, which comprises the above butylphthalide derivative or pharmaceutical composition.
An eighth object of the present invention is to provide an anti-dementia pharmaceutical preparation comprising the above butylphthalide derivative or the pharmaceutical composition.
In one embodiment of the invention, the mode of administration of the pharmaceutical formulation or pharmaceutical composition comprises oral, parenteral or topical administration.
In one embodiment of the present invention, parenteral administration includes, but is not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and transdermal administration.
The invention has the beneficial effects that:
(1) the butylphthalide derivative is safe and effective, and has good platelet aggregation inhibiting and antithrombotic activity. Wherein the inhibitor has ADP-induced platelet aggregation inhibiting activity IC50Can reach 0.09mM, and has significance superior to NBP and TiCld; at the same time, for AA-induced anti-platelet aggregation and inhibition activity IC50Up to 0.10 mM. In addition, the survival rate of the butylphthalide derivative in the 160mg/kg dose can reach 66.7 percent, the survival rate of the butylphthalide derivative in the 386mg/kg dose can reach 73.3 percent, and the butylphthalide derivative has stronger effect of inhibiting the formation of acute pulmonary thrombosis of mice than NBP or the compound II.
(2) The chemical synthesis method of the butylphthalide derivative is simple and easy to implement, and the price of the required medicine is low.
Drawings
FIG. 1 shows Compound I1Influence on the arteriovenous bypass thrombosis of rats.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 Compound I1Preparation of
Compound 3(1.0mmol) was dissolved in 20m L anhydrous dichloromethane and DCC (1.1mmol) and catalytic amount of DMAP were added with stirring to react at room temperature for 0.5h, then compound 1(1.0mmol) was added and reacted at room temperature for 6-8h, after completion of the reaction, filtration, concentration under reduced pressure and flash column chromatography (PE/EtOAc 15/1-5/1, v/v) gave 366mg of an orange solid product in 80% yield.
mp 94–96℃.MS(ESI):m/z 459.1[M+H]+.IR(cm-1,KBr):νmax763,1170,1254,1492,1731.1H NMR(300Hz,CDCl3):0.87(t,3H,CH3,J＝6.8Hz),1.26–1.50(m,4H,2×CH2),1.83–1.88(m,2H,CH2),2.08(s,3H,OOCCH3),4.53(t,2H,OCH2,J＝6.0Hz),6.65(t,1H,CH,J＝6.6Hz),7.40–7.44(m,3H,ArH),7.45(s,1H,C＝CH),7.60–7.65(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75Hz,CDCl3):170.4,164.7,153.8,144.7,136.1,133.4,130.6,130.3,129.4,129.4,128.3,128.3,127.4,126.6,123.3,115.2,72.7,36.3,28.0,22.5,21.2,13.9.HRMS(ESI):m/zcalcd for C23H22O4S3,[M+H]+459.0680；found459.0761.
EXAMPLE 2 Compound I2Preparation of
Compound 5a (1.0mmol) was dissolved in 20m L anhydrous dichloromethane and DCC (1.1mmol) and catalytic amount of DMAP were added with stirring to react at room temperature for 0.5h, then compound 1(1.0mmol) was added and reacted at room temperature for 6-8h, after completion of the reaction, filtration, concentration under reduced pressure and flash column chromatography (PE/EtOAc 15/1-5/1, v/v) gave 434mg of product as an orange oil in 84% yield.
MS(ESI):m/z 502.3[M+H]+.IR(cm-1,KBr):νmax764,1169,1276,1490,1739.1H NMR(300Hz,CDCl3):0.85(t,3H,CH3,J＝6.8Hz),1.26–1.45(m,4H,2×CH2),1.86–1.90(m,2H,CH2),2.33(s,6H,CH3NCH3),3.20–3.21(m,2H,OCOCH2N),6.65(t,1H,CH,J＝6.4Hz),7.40–7.45(m,3H,ArH),7.46(s,1H,C＝CH),7.60–7.62(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.1,164.7,153.8,144.5,136.1,133.3,130.7,130.4,129.4,128.3,127.9,127.1,126.7,123.3,123.1,72.8,45.2,45.2,36.3,28.0,25.6,22.4,13.9.HRMS(ESI):m/zcalcd for C25H27NO4S3,[M+H]+calcd 502.1102；found502.1184.
EXAMPLE 3 Compound I3Preparation of
Dissolving compound 5b (1.0mmol) in 20m L anhydrous dichloromethane, adding DCC (1.1mmol) and catalytic amount of DMAP with stirring, reacting at room temperature for 0.5h, adding compound 1(1.0mmol), reacting at room temperature for 6-8h, filtering, concentrating under reduced pressure, and performing flash column chromatography (PE/EtOAc 15/1-5/1, v/v) to obtain 434mg of orange oily product with 82% yield.
MS(ESI):m/z 530.2[M+H]+.IR(cm-1,KBr):νmax764,1169,1400,1491,1738.1H NMR(300Hz,CDCl3):0.85(t,3H,CH3,J＝6.8Hz),0.98(t,6H,2×NCH2CH 3,J＝7.1Hz),1.26–1.45(m,4H,2×CH2),1.86–1.96(m,2H,CH2),2.65(q,4H,2×NCH 2CH3,J＝7.1Hz),3.32–3.47(m,2H,OCOCH2N),6.63(t,1H,CH,J＝6.5Hz),7.40–7.43(m,3H,ArH),7.44(s,1H,C＝CH),7.60–7.62(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.1,164.7,153.8,144.7,136.1,133.3,130.7,130.4,128.5,128.3,127.9,127.5,127.1,126.7,123.3,123.1,72.6,54.2,47.6,36.4,28.0,22.4,22.4,13.9,12.3.HRMS(ESI):m/zcalcd for C27H31NO4S3,[M+H]+530.1415；found 530.1495.
EXAMPLE 4 Compound I4Preparation of
Dissolving compound 5c (1.0mmol) in 20m L anhydrous dichloromethane, adding DCC (1.1mmol) and catalytic amount of DMAP under stirring, reacting at room temperature for 0.5h, adding compound 1(1.0mmol), reacting at room temperature for 6-8h, filtering, concentrating under reduced pressure, and performing flash column chromatography (PE/EtOAc 15/1-5/1, v/v) to obtain 422mg of orange oily product with 80% yield.
MS(ESI):m/z 528.2[M+H]+.IR(cm-1,KBr):νmax764,1169,1276,1490,1738.1H NMR(300Hz,CDCl3):0.86(t,3H,CH3,J＝6.7Hz),1.26–1.28(m,4H,2×NCH2CH 2),1.32–1.45(m,4H,2×CH2),1.87–1.92(m,2H,CH2),2.62(q,4H,2×NCH2,J＝7.1Hz),3.32–3.45(m,2H,OCOCH2N),6.62(t,1H,CH,J＝6.6Hz),7.40–7.43(m,3H,ArH),7.44(s,1H,C＝CH),7.60–7.61(m,2H,ArH),7.73–7.75(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.3,164.7,153.8,144.6,136.1,133.3,130.7,129.4,128.7,128.3,127.5,123.3,117.3,72.8,56.9,53.9,36.3,31.9,29.7,28.0,23.8,22.7,22.4,14.1,13.9.HRMS(ESI):m/zcalcd for C27H29NO4S3,[M+H]+530.1259；found 528.1341.
EXAMPLE 5 Compound I5Preparation of
Dissolving compound 5d (1.0mmol) in 20m L anhydrous dichloromethane, adding DCC (1.1mmol) and catalytic amount of DMAP with stirring, reacting at room temperature for 0.5h, adding compound 1(1.0mmol), reacting at room temperature for 6-8h, filtering, concentrating under reduced pressure, and performing flash column chromatography (PE/EtOAc 15/1-5/1, v/v) to obtain 454mg of an orange oily product with 84% yield.
MS(ESI):m/z 542.2[M+H]+.IR(cm-1,KBr):νmax764,1169,1276,1490,1739.1H NMR(300Hz,CDCl3):0.86(t,3H,CH3,J＝6.7Hz),1.26–1.28(m,4H,2×NCH2CH 2),1.42–1.43(m,4H,2×CH2),1.57–1.61(m,2H,NCH2CH2CH 2),1.81–1.91(m,2H,CH2),2.50(q,4H,2×NCH2,J＝7.1Hz),3.16–3.30(m,2H,OCOCH2N),6.60(t,1H,CH,J＝6.6Hz),7.40–7.43(m,3H,ArH),7.43(s,1H,C＝CH),7.60–7.61(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.8,169.1,163.7,152.9,143.8,135.1,132.4,129.7,128.4,127.4,127.0,126.5,125.7,122.1,117.3,71.8,59.4,53.3,36.3,35.4,27.1,24.9,22.9,21.5,14.1,13.0.HRMS(ESI):m/zcalcd for C28H31NO4S3,[M+H]+542.1415；found542.1497.
EXAMPLE 6 Compound I6Preparation of
Compound 5e (1.0mmol) was dissolved in 20m L anhydrous dichloromethane and DCC (1.1mmol) and catalytic amount of DMAP were added with stirring to react at room temperature for 0.5h, then compound 1(1.0mmol) was added and reacted at room temperature for 6-8h, after completion of the reaction, filtration, concentration under reduced pressure and flash column chromatography (PE/EtOAc 15/1-5/1, v/v) gave 434mg of product as an orange oil in 80% yield.
MS(ESI):m/z 544.1[M+H]+.IR(cm-1,KBr):νmax764,1169,1400,1491,1739.1H NMR(300Hz,CDCl3):0.86(t,3H,CH3,J＝6.8Hz),1.42–1.43(m,4H,2×CH2),1.85–1.92(m,2H,CH2),2.50(q,4H,2×NCH2,J＝7.0Hz),3.18–3.48(m,2H,OCOCH2N),3.70–3.73(m,4H,2×OCH2),6.63(t,1H,CH,J＝6.5Hz),7.40–7.43(m,3H,ArH),7.43(s,1H,C＝CH),7.60–7.61(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):169.6,164.7,157.7,154.0,144.5,136.1,133.4,130.7,128.3,127.6,126.6,123.3,116.9,73.0,66.8,59.7,53.3,36.3,35.4,28.0,24.9,22.4,21.5,14.1,13.0.HRMS(ESI):m/zcalcd for C27H29NO5S3,[M+H]+544.1208；found 544.1288.
EXAMPLE 7 Compound I7Preparation of
Compound 5f (1.0mmol) was dissolved in 20m L anhydrous dichloromethane and DCC (1.1mmol) and catalytic amount of DMAP were added with stirring to react at room temperature for 0.5h, then compound 1(1.0mmol) was added and reacted at room temperature for 6-8h, after completion of the reaction, filtration, concentration under reduced pressure and flash column chromatography (PE/EtOAc 15/1-5/1, v/v) gave 454mg as an orange oil in 84% yield.
MS(ESI):m/z 557.2[M+H]+.IR(cm-1,KBr):νmax764,1169,1400,1491,1739.1H NMR(300Hz,CDCl3):0.86(t,3H,CH3,J＝6.7Hz),1.26–1.28(m,4H,2×NCH2CH 2),1.42–1.44(m,4H,2×CH2),1.81–1.89(m,2H,CH2),2.33(s,3H,NCH3),2.50(m,8H,4×NCH2),3.16–3.32(m,2H,OCOCH2N),6.62(t,1H,CH,J＝6.6Hz),7.40–7.43(m,3H,ArH),7.43(s,1H,C＝CH),7.60–7.61(m,2H,ArH),7.73–7.76(m,2H,ArH),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.8,169.1,163.7,152.9,143.8,135.1,132.4,129.7,128.4,127.4,126.5,126.0,122.1,117.3,71.8,57.3,55.6,46.6,36.3,35.4,27.1,24.9,22.9,21.5,14.1,13.0.HRMS(ESI):m/zcalcd for C28H32N2O4S3,[M+H]+557.1524；found 557.1690.
EXAMPLE 8 Compound I8Preparation of
Compound 5g (1.0mmol) was dissolved in 20m L anhydrous dichloromethane, DCC (1.1mmol) and catalytic amount of DMAP were added with stirring and reacted at room temperature for 0.5h, compound 1(1.0mmol) was added and reacted at room temperature for 6-8h, after completion of the reaction, filtration, concentration under reduced pressure and flash column chromatography (PE/EtOAc 15/1-5/1, v/v) gave 454mg as an orange oil in 84% yield.
MS(ESI):m/z 525.3[M+H]+.IR(cm-1,KBr):νmax764,1169,1400,1491,1739.1H NMR(300Hz,CDCl3):0.86(t,3H,CH3,J＝6.7Hz),1.42–1.44(m,4H,2×CH2),1.81–1.89(m,2H,CH2),4.24–4.42(m,2H,OCOCH2N),6.62(t,1H,CH,J＝6.6Hz),6.77(d,1H,C＝CH,J＝6.8Hz),7.11(d,1H,NCH＝,J＝6.8Hz),7.40–7.43(m,3H,ArH),7.43(s,1H,C＝CH),7.60–7.61(m,2H,ArH),7.73–7.76(m,2H,ArH),7.83(s,1H,NCH＝N),8.12(d,1H,ArH,J＝7.8Hz).13C NMR(75MHz,CDCl3):170.8,169.1,163.7,152.9,143.8,137.8,132.4,129.7,128.1,127.4,126.5,126.0,122.1,119.1,71.8,57.3,55.6,46.6,36.3,35.4,27.1,24.9,22.9,21.5,14.1,13.0.HRMS(ESI):m/zcalcd for C26H24N2O4S3,[M+H]+525.0898；found 525.1002.
Example 9 in vitro anti-platelet aggregation Activity Studies
The experimental method comprises the following steps: 10 male rabbits with the weight of 2.0-2.5 kg. Animals were raised at 25 ℃ and 60-75% relative humidity for 1 week and used for experiments. Collecting 2 rabbits, performing local anesthesia with lidocaine, collecting blood from common carotid artery by operation, collecting 3.8% sodium isoascorbate 1:9, centrifuging at 500r/min for 10min to obtain Platelet Rich Plasma (PRP), and collecting the restAdding PRP 240 mu L and test drug 30 mu L with different concentrations into a measuring tube, incubating for 5min, respectively taking 30 mu L Adenosine Diphosphate (ADP) (final concentration is 10 mu mol/L), 30 mu L thrombin (final concentration is 0.5U/m L) and 30 mu L Arachidonic Acid (AA) (final concentration is 1 mmol/L) as inducers, observing and recording the maximum aggregation rate within 5min, and calculating the inhibition rate (%) or IC of each test compound by using physiological saline (NS) as a control50The value is obtained.
Inhibition (%) ([ maximum aggregation rate within 5min of control group-maximum aggregation rate within 5min of sample group to be tested ]/[ maximum aggregation rate within 5min of control group ] × 100%.
And (3) testing results: the data of ADP and AA induced platelet aggregation activity of the compounds of the invention are listed in Table 1, and positive control drugs are NBP, Aspirin (ASP) and ticlopidine (Ticlid).
TABLE 1 inhibitory Activity of the Compounds of the present invention on ADP, AA induced platelet aggregation in rabbits
Figure GDA0002510442620000101
The pharmacological data show that the compounds have better inhibition effects on platelet aggregation induced by different inducers, and the inhibition effects on platelet aggregation are stronger than NBP and TiCld. Compound I1For ADP-induced anti-platelet aggregation, I1The inhibiting activity (0.09mM) of the compound is remarkably superior to NBP (0.73mM) and TiCld (0.36 mM); also, for AA-induced anti-platelet aggregation, I1The inhibitory activity (0.10mM) of (D) was also significantly better than NBP (0.58mM) and slightly better than ASP (0.14 mM).
EXAMPLE 10 active Compound I1Effect on pulmonary thrombosis in mice
The experimental method comprises the following steps: selecting male ICR mice with the weight of 30-35 g, and randomly dividing the mice into 12 groups according to the weight, wherein each group comprises 10 mice. Control group: i.g. 10% DMSO; aspirin (ASP) group: i.g. 160mg/kg; NBP group: i.g. 160mg/kg; test Compound I1Low and high dose groups (Low dose with NBP as Positive drug in equimolar amounts)Dose, high dose, equal weight to the positive drug NBP) for 7 days, 2h after the last dose, a mixed inducer containing 1mg/m L Type I collagen and 44.5 μ g/m L epinephrine hydrochloride is injected rapidly through the tail vein, the dose is 10m L/kg body weight, and the number of mice that die within 5min or the number of mice that have not recovered hemiplegia within 15min is observed and recorded.
And (3) testing results: table 2 shows the compounds I according to the invention1Effects on pulmonary thrombosis in mice, positive control drugs were NBP, Aspirin (ASP) and ticlopidine (Ticlid).
TABLE 2 Compounds I of the invention1Effect on pulmonary thrombosis in mice
Figure GDA0002510442620000102
Figure GDA0002510442620000111
As can be seen from Table 2, after 7 days of continuous administration of ICR mice (15 mice per group), the number of animal deaths caused by in vivo thrombosis induced by collagen-epinephrine injection within 5min and the number of unrecoverable paraplegic mice within 15min were reduced and varied from the blank group. Wherein: blank control group (12 deaths, survival rate of 20.0%), NBP administration group (160mg/kg, 7 deaths, survival rate of 53.3%), ASP administration group (160mg/kg, 6 deaths, survival rate of 60.0%), I1Equal weight administration group (160mg/kg, 5 deaths, survival rate 66.7%), I1Equimolar dosing group (386mg/kg, 4 deaths, 73.3% survival). This shows that I1Compared with NBP, the compound has stronger effect of inhibiting the formation of acute pulmonary thrombosis of mice, is equivalent to ASP, and has concentration dependence.
EXAMPLE 11 active Compound I1Effect on rat arteriovenous bypass thrombosis
The experimental steps are as follows: SD rats with the weight of 250-300 g are selected, and the SD rats are divided into 6 groups according to the weight of each half, and 10 rats in each group. Control group: i.g. 10% DMSO; aspirin (ASP) group: i.g. 80mg/kg; NBP group: i.g. 80mg/kg; to be receivedTest Compound I1The low dose and the high dose groups (the low dose is equal to the molar amount of the positive drug NBP, the high dose is equal to the weight of the positive drug NBP) are continuously administrated for 7 days, 2 hours after the last administration, a 3% pentobarbital sodium solution (30mg/kg) is injected into the abdominal cavity to anaesthetize the rat, the rat is fixed in a supine position, a median cervical incision is made, the right common carotid artery and the left external jugular vein are separated, a 6cm long silk thread (the silk thread needs to be weighed before being placed into the lumen) is placed in the middle section of a polyethylene tube, the polyethylene tube is filled with heparin physiological saline (50U/m L), the polyethylene tube is inserted into the separated blood vessel, the vena cava is made to form a loop, the silk thread is taken out after the blood flow is opened for 15 minutes, the residual blood is sucked by filter paper and then weighed immediately, and.
And (3) testing results: in FIG. 1, compounds I according to the invention are shown1The positive control drugs include NBP, Aspirin (ASP) and ticlopidine (Ticlid).
As can be seen in FIG. 1A, after 7 days of continuous administration to rats, I1The moisture content of thrombus formed by the groups (21.03 +/-4.24 mg, 24.07 +/-3.82 mg) dosed with equimolar amount and equal weight is lower than that of thrombus formed by the blank control group (33.83 +/-1.48 mg), and is lower than that of the group (28.75 +/-2.27 mg) dosed with NBP but slightly higher than that of the group (21.40 +/-1.86 mg) dosed with ASP. The results for thrombus dry weight are similar. The above results show that Compound I1Can obviously inhibit the formation of thrombus and is obviously higher than NBP with equal molar dose. In addition, the formation of mixed thrombus in the experimental model is generated by a series of active factors released by the injury of the vascular endothelium of the carotid artery of the rat, and platelet aggregation caused by the activation of platelets and white blood cells. Thus, suppose I1The antithrombotic mechanism of action is likely to be associated with anti-platelet aggregation.
Comparative example 1:
referring to example 9, data on ADP, AA-induced platelet aggregation activity in rabbits were determined for compounds of formula II. The results are shown in Table 3
The chemical structural formula of compound II is shown below:
Figure GDA0002510442620000121
wherein II1：n＝2；II2：n＝3；II3：n＝4；II4：n＝5；II5：n＝6；II6：n＝8；II7：n＝12。
TABLE 3 inhibitory Activity Effect of Compound II on ADP, AA induced platelet aggregation in rabbits
Figure GDA0002510442620000122
As can be seen from Table 3, for Compound II containing a carbon chain linker arm1-II7Wherein the platelet aggregation inhibitory activity is increased (n-2-6) and then decreased (n-6, 8,12) with an increase in the length of the carbon chain, and compound II5The inhibition effect of (n-6) is most prominent. However, and compound I1Compared with, II5(0.15mM) was less inhibitory to ADP-induced platelet aggregation than I1(0.09mM), and, in addition, II5The inhibition of AA-induced platelet aggregation was also inferior to that of I1。
With reference to example 10, compound II was assayed5Effect on pulmonary thrombosis in mice. The results are shown in Table 4.
TABLE 4 Effect of Compound II on pulmonary thrombosis in mice
Figure GDA0002510442620000123
Figure GDA0002510442620000131
As can be seen from Table 4, after ICR mice (15 mice per group) were continuously administered for 7 days, the number of animal deaths caused by in vivo thrombosis induced by collagen-epinephrine injection within 5min and the number of unrecoverable mice with paraplegia within 15min were both reduced and varied from the blank group. Compound II5Equal weight administration group (160mg/kg, 6 deaths, survival rate 60.0%), II5Equimolar dosing group (386mg/kg, 5 deaths, stockThe activity rate was 67.7%). However, the compounds I1Equal weight administration group (160mg/kg, 5 deaths, survival rate 66.7%), I1The equimolar dose group (386mg/kg, 4 deaths, 73.3% survival rate) is better than II5. This shows that I1Has better effect on inhibiting the formation of acute pulmonary thrombosis of mice than II5Strong and there is a concentration dependence.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (10)

1. A butylphthalide derivative for use in the preparation of a medicament for the prevention or treatment of a disorder associated with platelet aggregation, wherein the butylphthalide derivative has the chemical structure according to formula I:
Figure 380856DEST_PATH_IMAGE001
，
wherein:
r is selected from hydrogen atom and C1-C8Straight or branched alkyl, NR1R2；
R1And R2Can be the same or different and are each independently selected from a hydrogen atom, C1-C8A linear or branched alkyl group;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-to 7-membered aliphatic or aromatic heterocyclic ring, which ring group may be optionally substituted with the same or different substituents as follows, wherein the substituents are selected from: c1-C8Straight or branched alkyl, C1-C8Straight or branched alkoxy, hydroxy or halogen;
in the formula I, one chiral center 1 isSConfiguration orRConfiguration.
2. The butylphthalide derivative according to claim 1, wherein R is any one of a hydrogen atom, a methyl group, an ethyl group, a N-propyl group, an isopropyl group, a N-butyl group, an isobutyl group, a tert-butyl group, a N-pentyl group, an isopentyl group, a neopentyl group, a N-hexyl group, an isohexyl group, a dimethylamino group, a diethylamino group, a dipropylamino group, a di-N-butylamino group, a pyrrolyl group, a piperidinyl group, an imidazolyl group, a morphininyl group, a 4-hydroxypiperazinyl group, a 4-methylpiperidinyl group, an N-methylpiperazinyl group, and an N-hydroxyethylpiperazinyl group.
3. A pharmaceutical composition comprising the butylphthalide derivative of claim 1.
4. The pharmaceutical composition of claim 3, wherein the dosage form of the pharmaceutical composition is selected from any one of injection, lyophilized powder for injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
5. The pharmaceutical composition according to claim 3 or 4, wherein the pharmaceutical composition further comprises a pharmaceutical carrier and/or a pharmaceutical excipient.
6. The pharmaceutical composition of claim 5, wherein the drug carrier is selected from any one of microcapsules, microspheres, nanoparticles, and liposomes.
7. A pharmaceutical preparation for preventing or treating ischemic cardio-cerebral diseases, which comprises the butylphthalide derivative of claim 1 or the pharmaceutical composition of any one of claims 3 to 6.
8. A pharmaceutical preparation for improving cardio-cerebral circulatory disorders, which comprises the butylphthalide derivative of claim 1 or the pharmaceutical composition of any one of claims 3 to 6.
9. A pharmaceutical preparation against platelet aggregation or thrombosis comprising the butylphthalide derivative according to claim 1 or the pharmaceutical composition according to any one of claims 3 to 6.
10. An anti-dementia pharmaceutical preparation comprising the butylphthalide derivative according to claim 1 or the pharmaceutical composition according to any one of claims 3 to 6.
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