CN105693689A - Ferulic acid derivatives, preparation and application of ferulic acid derivatives - Google Patents
Ferulic acid derivatives, preparation and application of ferulic acid derivatives Download PDFInfo
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Abstract
The invention provides ferulic acid derivatives adopting a structure shown in formula I or formula II. Starting from the mechanism of various mechanisms causing brain injury after cerebral stroke and the action of ferulic acid in treatment of the cerebral stroke, alkane is taken as a joint arm, ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) and ferulic acid are connected through ether linkage and ester linkage, and the ferulic acid derivatives are obtained. The invention further provides the application of the ferulic acid derivatives in preparation of drugs for preventing and/or treating cerebral stroke diseases.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to a kind of ferulic acid derivative, preparation and application thereof, particularly relate to the application in prevention and/or treatment apoplexy class disease medicament of a kind of ferulic acid derivative。
Background technology
" apoplexy " (cerebralstroke) is also known as " apoplexy ", " cerebrovas-cularaccident " (cerebralvascularaccident, CVA)。It is a kind of acute cerebrovascular disease, is the one group of disease breaking suddenly or causing because angiemphraxis causes blood to cannot flow into brain brain tissue impairment due to cerebral vessels。
Worldwide, apoplexy is the cause of the death being number three in the whole world, is also the primary cause of disease causing adult disability。According to statistics, the U.S. has 50～750,000 people's morbidities every year。In China, apoplexy number of the infected reaches for 2,500,000/year, and death toll reaches for 1,600,000/year。Apoplexy has exceeded myocardial infarction, becomes the primary cause of disease (LiuL, etal., Stroke.2011 that compatriots are dead；42:3651-3654)。Apoplexy not only fatality rate is high, and the patient survived also can leave the sequela such as neurobehavioral function damage and cognitive disorder, causes heavy society and household economy burden, has the advantages that sickness rate height, mortality rate height and disability rate are high。
Apoplexy is broadly divided into two types。More than 70% is ischemia apoplexy, and it refers to that various thrombosis causes cerebrovascular to block in Different brain region, thus causing ischemic brain injury, most common of which is middle cerebral artery blocking。Internal carotid artery and vertebral artery occlusion and the narrow cerebral infarction that causes, the age is many more than 40 years old, and male is many compared with women, and severe patient can cause death。It is additionally the cerebral hemorrhage caused by rupture of blood vessel in brain less than 30%, finally also results in cerebral blood supply insufficiency and ischemic brain injury。Cerebral ischemia is also one of consequence of causing of sudden cardiac arrest。
Compared with the seriousness of apoplexy and the extent of injury, the medicine of current apoplexy is also very limited。Drug therapy clinically mainly has Thrombolytic Drugs, expands blood vessel medicine, platelet aggregation inhibitor and neuroprotective now。Such as, for ischemia apoplexy, internationally recognized sole drug treatment means is with tissue plasminogen activator's acute stage thrombolytic。But owing to the treatment window of tissue plasminogen activator is short and side effect notable (as causing cerebral hemorrhage and aggravation excititoxic etc.), at present can with the patients with cerebral ischemic of tissue plasminogen activator's treatment less than the 5% of patient populations。Existing research is it is also shown that apoplexy can cause a series of cells and Molecular responses mechanism in brain, and these mechanism weave ins ultimately result in brain injury。Such as, the neurological inflammatory injury mechanism that cerebral infarction causes neuronal death or the mechanism of damage mainly have an excessive inflammation response in the neuronal damage that neurotoxicity that overactivity oxygen-derived free radicals produces, excessive excitatory amino acid such as glutamic neuron cause is machine-processed, many Poly ADP-ribose polymerases excessive activation causes neuronal death and the brain that cerebral ischemia causes and causes。These pathology damage mechanism is to the development of apoplexy medicine and develops significant, and has become the important means researching and developing novel Treatment of Cerebral Stroke medicine and strategy for these corresponding medicaments sifting models of pathology damage Mechanism establishing。
To sum up, in view of apoplexy harm is big, and Current therapeutic means are extremely limited, thus research and develop novel stroke prevention and/or medicine is always up the focus of forward position, this area scholar's extensive concern, significant。
Summary of the invention
In view of this, the technical problem to be solved in the present invention is in that to provide a kind of ferulic acid derivative, preparation and application thereof, particularly in the application in prevention and/or treatment apoplexy class disease medicament。Ferulic acid derivative provided by the invention not only has better effect on the neurotoxicity that cell model suppresses excessive glutamate to cause, and can substantially reduce cerebral infarct volume in focal cerebral ischemic in mice animal model, thus there is prevention or therapeutical effect for apoplexy。
The invention provides a kind of ferulic acid derivative, there is the structure shown in Formulas I or Formula II,
Wherein, R is selected from-H or-CH2CH3, m=3～10；
Wherein, n=3～10。
Preferably, described ferulic acid derivative is specially 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester and 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] one or more in last of the ten Heavenly stems ester。
The invention provides the application in preparation prevention and/or treatment apoplexy class disease medicament of the ferulic acid derivative described in a kind of technique scheme any one。
Preferably, described ferulic acid derivative is specially 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester or 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems ester。
Preferably, the apoplexy that described apoplexy includes the apoplexy that caused by cerebral vessels embolism and/or cerebral ischemia causes。
Preferably, described apoplexy includes cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack, sudden cardiac arrest cause one or more in cerebral ischemia, cerebral hemorrhage and cerebral arteriosclerosis apoplexy of causing。
The invention provides a kind of preparation, including ferulic acid compounds and pharmaceutically acceptable adjuvant；
Described ferulic acid compounds is ferulic acid derivative described in any one and/or its pharmaceutically acceptable salt in technique scheme。
Preferably, the dosage form of described preparation is oral formulations, injection, suppository, inhalant or the dosage form that may be directly applied to cerebral ischemia position。
Preferably, the dosage form of described preparation is capsule, microcapsule, tablet, granule, pill, dispersed powders, liquid preparation, soft extract, suspending agent, syrup, gel, aerosol, patch, liposome, oral liquid, intravenous fluid or intramuscular injection。
Preferably, the dosage of described ferulic acid compounds is 0.05mg/kg～90mg/kg。
The invention provides a kind of ferulic acid derivative, there is the structure shown in Formulas I or Formula II, compared with prior art, the present invention causes mechanism and the ferulic acid effect in treatment apoplexy of brain injury from post-stroke number of mechanisms, with alkane for linking arm, by the hydrogen sulfide donor 5-p-hydroxybenzene-3H-1 of slow release, 2-dithiole-3-thioketone (ADT-OH) is connected by ehter bond, ester bond with ferulic acid, obtain Hybrid compounds, i.e. the noval chemical compound (ferulic acid derivative) of Resina Ferulae acids。Thus, the invention provides the application in preparation prevention and/or treatment apoplexy class disease medicament of this ferulic acid derivative, test result indicate that, above-mentioned ferulic acid and the ADT-OH compound by linking arm heterozygosis, not only suppress the neurovirulent effect that excessive glutamate causes to be better than parent compound ADT-OH at cell model；And Hybrid compounds substantially reduces cerebral infarct volume in focal cerebral ischemic in mice animal model, effect is better than ferulic acid, it was shown that this kind of ferulic acid derivative provided by the invention can have prevention and/or the effect for the treatment of for apoplexy。
Accompanying drawing explanation
Fig. 1 is the SYX-I of 3h intraperitoneal administration 0.22mmol/kg after Reperfu-sion in the MCAO that the present invention makes3Cerebral infarction volume percentage rate。
Detailed description of the invention
In order to be further appreciated by the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but it is to be understood that these describe to be intended merely to and further illustrate the features and advantages of the present invention, rather than the restriction to invention claim。Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes。Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are considered as including in the present invention。Method and the application of the present invention are described already by preferred embodiment, method described herein and application substantially can be modified or suitably change and combination by related personnel in without departing from present invention, spirit and scope, realize and apply the technology of the present invention。
The all raw materials of the present invention, be not particularly limited its source, that commercially buy or prepare according to conventional method well known to those skilled in the art。
The all raw materials of the present invention, are not particularly limited its purity, present invention preferably employs analytical pure or meet medicine purity rubric。
The invention provides a kind of ferulic acid derivative, there is the structure shown in Formulas I or Formula II,
Wherein, R is selected from-H or-CH2CH3, m=3～10；
Wherein, n=3～10。
The definition of described ferulic acid derivative is not particularly limited by the present invention, and with the definition of derivant well known to those skilled in the art, ferulic acid derivative provided by the invention is the compound that a kind of structure is brand-new, i.e. a kind of Resina Ferulae acids noval chemical compound。R independence of the present invention selected from hydrogen or ethyl group, described m can be 3～10, it is possible to is 3～8, it is also possible to is 3～5；N of the present invention can be 3～10, it is possible to is 3～8, it is also possible to is 3～5。
The chemical name of ferulic acid (FerulicAcid) is Ferulic acid, also known as caffeic acid-3-methyl ether, 3-(4-hydroxy 3-methoxybenzene base)-2-acrylic acid, it it is one of the derivant of cinnamic acid (also known as cinnamic acid), there is the structure shown in formula III
Ferulic acid finds at first in the seed of plant and leaf, is a kind of phenolic acid being widely present in plant, becomes the skeleton of cell wall with polysaccharide and protein bound in cell wall。Ferulic acid content in the Chinese crude drugs such as Resina Ferulae, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Rhizoma Cimicifugae, Semen Ziziphi Spinosae is higher, is one of the effective elements of the medicine in these, as one of quality index of Chinese patent medicine。In raw-food material, in coffee, rice husk, chinese cymbidium bean, Testa Tritici and Testa oryzae, ferulaic acid content is also higher。Research in pharmacological effect in recent years is found that pharmacological action and the biological activity of many ferulic acids, and toxicity is relatively low, thus has purposes widely in medicine, health product, cosmetic material and food additive etc.。
The specifically chosen of above-mentioned ferulic acid derivative is not particularly limited by the present invention, those skilled in the art can according to practical situation, effect data and the concrete cause of disease carry out selecting and adjusting, ferulic acid derivative of the present invention has and preferably includes 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester and 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] one or more in last of the ten Heavenly stems ester。
The preparation method of described ferulic acid derivative is not particularly limited by the present invention, preparation method with this compounds well known to those skilled in the art, those skilled in the art can carry out selecting and adjusting according to the situation such as practical situation and product requirement, and ferulic acid derivative of the present invention is preferably by the ester type compound of ferulic acid and ADTO (CH2)zObtain after X (z=3～10, X is halogen) reaction, be specifically as follows ferulic acid ethylester and ADTO (CH2)zObtain after Br reaction。
The invention provides the application in preparation prevention and/or treatment apoplexy class disease medicament of the ferulic acid derivative described in a kind of technique scheme any one。
Described ferulic acid derivative is preferably the above-mentioned compound with Formulas I or Formula II structure by the present invention, more specifically it is preferably 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester or 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems ester。
Described preparation is not particularly limited by the present invention, by well known to those skilled in the art prepare similar medicine in the way of。Described prevention and/or treatment are not particularly limited by the present invention, and with the definition of prevention well known to those skilled in the art and/or treatment, the present invention is preferably prevention, treatment or prevention and treatment。Described apoplexy class disease is had no particular limits by the present invention, with cerebral apoplexy well known to those skilled in the art, apoplexy of the present invention, on Crack cause, it is possible to include the apoplexy that caused by cerebral vessels embolism and/or apoplexy (apoplexy) that cerebral ischemia causes；Described apoplexy specifically can also include cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack, sudden cardiac arrest cause one or more in cerebral ischemia, cerebral hemorrhage and cerebral arteriosclerosis apoplexy of causing, described apoplexy can also be the apoplexy that the cerebrovascular complications such as diabetes cause, wherein said cerebral infarction preferably includes cerebral thrombosis, cerebral embolism or lacunar infarction etc.。
The present invention from ferulic acid treatment apoplexy in effect and apoplexy after the multiple mechanism causing brain injury。Ferulic acid includes in treatment apoplexy effect: antiplatelet aggregation, suppression platelet thrombus element A2(TXA2) generation, alleviating vascular spasm and antioxidation, suppression produce the enzyme of free radical, increase the activity of scavenging free radicals enzyme。Research shows, the mechanism of the therapeutical effect of cerebral ischemia is that ferulic acid can reduce cerebral tissue malonaldehyde (MDA) content and improve superoxide dismutase (SOD) activity by ferulic acid, reduce the ratio of MDA/SOD, thus the balance improved between free radical and scavenging free radicals enzyme, the damage suppressing free radical and the lipid peroxidation (Zingiberaceae sound etc., the Chinese Journal of Modern Applied Pharmacy magazine that cause。2006；23:185-188)。But, ferulic acid just shows Cerebral ischemia protection effect (Zhao Jinhui etc., Chinese Medicine guide when injecting dosage and being 0.92mmol/kg。2009；7:186-187)。In addition, after apoplexy, number of mechanisms causes brain injury, but the research and development of apoplexy medicine for a long time almost focus only on the drug molecule acting on single target spot completely, and the medicine of single molecular target, the apoplexy damage caused by number of mechanisms in treatment is extremely difficult to Expected Results。
Thus, the present invention is based on the principle of hybridization of drug design, by compatible to two kinds of medicines or both pharmacophoric groups in a molecule, form new hybrid molecule, thus reaching a kind of medicine effect for multiple pathomechanism, and then disclose with alkane for linking arm, by 5-p-hydroxybenzene-3H-1, the hybrid molecule that 2-dithiole-3-thioketone (ADT-OH) is connected by ehter bond, ester bond with ferulic acid, then above-mentioned being applied to by ferulic acid derivative is prevented and/or in treatment apoplexy class disease medicament。
The test of pesticide effectiveness shows, ferulic acid derivative disclosed by the invention in the minimal effective concentration of the hippocampus of mice neurocyte HT-22 of the glutamate induction model discrimination damaged is: 1 μM or 10 μMs。The neuroprotective of some of them hybrid molecule is significantly stronger than parent molecule 5-p-hydroxybenzene-3H-1,2-dithiole-3-thioketone。Additionally, the present invention is with 3-methoxyl group-4-{4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester representatively property compound, focal cerebral ischemia animal model finds when lumbar injection dosage is 0.22mmol/kg, show obvious cerebral ischemia therapeutical effect。
The present invention thus additionally provides a kind of preparation, including ferulic acid compounds and pharmaceutically acceptable adjuvant；
Described ferulic acid compounds is ferulic acid derivative described in any one or its pharmaceutically acceptable salt in technique scheme。
The present invention is to the preferred version in the preferred version of described ferulic acid derivative and specifically chosen and aforementioned ferulic acid derivative and specifically chosen basically identical, and this is no longer going to repeat them。Ferulic acid compounds of the present invention is preferably described ferulic acid derivative or its pharmaceutically acceptable salt of effective dose, forms with pharmaceutically acceptable adjuvant。In preparation of the present invention, the dosage of described ferulic acid derivative or its pharmaceutically acceptable salt is preferably 0.05mg/kg～90mg/kg, more preferably 0.1mg/kg～80mg/kg, more preferably 5mg/kg～70mg/kg, it is most preferred that for 15mg/kg～60mg/kg。
Those skilled in the art can by described ferulic acid derivative or its pharmaceutically acceptable salt, pharmaceutically acceptable various conventional adjuvants required during different dosage form are prepared in direct or indirect addition, described adjuvant is not particularly limited by the present invention, with conventional adjuvant well known to those skilled in the art, such as disintegrating agent, lubricant, emulsifying agent, binding agent etc., with traditional drug formulations method, make common formulations。
The dosage form of preparation of the present invention is not particularly limited, with common formulations well known to those skilled in the art, the present invention is preferably oral formulations, injection, suppository, inhalant or may be directly applied to the dosage form at cerebral ischemia position, more preferably includes capsule, microcapsule, tablet, granule, pill, dispersed powders, liquid preparation, soft extract, suspending agent, syrup, gel, aerosol, patch, liposome, oral liquid, intravenous fluid or intramuscular injection。
Pharmaceutical preparation of the present invention can in the following manner in applicable mode be administered: in oral, rectally, nasal-cavity administration, topical, oral administration, sublingual administration, parenterai administration such as subcutaneous, vein, muscle, intraperitoneal, sheath, in ventricle, in breastbone or intracranial injection or input, or the reservoir medication by a kind of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenous administration mode。
Using dosage and the using method of the preparation of prevention of the present invention or treatment apoplexy class disease depend on factors, including the subjective judgment of the age of patient, body weight, sex, natural health situation, nutriture, the activity intensity of compound, Time of Administration, metabolic rate, the course of disease order of severity and diagnosis and treatment doctor。Those skilled in the art can be easily determined by using dosage and using method according to above-mentioned factor。General pharmaceutical preparation of the present invention can use according to the dosage of 0.005～5000mg/kg/ days, it is possible to uses beyond this dosage range according to the different using dosages of disease severity or dosage form。
In order to further illustrate the present invention, below in conjunction with embodiment, a kind of ferulic acid derivative provided by the invention, preparation and application thereof being described in detail, protection scope of the present invention is not limited by the following examples。
Embodiment 1
3-methoxyl group-4-{3-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester (SYX-I1) synthesis
By (E)-FA ethyl ester (222mg, 1mmol), 5-[4-(3-bromo propoxy)-phenyl]-[1,2]-dithiole-3-thioketone (347mg, 1mmol), KI (17-34mg, 0.1～0.2mmol), potassium carbonate (139mg, 1mmol) joins in acetone, back flow reaction 8h at 100 DEG C。After reaction terminates, sucking filtration, mix sample and cross post, column chromatography, eluent (petroleum ether: ethyl acetate=8:1)。Obtain yellow powdery solid。Productivity 68%。
1HNMR(400MHz,CDCl3) δ 7.61 (dd, J=12.4,6.8Hz, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.08 (dd, J=8.3,1.6Hz, 1H, ArH), 7.06 (s, 1H, ArH), 6.99 (d, J=8.8Hz, 2H, ArH), 6.90 (d, J=8.2Hz, 1H, ArH), 6.31 (d, J=15.9Hz, 1H, C=CH), 4.29 4.21 (m, 6H, OCH2),3.88(s,3H,OCH3), 2.36 (p, J=6.0Hz, 2H, CH2), 1.34 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ215.10,172.96,167.17,162.17,150.22,149.53,144.35,134.62,128.56,127.79,124.21,122.39,116.15,115.46,112.69,110.09,65.23,64.78,60.38,55.89,28.97,14.33.
LC-MS:Calcd.ForC24H24O5S3[M+H]+489.0864,Found:489.0877.
Embodiment 2
3-methoxyl group-4-{4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester (SYX-I2) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(4-bromine butoxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellow powdery solid。Productivity 65%。
1HNMR(400MHz,CDCl3) δ 7.61 (dd, J=12.3,10.0Hz, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.09 (dd, J=8.3,1.8Hz, 1H, ArH), 7.05 (d, J=1.8Hz, 1H, ArH), 6.96 (d, J=8.8Hz, 2H, ArH), 6.87 (d, J=8.3Hz, 1H, ArH), 6.31 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2), 4.13 (q, J=5.6Hz, 4H, OCH2),3.88(s,3HOCH3),2.12–1.99(m,4H,CH2), 1.34 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ215.08,173.04,167.20,162.34,150.37,149.47,144.42,134.56,128.54,127.54,124.04,122.45,116.00,115.40,112.38,110.00,68.41,67.91,60.37,55.88,25.91,25.67,14.34.
LC-MS:Calcd.ForC25H26O5S3[M+H]+503.1021,Found:503.1037.
Embodiment 3
3-methoxyl group-4-{5-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester (SYX-I3) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(5-bromine amoxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellow powdery solid。Productivity 65%。
1HNMR(400MHz,CDCl3) δ 7.61 (dd, J=12.1,9.9Hz, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.08 (d, J=8.3Hz, 1H, ArH), 7.06 (s, 1H, ArH), 6.95 (d, J=8.8Hz, 2H, ArH), 6.86 (d, J=8.2Hz, 1H, ArH), 6.31 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2),4.12–4.02(m,4H,OCH2),3.89(s,3H,OCH3),1.98–1.86(m,3H,CH2), 1.68 (dt, J=14.7,7.5Hz, 3H, CH2), 1.34 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ214.98,173.08,167.19,162.38,150.44,149.39,144.43,134.47,128.52,127.35,123.92,122.45,115.84,115.34,112.28,109.92,68.59,68.06,60.33,55.88,30.89,28.70,22.54,14.31.
LC-MS:Calcd.ForC26H28O5S3[M+H]+517.1177,Found:517.1217.
Embodiment 4
3-methoxyl group-4-{6-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester (SYX-I4) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(6-bromine hexyloxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellow powdery solid。Productivity 67%。
1HNMR(400MHz,CDCl3) δ 7.66 7.57 (m, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.08 (dd, J=8.3,1.8Hz, 1H, ArH), 7.05 (d, J=1.8Hz, 1H, ArH), 6.98 6.93 (m, 2H, ArH), 6.86 (d, J=8.2Hz, 1H, ArH), 6.31 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2), 4.05 (dt, J=12.9,6.5Hz, 4H, OCH2),3.89(s,3HOCH3),1.94–1.82(m,4H,CH2), 1.56 (dd, J=8.8,5.4Hz, 4H, CH2), 1.34 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ215.06,173.11,167.23,162.48,150.57,149.46,144.49,134.53,128.55,127.35,123.96,122.49,115.88,115.41,112.32,110.01,68.74,68.23,60.36,55.94,28.95,28.93,25.74,25.71,14.34.
LC-MS:Calcd.ForC27H30O5S3[M+H]+531.1334,Found:531.1354.
Embodiment 5
3-methoxyl group-4-{7-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] oxygen base in heptan } cinnamic acid ethyl ester (SYX-I5) synthesis
(4-(7-bromine oxygen in heptan base) phenyl-1, prepared by 2-dithiole-3-thioketone, obtain yellow powdery solid by ferulic acid ethylester and 5-for the method for reference embodiment 1。Productivity 62%。
1HNMR(400MHz,CDCl3) δ 7.61 (t, J=11.9Hz, 3H, ArH, C=CH), 7.38 (s, 1H, C=CH), 7.09 7.06 (m, 1H, ArH), 7.05 (d, J=1.6Hz, 1H, ArH), 6.95 (d, J=8.8Hz, 2H, ArH), 6.85 (d, J=8.2Hz, 1H, ArH), 6.30 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2), 4.03 (dt, J=13.1,6.6Hz, 4H, OCH2),3.89(s,3H,OCH3), 1.84 (ddd, J=20.3,13.8,6.8Hz, 4H, CH2),1.55–1.43(m,6H,CH2), 1.33 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ215.01,173.10,167.20,162.48,150.58,149.42,144.48,134.47,128.52,127.27,123.89,122.47,115.80,115.38,112.27,109.98,68.82,68.30,60.32,55.92,30.89,29.00,28.92,25.82,14.33.
LC-MS:Calcd.ForC28H32O5S3[M+H]+545.1490,Found:545.1580.
Embodiment 6
3-methoxyl group-4-{8-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester (SYX-I6) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(8-bromine octyloxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellowish-brown pulverulent solids。Productivity 55%。
1HNMR(400MHz,CDCl3) δ 7.62 (dd, J=12.2,3.2Hz, 4H, ArH, C=CH), 7.08 (dd, J=8.3,1.8Hz, 1H, ArH), 7.05 (d, J=1.8Hz, 1H, ArH), 6.95 (d, J=8.9Hz, 2H, ArH), 6.85 (d, J=8.3Hz, 1H, ArH), 6.30 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2),4.07–3.98(m,4H,OCH2),3.89(s,3H,OCH3),1.91–1.76(m,4H,CH2),1.48(s,4H,CH2),1.43–1.37(m,4H,CH2), 1.33 (t, J=7.1Hz, 3H, CH3).
13CNMR(400MHz,CDCl3)δ214.26,173.63,167.18,162.60,150.58,149.37,144.47,134.28,128.64,127.18,123.73,122.46,115.72,115.39,112.22,109.94,68.83,68.34,60.28,55.88,29.16,29.12,28.92,25.80,25.78,14.29.
LC-MS:Calcd.ForC29H34O5S3[M+H]+559.1647,Found:559.1676.
Embodiment 7
3-methoxyl group-4-{9-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] oxygen base in the ninth of the ten Heavenly Stems } cinnamic acid ethyl ester (SYX-I7) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(9-bromine oxygen in ninth of the ten Heavenly Stems base) phenyl)-1,2-dithiole-3-thioketone, obtains yellow powdery solid。Productivity 75%。
1HNMR(400MHz,CDCl3) δ 7.61 (dd, J=12.3,8.5Hz, 3H, ArH, C=CH), 7.40 (s, 1H, C=CH), 7.08 (dd, J=8.3,1.7Hz, 1H, ArH), 7.05 (s, 1H, ArH), 6.96 (d, J=8.8Hz, 2H, ArH), 6.85 (d, J=8.2Hz, 1H, ArH), 6.30 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2), 4.03 (dt, J=10.5,6.7Hz, 4H, OCH2),3.89(s,3H,OCH3),1.89–1.78(m,4H,CH2),1.51–1.42(m,4H,CH2), 1.34 (dd, J=14.0,6.8Hz, 9H, CH2,CH3).
13CNMR(400MHz,CDCl3)δ215.00,173.18,167.25,162.54,150.64,149.42,144.53,134.48,128.54,127.22,123.86,122.50,115.76,115.40,112.26,109.99,68.91,68.39,60.33,55.93,30.89,29.34,29.21,29.18,28.98,25.88,25.85,14.32.
LC-MS:Calcd.ForC30H36O5S3[M+H]+573.1803,Found:573.1840.
Embodiment 8
3-methoxyl group-4-{10-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] oxygen base in the last of the ten Heavenly stems } cinnamic acid ethyl ester (SYX-I8) synthesis
Method with reference to embodiment 1 is prepared by ferulic acid ethylester and 5-(4-(10-bromine oxygen in last of the ten Heavenly stems base) phenyl)-1,2-dithiole-3-thioketone, obtains yellow powdery solid。Productivity 63%。
1HNMR(600MHz,CDCl3) δ 7.59 (ddd, J=19.1,17.4,12.7Hz, 3H, ArH, C=CH), 7.40 (s, 1H, C=CH), 7.08 (dd, J=8.3,1.9Hz, 1H, ArH), 7.05 (d, J=1.9Hz, 1H, ArH), 6.97 6.94 (m, 2H, ArH), 6.85 (d, J=8.3Hz, 1H, ArH), 6.30 (d, J=15.9Hz, 1H, C=CH), 4.26 (q, J=7.1Hz, 2H, OCH2),4.06–4.00(m,4H,OCH2),3.89(s,3H,OCH3),1.88–1.78(m,4H,CH2),1.49–1.43(m,4H,CH2), 1.34 (dd, J=14.3,7.1Hz, 11H, CH2,CH3).
13CNMR(600MHz,CDCl3)δ214.98,173.18,167.23,162.56,150.66,149.44,144.53,134.49,128.55,127.22,123.87,122.50,115.77,115.41,112.27,110.01,68.95,68.42,60.33,55.95,29.41,29.39,29.30,29.26,29.00,25.92,25.88,14.34.
LC-MS:Calcd.ForC31H38O5S3[M+H]+587.1960,Found:587.1997.
Embodiment 9～12
With reference to list of references Zou, H.；Wu, H.；Zhang, X.；Zhao, Y.；Stoeckigt, J.；Lou, Y.；Yu, Y.Bioorganic&MedicinalChemistry2010,18 (17), the method synthesis compound SYX-I of 6351-6359.9-12。
Embodiment 9
3-methoxyl group-4-{3-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid (SYX-I9) synthesis
By compound SYX-I1It is hydrolyzed into corresponding acid, obtains yellow powdery solid。Productivity 89%。
1HNMR (600MHz, DMSO) δ 7.85 (d, J=7.5Hz, 2H, ArH), 7.74 (s, 1H, C=CH), 7.55 (d, J=15.9Hz, 1H, C=CH), 7.34 (s, 1H, ArH), 7.20 (d, J=8.3Hz, 1H, ArH), 7.08 (d, J=10.7Hz, 2H, ArH), 7.00 (d, J=8.3Hz, 1H, ArH), 6.53 (d, J=15.9Hz, 1H, C=CH), 4.22 (t, J=6.1Hz, 2H, OCH2), 4.15 (d, J=6.9Hz, 2H, OCH2),3.79(s,3H,OCH3),2.22–2.15(m,2H,CH2).
13CNMR(101MHz,DMSO)δ215.24,174.27,168.35,162.40,150.52,149.61,144.99,134.64,129.51,127.75,124.18,123.35,117.26,115.98,113.20,111.00,65.32,65.25,60.26,28.89.
LC-MS:Calcd.ForC22H21O5S3[M+H]+461.0551,Found:461.0554.
Embodiment 10
3-methoxyl group-4-{4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid (SYX-I10) synthesis
By compound SYX-I2It is hydrolyzed into corresponding acid, obtains yellow powdery solid。Productivity 91%。
1HNMR (400MHz, DMSO) δ 7.88 (d, J=8.9Hz, 2H, ArH), 7.78 (s, 1H, C=CH), 7.52 (d, J=15.9Hz, 1H, C=CH), 7.32 (d, J=1.8Hz, 1H, ArH), 7.19 (dd, J=8.3,1.7Hz, 1H, ArH), 7.09 (d, J=8.9Hz, 2H, ArH), 6.99 (d, J=8.4Hz, 1H, ArH), 6.44 (d, J=15.9Hz, 1H, C=CH), 4.17 (d, J=6.6Hz, 2H, OCH2),4.08(s,2H,OCH2),3.80(s,3H,OCH3),1.90(s,4H,CH2).
13CNMR(400MHz,DMSO)δ215.21,174.34,168.37,162.59,150.52,149.55,144.64,134.57,129.49,127.51,124.02,123.10,117.12,115.93,112.96,110.92,68.32,68.21,56.10,25.85,25.67.
LC-MS:Calcd.ForC23H22O5S3[M+H]+475.0708,Found:475.0696.
Embodiment 11
3-methoxyl group-4-{4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid (SYX-I11) synthesis
By compound SYX-I4It is hydrolyzed into corresponding acid, obtains yellow powdery solid。Productivity 92%。
1HNMR (400MHz, DMSO) δ 7.87 (d, J=8.9Hz, 2H, ArH), 7.77 (s, 1H, C=CH), 7.52 (d, J=15.9Hz, 1H, C=CH), 7.31 (d, J=1.8Hz, 1H, ArH), 7.18 (dd, J=8.4,1.8Hz, 1H, ArH), 7.08 (d, J=8.9Hz, 2H, ArH), 6.97 (d, J=8.4Hz, 1H, ArH), 6.43 (d, J=15.9Hz, 1H, C=CH), 4.09 (t, J=6.4Hz, 2H, OCH2), 4.01 (t, J=6.4Hz, 2H, OCH2),3.80(s,3H,OCH3), 1.76 (d, J=5.9Hz, 4H, CH2),1.49(s,4H,CH2).
13CNMR(400MHz,DMSO)δ215.21,174.34,168.36,162.64,150.64,149.57,144.63,134.55,129.49,127.43,123.97,123.11,117.08,115.93,112.96,110.99,68.54,68.43,56.10,29.03,28.89,25.70,25.64.
LC-MS:Calcd.ForC25H26O5S3[M+H]+503.1021,Found:503.0992.
Embodiment 12
3-methoxyl group-4-{4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid (SYX-I12) synthesis
By compound SYX-I6It is hydrolyzed into corresponding acid, obtains yellow powdery solid。Productivity 88%。
1HNMR (600MHz, DMSO) δ 7.83 (d, J=8.7Hz, 2H, ArH), 7.71 (s, 1H, C=CH), 7.48 (d, J=15.9Hz, 1H, C=CH), 7.26 (s, 1H, ArH), 7.15 (d, J=8.3Hz, 1H, ArH), 7.04 (d, J=8.7Hz, 2H, ArH), 6.94 (d, J=8.3Hz, 1H, ArH), 6.39 (d, J=15.9Hz, 1H, C=CH), 4.03 (t, J=6.3Hz, 2H, OCH2), 3.95 (t, J=6.3Hz, 2H, OCH2),3.77(s,3H,OCH3),1.74–1.66(m,4H,CH2), 1.39 (d, J=4.9Hz, 4H, CH2),1.32(s,4H,CH2).
13CNMR(400MHz,DMSO)δ215.20,174.34,168.36,162.65,150.66,149.57,144.64,134.53,129.48,127.40,123.96,123.10,117.06,115.93,112.95,110.98,68.61,68.48,56.10,29.13,29.06,28.92,25.91,25.83,
LC-MS:Calcd.ForC27H30O5S3[M+H]+531.1334,Found:531.1343.
Embodiment 13
4-acetyl group-3-methoxybenzene acrylic acid-3-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester (SYX-I13) synthesis
By (E)-4-acetoxy-3-methoxybenzene acrylic acid (196mg, 0.83mmol), 5-(4-(3-bromine propoxyl group) phenyl)-1,2-dithiole-3-thioketone (288mg, 0.83mmol), KI (14mg, 0.083mmol), potassium carbonate (115mg, 0.83mmol) joins in round-bottomed flask, with acetone solution, back flow reaction 8h。After reaction terminates, sucking filtration, mix sample and cross post。Column chromatography, eluent (petroleum ether: ethyl acetate=8:1)。Obtain yellowish-brown oily liquids。Productivity 52%。
1HNMR(400MHz,CDCl3) δ 7.69 7.56 (m, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.11 (dd, J=10.8,2.6Hz, 2H, ArH), 7.05 (d, J=8.0Hz, 1H, ArH), 6.99 (d, J=8.8Hz, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.43 (t, J=6.2Hz, 2H, OCH2), 4.17 (dd, J=7.3,4.9Hz, 2H, OCH2),3.86(s,3H,OCH3),2.32(s,3H,CH3),2.28–2.19(m,2H,CH2).
13CNMR(400MHz,CDCl3)δ215.08,172.93,168.74,166.68,162.09,151.39,144.39,141.52,134.63,133.18,128.58,128.05,123.28,121.20,117.90,115.42,111.23,64.85,61.12,55.89,28.57,20.63.
LC-MS:Calcd.ForC24H22O6S3[M+H]+503.0657,Found:503.0681.
Embodiment 14
4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester (SYX-I14) synthesis
Method with reference to embodiment 13 is prepared by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-(4-(4-bromine butoxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellowish-brown oily liquids。Productivity 54%。
1HNMR(400MHz,CDCl3) δ 7.67 7.58 (m, 3H, ArH, C=CH), 7.41 (s, 1H, C=CH), 7.13 7.08 (m, 2H, ArH), 7.05 (d, J=8.0Hz, 1H, ArH), 7.00 6.95 (m, 2H, ArH), 6.37 (d, J=16.0Hz, 1H, C=CH), 4.30 (t, J=6.0Hz, 2H, OCH2), 4.09 (t, J=5.8Hz, 2H, OCH2),3.86(s,3H,OCH3),2.33(s,3H,CH3),1.99–1.91(m,4H,CH2).
13CNMR(400MHz,CDCl3)δ215.05,173.07,168.78,166.79,162.30,151.41,144.18,141.49,134.61,133.26,128.61,124.14,123.28,121.19,118.13,115.43,111.23,67.72,64.05,55.91,25.75,25.42,20.65.
LC-MS:Calcd.ForC25H24O6S3[M+H]+517.0813,Found:517.0867.
Embodiment 15
4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester (SYX-I15) synthesis
Method with reference to embodiment 13 is prepared by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-(4-(5-bromine amoxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellowish-brown oily liquids。Productivity 49%。
1HNMR(400MHz,CDCl3) δ 7.68 7.57 (m, 3H, ArH, C=CH), 7.42 (s, 1H, C=CH), 7.12 (dd, J=9.7,1.5Hz, 2H, ArH), 7.05 (d, J=8.0Hz, 1H, ArH), 6.99 6.94 (m, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.26 (t, J=6.6Hz, 2H, OCH2), 4.05 (t, J=6.3Hz, 2H, OCH2),3.86(s,3H,OCH3),2.33(s,3H,CH3),1.93–1.85(m,2H,CH2),1.84–1.77(m,2H,CH2), 1.62 (ddd, J=15.5,9.0,5.9Hz, 2H, CH2).
13CNMR(400MHz,CDCl3)δ215.05,173.09,168.78,166.84,162.39,151.38,144.06,141.44,134.56,133.30,128.57,124.03,123.25,121.18,118.24,115.40,111.21,68.08,64.36,55.90,29.69,28.43,22.57,20.64.
LC-MS:Calcd.ForC26H26O6S3[M+H]+531.0970,Found:531.0996.
Embodiment 16
4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] own ester (SYX-I16) synthesis
Method with reference to embodiment 13 is prepared by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-(4-(6-bromine hexyloxy) phenyl)-1,2-dithiole-3-thioketone, obtains yellowish-brown oily liquids。Productivity 50%。
1HNMR(400MHz,CDCl3) δ 7.68 7.53 (m, 3H), 7.14 7.08 (m, 2H), 7.05 (d, J=7.9Hz, 1H), 6.98 6.91 (m, 2H), 6.75 (s, 1H), 6.38 (d, J=16.0Hz, 1H), 4.23 (t, J=6.6Hz, 2H), 4.03 (dd, J=7.7,5.1Hz, 2H), 3.86 (s, 3H), 2.33 (s, 3H), 1.89 1.72 (m, 4H), 1.52 (dt, J=12.9,6.1Hz, 4H).
13CNMR(400MHz,CDCl3)δ194.12,170.05,168.74,166.84,162.00,151.34,143.94,141.38,133.30,127.98,124.86,123.21,121.15,118.30,116.12,115.13,111.16,68.11,64.49,55.86,28.93,28.59,25.70,25.66,20.61.
LC-MS:Calcd.ForC27H28O6S3[M+H]+545.1126,Found:545.1157.
Embodiment 17
4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester (SYX-I17) synthesis
(4-(7-bromine oxygen in heptan base) phenyl-1, prepared by 2-dithiole-3-thioketone, obtain yellowish-brown oily liquids by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-for the method for reference embodiment 13。Productivity 54%。
1HNMR(400MHz,CDCl3) δ 7.68 7.54 (m, 3H, ArH, C=CH), 7.40 (s, 1H, C=CH), 7.16 7.09 (m, 2H, ArH), 7.05 (d, J=7.9Hz, 1H, ArH), 6.96 (d, J=8.8Hz, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.22 (t, J=6.7Hz, 2H, OCH2), 4.03 (dd, J=8.4,4.5Hz, 2H, OCH2),3.86(s,3H,OCH3), 2.34 (d, J=8.3Hz, 3H, CH3),1.87–1.79(m,2H,CH2), 1.73 (dd, J=13.6,6.8Hz, 2H, CH2), 1.52 (dd, J=13.6,7.6Hz, 2H, CH2), 1.45 (d, J=2.8Hz, 4H, CH2).
13CNMR(400MHz,CDCl3)δ206.99,173.15,66.89,162.51,151.37,143.93,141.40,134.54,133.35,128.57,123.94,123.24,121.18,118.37,115.41,111.19,68.32,64.62,58.47,55.90,30.92,28.62,25.87,20.64,18.42.
LC-MS:Calcd.ForC28H30O6S3[M+H]+559.1283,Found:559.1352.
Embodiment 18
4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester (SYX-I18) synthesis
(4-(8-bromine octyloxy) phenyl-1, prepared by 2-dithiole-3-thioketone, obtain yellowish-brown oily liquids by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-for the method for reference embodiment 13。Productivity 48%。
1HNMR(400MHz,CDCl3) δ 7.68 7.55 (m, 3H, ArH, C=CH), 7.45 (s, 1H, C=CH), 7.15 7.08 (m, 2H, ArH), 7.05 (d, J=7.9Hz, 1H, ArH), 6.98 6.92 (m, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.21 (t, J=6.7Hz, 2H, OCH2), 4.02 (t, J=6.5Hz, 2H, OCH2),3.86(s,3H,OCH3),2.33(s,3H,CH3),1.85–1.77(m,2H,CH2), 1.72 (dt, J=13.5,6.7Hz, 2H, CH2),1.53–1.45(m,2H,CH2),1.40(s,6H,CH2).
13CNMR(400MHz,CDCl3)δ214.99,173.22,168.79,166.90,162.54,151.37,143.90,141.39,134.52,133.37,128.57,123.90,123.24,121.17,118.40,115.41,111.18,68.37,64.67,55.89,29.16,29.10,28.98,28.66,25.85,25.84,20.64.
LC-MS:Calcd.ForC29H32O6S3[M+H]+573.1439,Found:573.1525.
Embodiment 19
4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] ester (SYX-I in the ninth of the ten Heavenly Stems19) synthesis
(4-(9-bromine oxygen in ninth of the ten Heavenly Stems base) phenyl-1, prepared by 2-dithiole-3-thioketone, obtain yellowish-brown oily liquids by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-for the method for reference embodiment 13。Productivity 51%。
1HNMR(400MHz,CDCl3) δ 7.67 7.55 (m, 3H, ArH, C=CH), 7.39 (s, 1H, C=CH), 7.15 7.08 (m, 2H, ArH), 7.05 (d, J=7.9Hz, 1H, ArH), 6.95 (d, J=8.8Hz, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.20 (t, J=6.7Hz, 2H, OCH2), 4.01 (t, J=6.5Hz, 2H, OCH2),3.86(s,3H,OCH3),2.32(s,3H,CH3),1.85–1.76(m,2H,CH2),1.76–1.66(m,2H,CH2), 1.46 (d, J=7.5Hz, 2H, CH2),1.36(s,8H,CH2).
13CNMR(600MHz,CDCl3)δ214.97,173.12,168.72,166.85,162.51,151.33,143.82,141.34,134.44,133.34,128.51,123.85,123.19,121.13,118.39,115.38,111.15,68.38,64.68,55.86,29.35,29.19,29.11,28.98,28.65,25.88,20.61.
LC-MS:Calcd.ForC30H34O6S3[M+H]+587.1596,Found:587.1713.
Embodiment 20
4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1,2-dithiole-3-thioketone-5-base) phenoxy group] ester (SYX-I in the last of the ten Heavenly stems20) synthesis
(4-(10-bromine oxygen in last of the ten Heavenly stems base) phenyl-1, prepared by 2-dithiole-3-thioketone, obtain yellowish-brown oily liquids by (E)-4-acetoxy-3-methoxybenzene acrylic acid and 5-for the method for reference embodiment 9。Productivity 48%。
1HNMR(600MHz,CDCl3) δ 7.66 7.53 (m, 3H, ArH, C=CH), 7.45 (s, 1H, C=CH), 7.14 7.08 (m, 2H, ArH), 7.04 (d, J=8.0Hz, 1H, ArH), 6.95 (d, J=8.7Hz, 2H, ArH), 6.38 (d, J=16.0Hz, 1H, C=CH), 4.20 (t, J=6.7Hz, 2H, OCH2), 4.01 (t, J=6.5Hz, 2H, OCH2),3.86(s,3H,OCH3),2.32(s,3H,CH3),1.83–1.77(m,2H,CH2), 1.70 (dt, J=13.9,6.8Hz, 2H, CH2), 1.45 (dd, J=14.4,6.9Hz, 2H, CH2), 1.39 (d, J=7.8Hz, 2H, CH2),1.33(s,8H,CH2).
13CNMR(600MHz,CDCl3)δ214.94,173.19,168.74,166.87,162.54,151.33,143.82,141.35,134.46,133.36,128.54,127.97,123.20,121.14,118.41,115.39,111.16,68.41,64.72,55.87,29.39,29.38,29.25,29.18,29.00,28.67,25.90,20.62.
LC-MS:Calcd.ForC31H36O6S3[M+H]+601.1752,Found:601.1873.
Embodiment 21
Embodiment 3-SYX-I3The synthesized compound protective effect to glutamate induction HT22 Death of hippocampus neurons
1, experiment material and instrument
Hippocampus neurons in mice cell line HT22,24 porocyte culture plates (Corning), glutamic acid (Glutamate, Sigma), DMEM culture medium (GIBCO), hyclone (GIBCO), 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (MTT, Sigma), dimethyl sulfoxide (traditional Chinese medicines group), microplate reader (TECAN)。
2, experimental technique
2.1, cell is cultivated: HT22 cell takes out from liquid nitrogen container, thaws rapidly in 37 DEG C of water-baths, with cotton ball soaked in alcohol wiping cryopreservation tube outer wall after defrosting, take into super-clean bench, cell is equipped with in the centrifuge tube of 10mL culture medium, puts in centrifuge 1000 turns, centrifugal 3min。Centrifugal end, abandons supernatant, adds the 10mL DMEM containing 10%FBS in centrifuge tube, and cell suspension is made in piping and druming, by cell suspension inoculation in 100 × 20mm culture dish。At 37 DEG C, 5%CO2When, cultivates。Within second day, press 2 × 104The density in/hole is inoculated in 24 orifice plates。
2.2, cell packet and process: cell, after 24 orifice plates cultivate 24h, is simultaneously introduced the glutamic acid of 5mM and the compound of embodiment 1～20 synthesis of final concentration of 0.1,1,5,10,50,100 μMs, and cellular control unit adds the DMSO of same volume。After dosing 24 hours, detect survivaling cell with mtt assay。
2.3, MTT detection: 24h after cell process, every hole adds the MTT50 μ L of 0.5mg/mL, at 37 DEG C, 5%CO2Continue to hatch 4h under condition, supernatant is discarded, add dimethyl sulfoxide (DMSO) 500 μ L cell lysis。Detecting absorbance by microplate reader at 570 wavelength places, cell survival rate represents with the percentage ratio of dosing group cell with the absorbance not adding the cell that glutamic acid processes。, all data all use software SPSS17.0 to add up, and each group difference adopts onewayanova inspection。P < 0.01 thinks statistically pole significant difference。Result is in Table 1。
The impact on HT22 cell survival rate in glutamate-induced neuronal damage model of table 1 ferulic acid derivative
5mM glutamic acid can induce HT22 cell injury, survival rate < 47.47%。From table 1 result; the embodiment 1～6 of final concentration of 1～100 μM; the compound of 9～12 synthesis can significantly inhibit the HT22 cell injury that glutamic acid causes; significantly improve cell survival rate; each Compound cellular survival rate is all higher than 65%; effectively protection concentration range 1～100 μM, detects that minimum effective protection concentration is 1 μM, and the minimum effective protection concentration of parent molecule ADT-OH is 10 μMs。This shows to cause in HT22 neuronal death models at excessive glutamate by reactive oxygen free radical toxicity, by the protective effect of neuronal cell is higher with the Hybrid compounds that ferulic acid is connected by ehter bond or ester bond linking arm for ADT-OH。Compound SYX-I14-SYX-I20Due to poorly water-soluble, the HT22 cytoprotection of glutamate induction damage is poor。
Embodiment 22
Ferulic acid derivative blocks the cerebral protection in model in mouse brain medium-sized artery
1, experiment material and instrument
ICR mice, male, body weight 30 ± 2.0g, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center。Raising under room temperature environment, light and shade cycle 12h, ad lib, drinking-water is not limit。
2, 3, 5-triphenyltetrazolium chloride (TTC) (Sigma), 0.9% normal saline (Anhui Double-Crane Pharmaceutical Co., Ltd), isoflurane (Shandong Ke Yuan drugmaker), 4% paraformaldehyde (Chemical Reagent Co., Ltd., Sinopharm Group), operating microscope (Shenzhen Rui Wode instrument Co., Ltd), dimethyl sulfoxide (DMSO), Semen Maydis oil (Sigma) electric heating constant temperature tank SSW-600-2S (Shanghai Bo Xun Industrial Co., Ltd.), digital camera (Canon), laser-Doppler rheoencephalograph PeriFluxsystem5000 (PERIMADAB)。
2, experimental technique
2.1, middle cerebral artery thromboembolism model (MCAO) makes: make right side of mice middle cerebral artery bolt (middlecerebralarteryocclusion, MCAO) model with reference to Longa method and other reforming Longa method。Operating procedure is as follows: mice is with after isoflurane anesthesia。Anesthetized mice is faced upward position and is fixed, conventional iodine disinfection skin of neck and skin of head。Laser-Doppler cerebral blood flow is measured probe and is fixed on the midpoint of right side of mice ear eye line, to monitor cerebral cortex blood flow in real time。About 1.5cm otch is made in cervical region center, expose right carotid artery triangle, successively chorista under operating microscope, first common carotid artery is isolated, press from both sides at nearly aortic bifurcation place with microvessel clamp temporarily and close common carotid artery, separate right side external carotid artery and internal carotid artery again, separate external carotid artery trunk, at its far-end 0.5cm place 5-0 suture ligature external carotid artery。Press from both sides with microvessel clamp simultaneously temporarily and close internal carotid artery, and between common carotid artery bifurcated mouth and external carotid artery distal colorectal binding ligation seam zygonema, it's not serious, inside external carotid artery distal colorectal binding, an osculum is cut subsequently with eye scissors, handling bolt line with microforceps (adopts heating to make head end somewhat expand, being coated silica gel, alcohol disinfecting again, bolt line length is about 2cm, the end of a thread diameter 0.22 ± 0.01cm)。By external carotid artery otch inlet wire, lift external carotid artery distal colorectal binding, after entering common carotid artery bifurcated mouth to bolt the end of a thread end, tighten stitching thread。External carotid artery is cut off again by external carotid artery incision, and unclamp internal carotid artery vascular clamp, tractive external carotid artery stump is to increase it in the angle of internal carotid artery gently, slowly advance bolt line so as to entered internal carotid artery by external carotid artery by crotch, until having light resistance and observing that on laser-Doppler rheoencephalograph cerebral cortex blood flow sharply declines (blood flow should drop to less than the 25% of base value) suddenly, show that bolt the end of a thread portion has arrived at the initial part of middle cerebral artery and has been, block the blood flow of middle cerebral artery。The record thromboembolism time started, stitching thread on external carotid artery is tightened, and unclamp common carotid artery folder, again sterilize, skin of sewing up the incision。After medium-sized artery blocking 60min, extract bolt line, recover middle cerebral artery blood for carrying out Reperfu-sion。In art and postoperative electric hot plate keep anus temperature within the scope of (37.0 ± 0.5) DEG C, until animal revives。
2.2, animal packet and administration: animal is randomly divided into 2 groups, respectively solvent injection matched group and SYX-I3Administration group, often 8 mices of group。The SYX-I of 15mg3First dissolve with 250 μ LDMSO, then be diluted to, with 750 μ L Semen Maydis oil, the solution that whole solubility is 15mg/mL。The dosage lumbar injection SYX-I of 0.22mmol/kg is pressed when postischemic reperfusion 3h3。Solvent injection control group mice gives the same volume Semen Maydis oil containing 25%DMSO。
2.3, cerebral infarction volume measures: after mouse brain medium-sized artery blocking (MCAO) Reperfu-sion 24h, after anesthesia, broken end takes brain rapidly, cerebral tissue removes olfactory bulb, cerebellum and low brain stem after stripping, interval 1mm does 5 brain coronal section continuously, it is placed in 2%TTC solution, 37 DEG C of lucifuge temperature baths, every 15min turn-over once, temperature bath 30min altogether。With TTC Determination Staining cerebral infarction area size。TTC is reduced by mitochondrion catalase, and normal cerebral tissue's dyeing can be made to take on a red color, and ischemic infarction tissue is then white。With the fixing 24h of 4% paraformaldehyde solution after dyeing, digital camera is taken pictures, and calculates Infarction volume percentage ratio with software analysis, and result is expressed as the ratio of ischemia side Infarction volume and offside brain volume。All data all adopt means standard deviation (SD) to represent。Each group difference compares employing t inspection。P < 0.01 thinks statistically significant difference。Statistical result is shown in that Fig. 1, Fig. 1 are the SYX-I of 3h intraperitoneal administration 0.22mmol/kg after Reperfu-sion in the MCAO that makes of the present invention3Cerebral infarction volume percentage rate。
After the visible artery occlusion in the brain of Fig. 1 result 24 hours, compared with solvent control group mice, the SYX-I of injection3Significantly reduce cortex, striatum and cerebrum hemispheric infarction volume, it was shown that SYX-I3The Ischemia Brain Damage that middle cerebral artery blocking is caused has significant protective effect。
Above a kind of ferulic acid derivative provided by the present invention, preparation and application thereof are described in detail。Principles of the invention and embodiment are set forth by individual example specifically used herein, and the explanation of above example is only intended to help to understand method and the core concept thereof of the present invention。It should be pointed out that, for those skilled in the art, under the premise without departing from the principles of the invention, it is also possible to the present invention carries out some improvement and modification, these improve and modify in the protection domain also falling into the claims in the present invention。
Claims (10)
1. a ferulic acid derivative, it is characterised in that there is the structure shown in Formulas I or Formula II,
Wherein, R is selected from-H or-CH2CH3, m=3～10；
Wherein, n=3～10。
2. ferulic acid derivative according to claim 1, it is characterized in that, described ferulic acid derivative is specially 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester and 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] one or more in last of the ten Heavenly stems ester。
3. the application in preparation prevention and/or treatment apoplexy class disease medicament of the ferulic acid derivative described in claim 1。
4. application according to claim 3, it is characterized in that, described ferulic acid derivative is specially 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid ethyl ester, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] amoxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptan oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid ethyl ester, 3-methoxyl group-4-{9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems oxygen base cinnamic acid ethyl ester, 3-methoxyl group-4-{3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propoxyl group } cinnamic acid, 3-methoxyl group-4-{4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butoxy } cinnamic acid, 3-methoxyl group-4-{5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] hexyloxy } cinnamic acid, 3-methoxyl group-4-{8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] octyloxy } cinnamic acid, 4-acetyl group-3-methoxybenzene acrylic acid 3-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] propyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-4-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] butyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-5-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] pentyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-6-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] own ester, 4-acetyl group-3-methoxybenzene acrylic acid-7-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] heptyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-8-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] monooctyl ester, 4-acetyl group-3-methoxybenzene acrylic acid-9-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] ninth of the ten Heavenly Stems ester or 4-acetyl group-3-methoxybenzene acrylic acid-10-[4-(3H-1, 2-dithiole-3-thioketone-5-base) phenoxy group] last of the ten Heavenly stems ester。
5. apply according to claim 3, it is characterised in that the apoplexy that described apoplexy includes the apoplexy that caused by cerebral vessels embolism and/or cerebral ischemia causes。
6. apply according to claim 3, it is characterised in that described apoplexy includes cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack, sudden cardiac arrest cause one or more in cerebral ischemia, cerebral hemorrhage and cerebral arteriosclerosis apoplexy of causing。
7. a preparation, it is characterised in that include ferulic acid compounds and pharmaceutically acceptable adjuvant；
Described ferulic acid compounds is ferulic acid derivative described in any one and/or its pharmaceutically acceptable salt in claim 1～2。
8. preparation according to claim 7, it is characterised in that the dosage form of described preparation is oral formulations, injection, suppository, inhalant or the dosage form that may be directly applied to cerebral ischemia position。
9. preparation according to claim 7, it is characterized in that, the dosage form of described preparation is capsule, microcapsule, tablet, granule, pill, dispersed powders, liquid preparation, soft extract, suspending agent, syrup, gel, aerosol, patch, liposome, oral liquid, intravenous fluid or intramuscular injection。
10. preparation according to claim 7, it is characterised in that the dosage of described ferulic acid compounds is 0.05mg/kg～90mg/kg。
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| CN111440068A (en) * | 2020-04-29 | 2020-07-24 | 陕西中医药大学 | Cinnamate derivatives and their use as tyrosinase inhibitors and gels |
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| CN111035632A (en) * | 2019-12-27 | 2020-04-21 | 天津市肿瘤医院 | Activator of Nrf2 and application of activator in preparation of drugs for preventing and treating environmental toxic substances |
| CN111440068A (en) * | 2020-04-29 | 2020-07-24 | 陕西中医药大学 | Cinnamate derivatives and their use as tyrosinase inhibitors and gels |
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