CN107163012A - Dioxy substituted phthalide compound of one class, 3 alkyl 5,6 and its production and use - Google Patents
Dioxy substituted phthalide compound of one class, 3 alkyl 5,6 and its production and use Download PDFInfo
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- 0 C*c(c(O*)c1)cc(C(*)O2)c1C2=O Chemical compound C*c(c(O*)c1)cc(C(*)O2)c1C2=O 0.000 description 1
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- UOUWBHQPMHVVJI-UHFFFAOYSA-N CC(CC=C)C(c(c1c2)cc(OC)c2OC)OC1=O Chemical compound CC(CC=C)C(c(c1c2)cc(OC)c2OC)OC1=O UOUWBHQPMHVVJI-UHFFFAOYSA-N 0.000 description 1
- UGMIVWSKMRFFEI-UHFFFAOYSA-N COc(cc(C(CC=C)OC1=O)c1c1)c1OC Chemical compound COc(cc(C(CC=C)OC1=O)c1c1)c1OC UGMIVWSKMRFFEI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention provides dioxy substituted phthalide compound of 3 alkyl of a class 5,6 and its production and use.Shown in the structure of phthalide analog compound such as formula (I)：Wherein, R1、R2And R3Definition as described in the description and the claims.Phthalide analog compound of the invention is convieniently synthesized, stability and security are preferable, with significant anti-inflammatory activity and neuroprotection, available for the medicine for preparing prevention and/or treatment the nervous system disease.
Description
Technical field
The present invention relates to class 3- alkyl -5,6- dioxy substituted phthalide compounds and its production and use, belong to doctor
Medicine technical field.
Background technology
Neuroinflamation and the pathogenesis of many nervous system diseases are closely related.These diseases are related to alzheimer
Disease, vascular dementia, Parkinson's, multiple sclerosis, ALS disease, diabetic neuropathy, and ischemic
Property cerebral apoplexy, hemorrhagic apoplexy, brain tissue impairment caused by wound etc..In addition, long-term or excessive inflammatory reaction is also possible to
Cause the mental illnesses such as depression and anxiety.Inflammation in brain is thin by the microglia activated and the astroglia of reactivity
What born of the same parents were induced.These cells are to play under the intrinsic immunocyte of intracerebral, physiological status to remove disease in central nervous system
The effect of the allogenic materials such as pathogenic microorganism and itself non-viable non-apoptotic cell, to maintain the stabilization of environment in nerve fiber；Under pathological state,
Spongiocyte sustained activation under the stimulation of various cause of disease materials, largely secretes a variety of inflammatory factors, such as tumor necrosis factor-alpha,
Interleukin -1β and interferon-γ etc., form pathology cascade reaction, cause neure damage even dead, induce or aggravate nerve
System lesion.In recent years research discovery, dangerous associated molecular pattern (DAMPs)-peroxide of Post stroke nerve cell release
Reduce enzyme family (Prxs) lose antioxidation activity, but can activating macrophage TLR2/TLR4 and mediate neuritic, be palsy
Central pathological physiological mechanism [the Nature Medicine.2011,17 of tissues following MCAO in rats damage:796；Nature
Medicine.2012,18:858]。
Another key factor of influence nervous function is the insufficient or unbalance of body substance and energy, especially
It is caused by cerebrovascular disease glycosyloxy supply lack and other material energy metabolisms it is unbalance.For example, nerve retrograde affection
Generation development and the Abnormality of Glycolipid Metabolism such as diabetes, obesity, hypercholesterolemia between there is obvious positive correlation.In hair
Sick early stage, utilization and brain blood flow of the brain to sugar is decreased obviously, and is caused patient's brain microcirculation blood flow state change, is limited
The compensatory of brain blood flow has been made, has made the deficiencies such as oxygen, the glucose of supply brain, the disorderly of nervous system material energy metabolism is ultimately caused
Disorderly, the nervous system disease is triggered.
Therefore, the inflammatory factor suppressed under pathological state excessively discharges, and the material energy metabolism for improving brain is to mitigate god
Important Intervention Strategy through damage.
China's natural pharmaceutical resources enrich, and applicating history is long, are the treasures of modern medicines research and development.To from biography
It is still the effective means for finding original new drug so far with structural modification that the natural products of system medicine, which carries out screening active ingredients,.Butylphthalide
(Butylphthalide, NBP) is that a kind of obtained phthalide compound is extracted from celery seed.Ligusticum wallichii, Radix Angelicae Sinensis, Jehol Ligusticum Rhizome etc. also contain
There is the composition.The butylphthalide of natural origin is with optically active levo form.Its artificial synthesized racemic modification is made at present
For the original new chemical entities medicine of China be used clinically for gently, the treatment of moderate acute ischemic cerebral apoplexy.Research shows,
Butylphthalide has significant neuroprotection, can increase ischemic region cerebral blood flow (CBF) and the microcirculation of reconstruct ischemic region, protective wire
Mitochondria function, suppress platelet aggregation and thrombosis, improve the energetic supersession after global cerebral ischemia, mitigate nervous function damage
Degree, is related to multiple links of cerebral ischemia pathology, has significant therapeutic effect to cerebral apoplexy.In addition, butylphthalide is to A Er
DPN caused by Zi Haimo diseases, vascular dementia, Parkinson's, diabetes, memory disorders, cerebral apoplexy, traumatic brain injury,
Many the nervous system diseases such as epilepsy, depression, which also have, to have some improvement.
But there is also some shortcomings for butylphthalide.For example, the compound is higher boiling grease, its polishing purification is to life
The requirement for producing equipment is high；Unstable in vivo, metabolite clearance is fast；It is grease under normal temperature, is not easy to prepare oral solid formulation,
Only soft capsule is for being administered orally at present；With special odor, discomfort may be caused.
Research finds that in blood plasma ring closure reaction generation butyl benzene can quickly occur for 2- (Alpha-hydroxy amyl group) benzoic acid and its salt
Phthalein.Butylphthalide and alkali reaction are changed into pro-drug, i.e. 2- (Alpha-hydroxy amyl group) benzoic acid and its salt, butyl can be improved
The defect of phthalide itself poorly water-soluble.But, 2- (Alpha-hydroxy amyl group) benzoic acid and its salt, including the nothing such as potassium, sodium, calcium, magnesium, zinc
The organic amine salt such as machine salt and benzylamine, morpholine, diethylamine, often have that crystallinity is poor, hygroscopicity strong, easily decompose, it is acid or in
The shortcomings of unstable under property environment.In addition, the sylvite of 2- (Alpha-hydroxy amyl group) benzoic acid or the aqueous solution of sodium salt are (usual in alkalescence
pH>9), there is certain physiological stimulation.
The present inventor in view of the shortcomings of the prior art, has designed and synthesized a series of phthalide compound, therefrom screened
Active stronger, security more preferably, patent medicine property more preferably phthalide compound.
The content of the invention
To overcome the defect and deficiency that butylphthalide is present, more preferable phthalide-type medicine is obtained, applicant proposed this hair
It is bright.
There is provided a class phthalide compound or its pharmaceutically acceptable solvate, precursor medicine for the first aspect of the present invention
Thing, it is characterised in that selected from formula I：
Wherein：R1Selected from C3-C6 alkyl；R2、R3Independently selected from hydrogen, C1-C3 alkyl, acetyl group.
" alkyl " of the present invention refers to, the aliphatic group of straight or branched, including alkyl, alkenyl, alkynyl.
" solvate " of the present invention refers to, the compound that formula I is represented is and one or more in crystallization process
The aggregation of solvent molecule association.Solvent molecule can be water or other organic solvents (such as ethanol, isopropanol, ether, second
Acetoacetic ester, acetone etc.).
" pro-drug " of the present invention refers to, the phthalide compound that formula I is represented reacts with alkali, occurs lactone open loop
The carboxylic acid and its salt for reacting and generating.Above-mentioned alkali includes inorganic base (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, hydroxide
Calcium etc.), organic base (such as benzylamine, morpholine, ethylenediamine, monoethanolamine, piperazine, choline, methylamine, dimethylamine, trimethylamine, ethamine, diethyl
Amine, triethylamine etc.).Above-mentioned carboxylic acid and its salt can change into the parent drug (phthalide that formula I is represented under physiological condition in vivo
Compound).
On the basis of logical structure shown in formula I, phthalide compound of the present invention, it is characterised in that R1Selected from n-propyl, just
Butyl, n-pentyl, 2- pi-allyls, 2- alkene butyl, 3- alkene butyl, 1- methyl -3- alkene butyl, 1- methyl -2- pi-allyls, 2- first
Base -2- pi-allyls, 1,1- dimethyl -2- pi-allyls, 1,2- dimethyl -2- pi-allyls, 3- methyl -2- alkene butyl, 2,2- diformazans
Base -3- alkene butyl, 3- methyl -3- alkene butyl, 4- methyl -3- alkene amyl group, 1- methyl isophthalic acids-vinyl, 1- ethyl -1- vinyl,
1- propyl group -1- vinyl, 2- propargyls, 3- alkynes butyl；R2And R3Independently selected from hydrogen, methyl, acetyl group.
Phthalide compound of the present invention, further preferably from following compound：
The second aspect of the present invention, described phthalide compound can be prepared via a method which to obtain：
Compound 1 and HCl, 10~80 DEG C of 37% formalin are reacted 4~12 hours, obtain compound 2.With CCl4Or benzene
For solvent, benzoyl peroxide is catalyst, and 20~100 DEG C of reactions 2~8 of compound 2 and N-bromosuccinimide (NBS) are small
When, obtain compound 3.Compound 3 is reacted 1~4 hour for 20~100 DEG C with water, generates compound 4.Compound 4 and alkyl halide
RMgBr (such as R1MgBr、R1MgCl etc.) reaction generation target compound 5.
The third aspect of the present invention is there is provided a kind of pharmaceutical composition, and it includes one or more phthalides of safe and effective amount
Compound and its pharmaceutically acceptable solvate, pro-drug.
" composition " of the present invention refers to, passes through the product for mixing more than one materials or component.This hair
Bright composition is comprising described in 1wt% (percentage by weight) to 95wt%, preferably 10wt% to 80wt% first aspect
Phthalide compound and its pharmaceutically acceptable solvate, pro-drug, with the gross weight meter of described pharmaceutical composition.
" safe and effective amount " of the present invention refers to that the dosage of phthalide compound of the invention is enough to be obviously improved
The state of an illness, and be unlikely to produce serious side effect.The safe and effective amount of the compounds of this invention can be according to method of administration, the year of patient
Age, body weight, disease type and its order of severity etc. change.For body weight 60kg people, being administered daily dosage is usually
10mg to 1500mg, it is therefore preferable to 30mg to 600mg.Once or it can be administered multiple times.
As one of preferred embodiment, the pharmaceutical composition can further add one or more pharmaceutically acceptable
Carrier pharmaceutically acceptable pharmaceutical preparation is made.
" pharmaceutically acceptable carrier " of the present invention refers to, one or more biocompatible solids or liquid filler or
Gelatinous mass, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " is herein
Refer to, in composition each component energy and the phthalide compound of the present invention and they between mutually admix, and significantly reduce phthalide
The drug effect of compound.Pharmaceutically acceptable carrier includes sugared (such as sucrose, lactose, glucose), starch (such as potato shallow lake
Powder, cornstarch etc.), cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate
Deng), dextrin and its derivative, superfine silica gel powder, gelatin, talcum powder, calcium sulfate, kollag (such as magnesium stearate, stearic acid
Deng), vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, castor oil, cottonseed oil, maize germ oil, palm oil),
Alcohols solvent (such as ethanol, propane diols, glycerine, mannitol, sorbierite, polyethylene glycol), surfactant, emulsifying agent, wetting
Agent, colouring agent, flavouring, stabilizer, antioxidant, preservative, without heat source water.
" pharmaceutical preparation " of the present invention includes tablet, capsule, pill, granule, pill, powder, lozenge, note
Penetrate agent, freeze-dried powder, syrup, oral liquid, patch, inhalation powder spray, spray, by oral administration, intravenous injection, intramuscular injection,
Hypodermic injection, the administration of sublingual, transdermal, mouthspray, nasal spray approach.
There is provided the phthalide compound described in first aspect and its pharmaceutically acceptable solvation for the fourth aspect of the present invention
The purposes of pharmaceutical composition described in thing, pro-drug or the third aspect, for preparing prevention and/or treatment the nervous system disease
Medicine.
" the nervous system disease " of the present invention includes alzheimer disease, Parkinson's, multiple sclerosis, flesh and withered
Contracting Lateral Sclerosis, diabetic neuropathy, cerebral arterial thrombosis, hemorrhagic apoplexy, neurotrosis, suppression caused by brain trauma
Strongly fragrant disease, vascular dementia, neuropathic pain.
In another preference, prevention and/or the treatment the nervous system disease is the inflammation by suppressing under pathological state
Inflammation factor excessively discharges realization.
It is by improving the cerebrovascular and blood for the prevention and/or treatment the nervous system disease in another preference
Stream mode, regulation intracerebral material energy metabolism is realized.
There is provided the phthalide compound described in first aspect and its pharmaceutically acceptable solvation for the fifth aspect of the present invention
The purposes of pharmaceutical composition described in thing, pro-drug or the third aspect, is used for：
(a) prepare prevention and/or treat the medicine that neural cell injury is induced by inflammation；
(b) it is used to prepare prevention and/or treats the medicine that neural cell injury is induced by cerebrovascular occlusion.
Beneficial effect
Phthalide compound disclosed in this invention can mitigate the cellular inflammation damage of peroxidase 4 (Prx4) induction,
With significant neuroprotection, its effect is better than butylphthalide；Phthalide compound disclosed in this invention is solid for crystallinity
Body, is difficult moisture absorption, relatively stable without obvious smell, physicochemical properties, compared to the butylphthalide under normal temperature being grease, energy
Conveniently prepare oral solid formulation；Phthalide compound disclosed in this invention is stablized in the range of pH1~9, in blood plasma
In stability be better than butylphthalide；Phthalide compound toxicity disclosed in this invention is low, and security is good.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：
Fig. 1 is for blank group, model group and through various concentrations the compounds of this invention (C-1 to C-6) and butylphthalide (NBP) place
The concentration of RAW264.7 macrophages secretes NO after reason.Compared with model group：*P<0.05、**P<0.01.
Fig. 2 is that the compounds of this invention (C-1 to C-3) and butylphthalide (NBP) change to focal cerebral ischemia neuropathology
Influence.
Embodiment
Following examples are that the present invention is further illustrated, but are never limited the scope of the present invention.Referring to
Embodiment is further elaborated on the present invention, it should be appreciated to those skilled in the art that the present invention is not limited to these implementations
Example and the preparation method used.Moreover, those skilled in the art can be equal according to description of the invention to the present invention
Replace, combine, improve or modify, but these are intended to be included in the scope of the present invention.
Embodiment 1The preparation of 5,6- dimethoxy phthalides
By 37% formalin 280ml, HCl gases are slowly introducing 2 hours, add 3,4- dimethoxybenzoic acids
36.4g, 60 DEG C are reacted 10 hours and are continually fed into HCl.After reaction solution is concentrated under reduced pressure, add water 240ml, stirs, ammonification water
PH7 is adjusted to, stands and separates out precipitation.Precipitation filtering, is washed with water for several times, then is recrystallized with MeOH, obtains clear crystal 23.5g.
Embodiment 2The preparation of 3- hydroxyl -5,6- dimethoxy phthalides
5,6- dimethoxy phthalides 6.76g, benzoyl peroxide 116mg, N-bromosuccinimide 7.0g are dissolved in
CCl488ml, is heated to reflux 4 hours.4 DEG C of reaction solution is placed 12 hours.Filtering, removes precipitation.Filtrate concentrates, and add water 30ml, plus
Heat backflow 1.5 hours.4 DEG C of reaction solution is placed 12 hours.Filtering, frozen water washing filter cake, 50 DEG C are dried under reduced pressure, and obtain white solid
4.38g。
Embodiment 3The preparation of 3- (3 '-methyl -2 '-alkene) butyl -5,6- dimethoxy phthalides
Mg powder 1.0g, N2Protection, adds and the 5ml -2- alkene butyl -1- bromines of methyl containing 3- is added dropwise at anhydrous THF 10ml, 5 DEG C
THF solution (3- methyl -2- alkene butyl -1- bromines 5.6g is dissolved in THF 15ml), after question response triggers, instills surplus solution, 5 DEG C anti-
Answer 2 hours, produce RMgBr.3- hydroxyl -5,6- dimethoxy phthalides 3.0g, which is dissolved at anhydrous THF 27ml, 0 DEG C, to be instilled newly
In the grignard reagent solution of system, 30 DEG C are reacted 12 hours.Add saturation NH4Cl solution 10ml, question response steadily adds 10% afterwards
Hydrochloric acid 13ml, is reacted at room temperature 2 hours.Reaction solution is extracted with ethyl acetate.Upper silicagel column after organic phase concentration, eluant, eluent is oil
Ether-ethyl acetate (5:1) white solid 2.1g, 3- (3 '-methyl -2 '-alkene) butyl -5,6- dimethoxy phthalide, is obtained：HR-
TOF-MS(m/z)：261.1122 ([M-H]-, calculated value：261.1127, [C15H17O4]-)；1H-NMR (400MHz, CDCl3)：δ
7.25 (1H, s), δ 7.23 (1H, s), δ 5.49 (1H, t), δ 5.02 (1H, t), δ 3.88 (3H, s), δ 3.84 (3H, s), δ 2.77
(1H, m), δ 2.46 (1H, m), δ 1.64 (3H, s), δ 1.58 (3H, s).
The preparation of the 3- propargyl -5,6- dimethoxy phthalides of embodiment 4
Mg powder 3.0g, N2Protection, the THF for adding the dropwise addition 15ml -1- bromines of propargyl containing 2- at anhydrous THF 30ml, 5 DEG C is molten
Liquid (2- propargyl -1- bromines 4.5g is dissolved in THF 40ml), question response trigger after, instill surplus solution, 10 DEG C react 1 hour, i.e.,
Obtain RMgBr.3- hydroxyl -5,6- dimethoxy phthalides 9.0g is dissolved in the grignard examination that brand-new is instilled at anhydrous THF 80ml, 0 DEG C
In agent solution, 45 DEG C are reacted 8 hours.Add saturation NH4Cl solution 40ml, question response steadily adds 10% hydrochloric acid 40ml, room afterwards
Temperature reaction 4 hours.Reaction solution is extracted with ethyl acetate.Upper silicagel column after organic phase concentration, eluant, eluent is petroleum ether-ethyl acetate
(3:1) white solid 6.8g, 3- propargyl -5,6- dimethoxy phthalide, is obtained：White solid；HR-TOF-MS(m/z)：
231.0651([M-H]-, calculated value：231.0657, [C13H11O4]-)；1H-NMR (400MHz, CDCl3)：δ 7.29 (1H, s), δ
7.11 (1H, s), δ 5.45 (1H, q), δ 3.99 (3H, s), δ 3.95 (3H, s), δ 2.95 (1H, m), δ 2.68 (1H, m), δ 2.09
(1H, t).
Embodiment 5The plasma stability of phthalide compound
1 will be pressed with phosphate buffer (pH7.4)：The μ l of male SD rat blood plasma 195 of 1 dilution are added in centrifuge tube, so
It is 40 μm of μ l of ol/L test-compounds DMSO solution 5 to add concentration afterwards, and close plug, whirlpool is mixed, and 37 DEG C hatch 3 hours.Use cold second
The μ l stopped reactions of nitrile 600, mix and centrifuge immediately, carry out HPLC measure.To hatch the compound concentration of zero-time as 100%,
Calculate remaining percentage.As a result it is as follows：
| Numbering | Compound name | Remaining percentage |
| C-1 | 3- (3 '-methyl -2 '-alkene) butyl -5,6- dimethoxy phthalides | 94.1% |
| C-2 | 3- (1 ', 1 '-dimethyl -2 '-alkene) propyl group -5,6- dimethoxy phthalides | 89.4% |
| C-3 | 3- (1 '-methyl -2 '-alkene) propyl group -5,6- dimethoxy phthalides | 91.6% |
| C-4 | 3- propargyl -5,6- dimethoxy phthalides | 88.9% |
| C-5 | 3- (2 '-methyl -2 '-alkene) propyl group -5,6- dimethoxy phthalides | 93.7% |
| C-6 | 3- normal-butyl -5,6- dimethoxy phthalides | 87.0% |
| C-7 | 3- (2 '-alkene) butyl -5,6- dimethoxy phthalides | 85.7% |
| C-8 | 3- (1 ', 2 '-dimethyl -2 '-alkene) propyl group -5,6- dimethoxy phthalides | 89.3% |
| C-9 | 3- (3 '-alkene) butyl -5,6- dimethoxy phthalides | 83.5% |
| NBP | NBP | 71.8% |
Embodiment 6Phthalide compound secretes NO influence to cell
The RAW264.7 macrophages in exponential phase are taken, adjustment cell density is 5 × 105Individual/ml, is inoculated in 96
Orifice plate, 100 μ l/ holes, is placed in 37 DEG C, 5%CO2Cultivated in incubator.After after cell attachment 20 hours, culture medium in hole is discarded,
And add 80 μ l/ holes basal mediums, while plus 10 μ l/ holes various concentrations test-compound processing, after 1 hour add
Prx4, final concentration of 20nmol/ml, cell supernatant is collected after 20 hours.Using colorimetric method, with NaNO2Colour developing, in 550nm
NO contents are detected at wavelength, Fig. 1 is as a result seen.
As a result show, Prx4 can stimulate RAW264.7 macrophages to be inflamed reaction, cause NO contents to dramatically increase, and
The phthalide compound of the present invention can suppress NO secretions increase caused by Prx4, mitigate the degree of Cellular inflammatory damage, and effect is excellent
In NBP.
Embodiment 7To the neuroprotection of cerebral ischemia mouse
SPF grades of male C57 mouse, random packet, every group 8, reference literature prepares the of short duration knot of mouse bilateral common carotid arteries
Cerebral ischemic model (the Free Radical Biology and Medicine.2011,50 of bundle:1780-1786；
Neuropharmacology.2014,77:453-464).When Ischemia Reperfusion, 24 hours, 48 hours, difference abdomen
Chamber injection give 30mg/kg different phthalide compounds (C-1 groups, C-2 groups, C-3 groups, NBP groups) or blank solvent (Sham groups with
Model groups).After Reperfu- sion 72 hours, neurogenic behavior rating is carried out, animal is put to death and takes brain Nissl dyeing detection hippocampus CA1s
The survived neuronal cell number at same position, is as a result shown in Fig. 2 in area and corpus straitum CPu brain areas.
Compared with sham-operation group (Sham groups), mouse bilateral common carotid arteries it is of short duration ligation and cause cerebral ischemia, cause model
Group (Model groups) animal nerve behavior disorder, neuron loss and astroglia excessive activation；And given after cerebral ischemia reperfusion
Different phthalide compounds are given to treat, C-1, C-2, C-3 show stronger neuroprotection, can not only improve the low filling shape of brain
The mouse neurobehavioral function of postoperative 24 hours, 48 hours and 72 hours under state, moreover it is possible to increase the god of hippocampus and corpus straitum brain area
Through first cell number, and effect is better than NBP.
Embodiment 8To the acute toxicity of mouse
SPF grades of ICR mouse, 18~20g, male and female half and half, after adaptability is fed 3 days, fasting is weighed random point for 12 hours
Group：Solvent group and administration group (C-1, C-2, C-3).Each test-compound is matched somebody with somebody with 0.5% carboxymethylcellulose sodium solution before use
Suspension decoction processed, given low is 1.0g/20ml/kg；Solvent group gavage 20ml/kg blank solvent.After administration, 48 hours
Interior animal single cage is raised, 2 hours Continuous Observations after medicine, and ditto the weight of animals is weighed within 7 days, 14 days after medicine.
Under the experiment condition, C-1, C-2, C-3 given low 1.0g/kg are showed no any adverse reaction to ICR mouse；
In 14 day observation period, the mouse weight of each administration group and solvent group, which increases, has no difference, without animal dead.As a result show, C-
1st, the safe dose that mouse stomach is administered by C-2, C-3 is all higher than 1.0g/kg.
Embodiment 9The preparation of tablet
1. prescription (1000 amounts)：
| 3- (3 '-alkene) butyl -5,6- dimethoxys phthalide (C-9) | 100g |
| Starch | 50g |
| Microcrystalline cellulose | 20g |
| Magnesium stearate | 2g |
| Sodium carboxymethylcellulose | 5g |
| 50% ethanol | In right amount |
2. preparation method：By 3- (3 '-alkene) butyl -5,6- dimethoxys phthalide, starch, microcrystalline cellulose, carboxymethyl cellulose
Sodium powder is broken, mix, and softwood is made as wetting agent with 50% appropriate amount of ethanol, crosses 20 mesh sieves and pelletizes, 60~80 DEG C of dryings, whole grain, plus
Magnesium stearate is mixed, tabletting, film coating.
Embodiment 10The preparation of injection
1. prescription (1000 bottles of amounts)：
| 3- normal-butyl -5,6- dimethoxys phthalides (C-6) | 50g |
| PEG-400 | 2L |
| Injection ethanol is added to | 5L |
2. preparation method：By 3- (3 '-methyl -2 '-alkene) butyl -5,6- dimethoxy phthalide add PEG-400, stirring and dissolving,
Again plus ethanol is to enough, stir evenly, solution filtration, embedding.Before use with 0.9% sodium chloride injection or 5% glucose injection
Dilution, drip-feed.
Claims (10)
1. phthalide compound, it is characterised in that：Structural formula such as formula I：
Wherein：R1Selected from C3-C6 alkyl；R2、R3Independently selected from hydrogen, C1-C3 alkyl, acetyl group.
2. phthalide compound according to claim 1, it is characterised in that：R1Selected from n-propyl, normal-butyl, n-pentyl, 2- alkene
Propyl group, 2- alkene butyl, 3- alkene butyl, 1- methyl -3- alkene butyl, 1- methyl -2- pi-allyls, 2- methyl -2- pi-allyls, 1,1- bis-
Methyl -2- pi-allyls, 1,2- dimethyl -2- pi-allyls, 3- methyl -2- alkene butyl, 2,2- dimethyl -3- alkene butyl, 3- methyl -
3- alkene butyl, 4- methyl -3- alkene amyl group, 1- methyl isophthalic acids-vinyl, 1- ethyl -1- vinyl, 1- propyl group -1- vinyl, 2- alkynes
Propyl group, 3- alkynes butyl；R2And R3Independently selected from hydrogen, methyl, acetyl group.
3. phthalide compound according to claim 1, it is characterised in that：Including following compound：
4. the pharmaceutically acceptable solvate or pro-drug of the phthalide compound described in claim any one of 1-3, its
It is characterised by：
The solvate refers to：Formula I represent compound in crystallization process, with one or more solvent molecules association and
Into aggregation；
It is preferred that, the solvent molecule is water or such as ethanol, isopropanol, ether, ethyl acetate, acetone and other organic solvent；
The pro-drug refers to：The phthalide compound that formula I is represented reacts with alkali, the carboxylic for occurring lactone ring-opening reaction and generating
Acid and its salt；
Described alkali includes inorganic base, organic base；
Further preferably, the inorganic base includes sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide；
Further preferably, the organic base include as benzylamine, morpholine, ethylenediamine, monoethanolamine, piperazine, choline, methylamine, dimethylamine,
Trimethylamine, ethamine, diethylamine, triethylamine etc..
5. pharmaceutical composition, it is characterised in that：Described pharmaceutical composition is included：(a) therapeutically effective amount be selected from claim
The phthalide compound described in phthalide compound and claim 4 in 1-3 described in any one it is pharmaceutically acceptable molten
One or more in agent compound, pro-drug；And (b) one or more pharmaceutically acceptable carriers.
6. the medicine of the phthalide compound described in phthalide compound and claim 4 in claim 1-3 described in any one
Pharmaceutical composition on described in acceptable solvate, pro-drug or claim 5 is preparing prevention and/or treatment god
Purposes in medicine through systemic disease.
7. purposes according to claim 6, it is characterised in that：Described the nervous system disease include alzheimer disease,
Parkinson's, multiple sclerosis, ALS disease, diabetic neuropathy.
8. purposes according to claim 6, it is characterised in that：Described the nervous system disease include cerebral arterial thrombosis,
Neurotrosis, depression, vascular dementia, neuropathic pain caused by hemorrhagic apoplexy, brain trauma.
9. the medicine of the phthalide compound described in phthalide compound and claim 4 in claim 1-3 described in any one
Pharmaceutical composition on described in acceptable solvate, pro-drug or claim 5 prepare prevention and/or treat by
Inflammation induces the purposes in the medicine of neural cell injury.
10. the medicine of the phthalide compound described in phthalide compound and claim 4 in claim 1-3 described in any one
Pharmaceutical composition on described in acceptable solvate, pro-drug or claim 5 prepare prevention and/or treat by
Cerebrovascular occlusion induces the purposes in the medicine of neural cell injury.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111415A (en) * | 2018-10-25 | 2019-01-01 | 安徽中医药大学 | A kind of dendrobium nobile alcaloid-derivatives, preparation method and medical usage |
| CN114478450A (en) * | 2022-01-10 | 2022-05-13 | 四川大学 | Benzyloxybelphthalide compound, preparation method and application thereof |
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| CN106432161A (en) * | 2016-07-19 | 2017-02-22 | 四川大学 | 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof |
| CN108727352B (en) * | 2017-04-14 | 2021-04-23 | 四川大学 | Piperidine alkane carbamoyl phthalide compounds, preparation method and application thereof |
| KR20220156597A (en) * | 2020-03-20 | 2022-11-25 | 씨에스피씨 엔비피 파머슈티컬 캄파니 리미티드 | Uses of Butylphthalide and Its Derivatives |
| CN112794831B (en) * | 2021-04-06 | 2021-07-27 | 北京理工大学 | 3- (3' -hydroxybutyl) isobenzofuran-1 (3H) -one derivative, composition, preparation method and application thereof |
| KR20240029075A (en) * | 2021-07-21 | 2024-03-05 | 쟝쑤 차이 타이 펑하이 파머큐티컬 컴퍼니 리미티드 | Compounds that treat conditions associated with ischemic brain injury |
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| CN101402623A (en) * | 2008-11-19 | 2009-04-08 | 中国科学院上海有机化学研究所 | 3-substituted benzene phthalein compounds with biological activity |
| WO2013102935A2 (en) * | 2012-01-03 | 2013-07-11 | Council Of Scientific & Industrial Research | Cu-MEDIATED ANNULATION FOR THE EFFECTIVE SYNTHESIS OF 3-SUBSTITUTED PHTHALIDES |
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| EP1937250B1 (en) * | 2005-05-24 | 2011-10-19 | DSM IP Assets B.V. | Ligustilide derivatives for the treatment of inflammatory disorders |
| EP2068863B1 (en) * | 2006-08-11 | 2010-12-15 | DSM IP Assets B.V. | Ligustilide for the treatment of disorders of the central nervous system |
| CN106432161A (en) * | 2016-07-19 | 2017-02-22 | 四川大学 | 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof |
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| CN101402623A (en) * | 2008-11-19 | 2009-04-08 | 中国科学院上海有机化学研究所 | 3-substituted benzene phthalein compounds with biological activity |
| WO2013102935A2 (en) * | 2012-01-03 | 2013-07-11 | Council Of Scientific & Industrial Research | Cu-MEDIATED ANNULATION FOR THE EFFECTIVE SYNTHESIS OF 3-SUBSTITUTED PHTHALIDES |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111415A (en) * | 2018-10-25 | 2019-01-01 | 安徽中医药大学 | A kind of dendrobium nobile alcaloid-derivatives, preparation method and medical usage |
| CN109111415B (en) * | 2018-10-25 | 2022-08-23 | 安徽中医药大学 | Dendrobium alkaloid derivative, preparation method and medical application |
| CN114478450A (en) * | 2022-01-10 | 2022-05-13 | 四川大学 | Benzyloxybelphthalide compound, preparation method and application thereof |
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| WO2018014834A1 (en) | 2018-01-25 |
| CN107163012B (en) | 2020-08-04 |
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