CN109091483A - Compounds for treating stroke and reducing nerve damage and uses thereof - Google Patents

Compounds for treating stroke and reducing nerve damage and uses thereof Download PDF

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Publication number
CN109091483A
CN109091483A CN201810600675.8A CN201810600675A CN109091483A CN 109091483 A CN109091483 A CN 109091483A CN 201810600675 A CN201810600675 A CN 201810600675A CN 109091483 A CN109091483 A CN 109091483A
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represent
formula
compound
brain
acid
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吴郁彬
罗吉孟
石英珠
梁惠如
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Jiya Biotechnology Co ltd
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Jiya Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to compounds useful for treating stroke and reducing nerve damageAnd uses thereof. The present invention discloses the use of a compound of the formula:

Description

For treating apoplexy and reducing the compound and application thereof of neurotrosis
Technical field
The present invention relates to for treating apoplexy and mitigating the compound and application thereof of neurotrosis.
Background technique
Cerebrovascular accident (cerebrovascular accident, CVA), is commonly called as headstroke (stroke), refers to brain The extremely caused brain function rapid loss of blood supply.The most common factor is thrombus, embolism and bleeding.It is due to brain The blood supply in portion is destroyed so that brain local cells can not obtain enough nutrients and oxygen, cause the function of nerve by Damage.Apoplexy can be divided into hemorrhagic stroke (hemorrhage stroke) and ishemic stroke (ischemia stroke).Ischemic Property apoplexy or hemorrhagic cerebral apoplexy all may cause brain function exception.Hemorrhagic stroke usually has due to intracerebral hemorrhage Compared with high mortality.For ishemic stroke due to cerebral ischaemia caused by cerebral thrombosis and cerebral embolism, the death rate is usually lower, but holds Easily lead to the damage in terms of nerves behavioral ability.Common stroke symptom include can not move unilateral limbs or unilateral body without Sense can not understand other people language, can not speak, feel very dizzy, lose the unilateral visual field etc..The patient of apoplexy may also have The long-term sequelaes such as pneumonia, the urinary incontinence.
Hypertension is the Major Risk Factors of apoplexy.Other factors include age, apoplexy medical history, Temporary ischemia heart Disease, diabetes, high cholesterol, smoking and atrial fibrillation etc..Therefore, the drug of apoplexy is treated and prevented at present, more typically Person is anticoagulation medicine (warfarin (Warfarin) TAB, COFaRin TAB, dabigatran (Dabigatran)), antiplatelet Drug (such as aspirin (Aspirin), clopidogrel (Clopidogrel), ticlopidine (Ticlopidine), double phonetic reach Not (Dipyridamole) and brain Kangping (Aggrenox)), Brain circlulation improve drug (pentoxifylline (Pentoxifylline), biloba extract object, Piracetam (Piracetam) and nicametate (Nicametate)), anti-agglutinant (anticoagulants), blood-pressure drug, Pitavastatin class (statins) etc..
In view of the side effect of said medicine, those skilled in the art actively find low bio-toxicity, few side effects and have Protect the alternative medicine of apoplexy back brain neurotrosis function.For example, Chinese Patent No. CN 101,406,569 B open uses The medical composition of traditional Chinese medicine composition for treating cranial vascular disease.9333207 B2 disclosure of U.S. Patent No. US uses 1- Buddha's warrior attendant Alkane ethyoxyl-morpholinyl -2- propyl alcohol (1-adamantylethyloxy-3-morpholino-2-propanol) treats brain blood Neurodegenerative disease in pipe lesion and central nervous system.TaiWan, China patent I 461204 open antrodias (Antrodia camphorata) treats the effect of apoplexy.U.S. Patent No. US 8,486,460 B2 disclose for reducing in The herbal composite of wind possibility and method for treating apoplexy.
There is still a need for the new method/medical compositions for the treatment apoplexy for developing without side-effects and hypotoxicity.
Summary of the invention
The present invention provides a kind of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) compound and is preparing The purposes in drug for treating apoplexy and reduction neurotrosis:
Wherein R1Represent O, α-OH or β-H；R2Represent H or OH；R3Represent O, α-H, β-OAc or H2；R4Represent H or OH；R5 Represent H or OH；R6Represent COOH or COO (CH2)n-CH3；R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represents single Key or double bond；N represents 0 to 3 integer；Or
Wherein R21Represent CH3, COOH or COO (CH2)n-CH3, n represents 0 to 3 integer；Each R22、R23And R24It can be with Represent OCH3Or R22With R23O-CH can be formed together2-O；Or R23With R24O-CH can be formed together2-O。
In one embodiment of the invention, compound may is that
Wherein R1Represent O or α-OH；R2Represent H or OH；R3Represent O, β-OH or H2；R4Represent H or OH；R7Represent H, OH or OAc；Dotted line represents singly-bound or double bond.
In one embodiment of the invention, compound may is that
Wherein R1Represent O or α-OH；R2Represent H or OH；R3Represent O, β-OH or H2；R4Represent H or OH；Dotted line represents singly-bound Or double bond R5Represent H or OH；R6Represent COOH or COOEt；R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represents single Key or double bond.
In one embodiment of the invention, compound may is that
Wherein R1Represent O, α-OH or β-H；R3Represent O, α-H, β-OAc or H2；R5Represent H or OH；R6Represent COOMe.
In one embodiment of the invention, compound may is that
Wherein R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represents singly-bound or double bond.
In one embodiment of the invention, compound can be lanostane, such as shown below:
In one embodiment of the invention, formula (Ia) compound is dehydroeburicoic acid (dehydroeburicoic Acid), as shown below:
In one embodiment of the invention, formula (Ia) compound is dehydrosulphurenic acid (dehydrosulphurenic acid (dehydrosulfurenic acid), such as shown below:
In one embodiment of the invention, formula (II) compound is 4,7- dimethoxy -5- methyl-1, and 3- benzo two is disliked Luxuriant (4,7-Dimethoxy-5-methyl-1,3-benzodioxole), such as shown below:
In one embodiment of the invention, formula (Ib) compound is antrodia acid A
((6R)-2-methyl-3-methylidene-6-[(4S,5S,10S,13R,14R17R)-4,10,13- trimethyl-3,11-di oxo-2,4,5,6,7,12,14,15,16,17-decahydro-1H-cyclopenta[a] Phenanthren-17-yl] heptanoic acid), it is such as shown below:
In one embodiment of the invention, formula (Ib) compound is antrodia acid B
((2S,6R)-2-methyl-3-methylidene-6-[(4S,5S,10S,13R,14R,17R)-4,10,13- trimethyl-3,7,11-trioxo-1,2,4,5,6,12,14,15,16,17-decahydrocyclopenta[a] Phenanthren-17-yl] hept anoic acid), it is such as shown below:
In one embodiment of the invention, formula (Ib) compound is antrodia acid C
((6R)-6-[(4S,5S,7S,10S,13R,14R,17R)-7-hydroxy-4,10,13-trimethyl-3,11- dioxo-2,4,5,6,7,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]- 2-methyl-3-methyli deneheptanoic acid), such as shown below:
In one embodiment of the invention, formula (Ib) compound is antrodia acid H
((2S,6R)-6-[(3R,4S,5S,10S,12S,13R,14R,17R)-3,12-dihydroxy-4,10,13- trimethyl-7,11-dioxo-2,3,4,5,6,12,14,15,16,17-decahydro-1H-cyclopenta[a] Phenanthren-17-yl] -2-meth yl-3-methylideneheptanoic acid), it is such as shown below:
In one embodiment of the invention, formula (Ib) compound is antrodia acid K
((6R)-2-methyl-3-methylidene-6-[(4R,10S,13R,14R,17R)-3,4,7- trihydroxy-4,10,13-tri methyl-11-oxo-2,3,5,6,7,12,14,15,16,17-decahydro-1H- Cyclopenta [a] phenanthren-17-yl] heptanoic acid), it is such as shown below:
In a preferred embodiment of the invention, apoplexy is ishemic stroke.
On the other hand, the present invention also provides formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) chemical combination Object is in preparation for treating the purposes in apoplexy and the drug for reducing neurotrosis.
It yet still another aspect, the present invention provides a kind of medical composition for treating apoplexy and reducing neurotrosis, packet Formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or (II) compound and one or more medicine containing therapeutically effective amount Upper acceptable carrier.
It should be appreciated that above-mentioned general description and described in detail below only exemplary and explanatory, rather than to this The limitation of invention.
Detailed description of the invention
When read in conjunction with the accompanying drawings, it is better understood with above-mentioned general introduction and of the invention described in detail below.In order to say Currently preferred embodiment is shown in the attached drawings in bright the object of the invention.
Fig. 1 is to control in one embodiment of the invention in initiation ischemia apoplexy (MCAO operation) administering in first 10 minutes Treat the time flow chart for using compound.Wherein, progress neurobehavioral assessment in 0.5,1.5 and 24 hour after the operation.
Fig. 2A to Fig. 2 C be one embodiment of the invention neurobehavioral analysis and assessment in determine rat nerve injury The schematic diagram of degree method.
Fig. 3 be in one embodiment of the invention each control group and experimental group 0.5,1.5,24 hour after MCAO operation Progress neurobehavioral assessment analysis as a result, wherein data is indicated with average value ± standard deviation, * * expression p value < 0.01, * * * indicates p value < 0.001, sample number 3-5.
Fig. 4 A is the brain sectional view in one embodiment of the invention, is cut by range of the brain from front end to 15mm Seven, every has thickness 2mm, and removes the part of brain tip 1mm.
Fig. 4 B is the brain blocking part and infarct volume of each compound and control group in embodiment according to Fig. 4 A Percentage, analysis brain infraction region be brain from front end to the range of 15mm, wherein data are with average value ± standard deviation Difference indicates that * indicates that p value < 0.05, * * indicates that p value < 0.01, * * * indicates p value < 0.001, sample number 3-5.
Fig. 4 C is the total infarct volume (Infarct of the brain of each compound and control group in embodiment according to Fig. 4 A Volume, %), brain block analyzed area be brain from front end to the range of 15mm, wherein data are with average value ± standard Deviation indicates that * * indicates that p value < 0.01, * * * indicates p value < 0.001, sample number 3-5.
Fig. 5 be in one embodiment of the invention each control group and experimental group 24 hours after MCAO operation consent and operation Changes of weight analysis chart, wherein data are indicated with average value ± standard deviation, * indicate p value < 0.05, * * * indicate p value < 0.001, sample number 3-5.
Specific embodiment
Unless otherwise defined, there is all technical and scientific terms used herein field of the present invention tool usually to know The meaning that the personnel of knowledge can routinely understand.
The present invention provides formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) and formula (II) compounds to use in preparation Purposes in treatment apoplexy and the drug of reduction neurotrosis, wherein R1Represent O, α-OH or β-H；R2Represent H or OH；R3Generation Table O, α-H, β-OAc or H2；R4Represent H or OH；R5Represent H or OH；R6Represent COOH or COO (CH2)n-CH3；R7Represent H, OH Or OAc；R8Represent CH3Or COOH；Dotted line represents a singly-bound or a double bond；R21Represent CH3, COOH or COO (CH2)n-CH3, n generation The integer of table 0 to 3；Each R22、R23And R24OCH can be represented3Or R22With R23O-CH can be formed together2-O；Or R23With R24O-CH can be formed together2-O。
According to the present invention, compound may is that
R1 R2 R3 R4 Δ
Antcin A O H H2 H
Antcin B O H O H
Antcin C O H β-OH H
Antcin D O H O OH
Antcin E O H H2 14
Antcin F O H β-OH 14
Antcin K α-OH OH β-OH H
According to the present invention, compound is also possible to:
According to the present invention, compound may is that
R6=COOMe
According to the present invention, compound may is that
According to the present invention, compound may is that
(lanostane).
According to the present invention, the compound of formula (II) may is that
According to the present invention, the compound of formula (Ia) may is that
(dehydrotumulosic acid urea)；
(dehydrotumulosic acid)；
(3- table-dehydrotumulosic acid)；
(dehydrosulphurenic acid)；
(dehydrotumulosic acid urea-methyl esters)；
((20 ξ) -3 β, 15 α, 16 α-trihydroxy -24- methyl wool steroid - 7,9 (11), 24 (241)-triolefin -21- acid；15 Alpha-hydroxy dehydrotumulosic acids)；
(- 3 table dehydrotumulosic acid ester (methyl) of methyl 25- hydroxyl)；
(dehydroabietate)；
(15 α-acetyl group dehydrosulphurenic acid)；
(15α-acetyldehydrosulphurenic acid)；
(dehydrosulphurenic acid)；
(29- hydroxyl dehydroabietate ((3 β, 16 α) -3- (acetoxyl group) -16,29- dihydroxy -24- methylene wool Steroid -7,9 (11)-diene -21- acid)；And
(dehydroeburicoic acid).
According to the present invention, the compound of formula (Ib) may is that
(antrodia acid A)；
(antrodia acid B)；
(antrodia acid C)；
(antrodia acid H)；And
(antrodia acid K).
According to the present invention, the compound of formula (II) may is that
(4,7- dimethoxy -5- methyl-1,3- benzo two dislike cyclopentadienyl).
In the present invention, these compounds are proved effectively to treat apoplexy, especially ishemic stroke, and reduce nerve Damage.Especially dehydroeburicoic acid, 4,7- dimethoxy -5- methyl-1,3- benzo two dislike cyclopentadienyl, dehydrosulphurenic Acid and dehydrosulphurenic acid provide significant effect in wind and reduction neurotrosis in the treatment.
Therefore, the present invention provides formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) compound and is preparing The purposes in drug for treating apoplexy and reduction neurotrosis.
On the other hand, the present invention provides a kind of method treated apoplexy and reduce neurotrosis, and this method includes to having The individual administering needed includes formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) chemical combination of therapeutically effective amount The medical composition of object.
Terminology used herein " therapeutically effective amount " refers to compared with the corresponding individual for not yet receiving the amount, compound or medicine The amount of agent causes to treat, healing, prevention or improvement disease, obstacle or side effect, or reduce the tempo of disease or illness Effect.The term further includes the amount for effectively enhancing normal physiological function within its scope.
In order to use in the treatment, the therapeutically effective amount of compound is formulated as to the medical composition for being used to be administered.Therefore, The present invention also provides the formula (Ia) comprising therapeutically effective amount, formula (Ib), formula (Ic), formula (Id), formula (Ie) or (II) compounds With the medical composition of one or more pharmaceutically acceptable carriers.
Terminology used herein " pharmaceutically acceptable carrier " refers to acceptable carrier, diluent or excipient, It is compatible with other ingredients of preparation and for administer medical composition individual be not harmful.According to wanting for pharmaceutical preparation It asks, this field is usually known or any carrier for using, and diluent or excipient can be used for the present invention.
According to the present invention, medical composition may be adapted to administer by any approach appropriate, including but not limited to oral, directly Intestines, nasal cavity, part, vagina or non-oral routes.In a specific embodiment of the invention, which is configured to For oral administration.Such preparation can be prepared by any method known to field of medicaments.
The present invention is further illustrated by the following examples, these embodiments should be construed as only having it is illustrative, and It is non-to limit to rest part of the invention in any way.Without further elaborating, the personnel that this field has usual knowledge can Based on description herein, the present invention is made full use of.
Prepare embodiment
Embodiment 1 prepares active constituent: dehydroeburicoic acid and 4,7- dimethoxy -5- methyl-1,3- benzo two dislike cyclopentadienyl
It by 100 grams of antrodia fructification (g), flows back in such a way that methanol is heated to reflux 6 hours, collects extract liquor and depressurized After concentrate drying, totally 15 grams of antrodia methanol extraction object are obtained.
Above-mentioned 15 grams of antrodia fructification methanol extraction object are taken, with silica-filled, through eluent " n-hexane/acetic acid second Ester/methanol " makees gradient elution and carries out tubing string separation (3x12cm), obtains dehydroeburicoic acid (number: AR-04-41S), 4,7- bis- Methoxyl group -5- methyl-1,3- benzo two dislike cyclopentadienyl (number: AR-04-15S) and dehydrosulphurenic acid (number: AR-04- 1822S)。
It was found that obtaining following three kinds of compounds:
Dehydroeburicoic acid (number: AR-04-41S), has following structural:
4,7- dimethoxy -5- methyl-1s, 3- benzo two dislike cyclopentadienyl (number: AR-04-15S), have following structural:And
Dehydrosulphurenic acid (number: AR-04-1822S), has following structural:
Embodiment 2: Efficacy experiments
Experimental animal
It is the domestication by 1 week using the male SD rat of 7 week old purchased from Le Sike biotechnology company in experiment And quarantine.These rats are the assessments for ishemic stroke.
Raise environment
These rat feedings are stood in industrial research institute biomedicine experiment animal.The light application time in raising area, which automatically controls, is 12 hours bright, 12 hours dark, room temperatures: 23 ± 2 DEG C, relative humidity: 40-70%.Animal can freely obtain sufficient food and drink Water.Clinicing symptom observation is carried out daily by the court veterinarian and testing crew respectively during quarantine and test and is noted down, with true Protect experimental animal health status.
Animal observation
Clinical observation is carried out during test daily, and records whether animal has other clinical symptoms or death.Official holiday day As usual clinicing symptom observation is carried out.It was found that and recording dead and all abnormal symptoms with different degrees of seriousness in animal In clinicing symptom observation record.Dead animal must also be dissected, to find out the possible cause of death.
Animal packet and individual identification
After experimental animal is tamed 1 week, the rat being in a good state of health is selected.After weighing, the grouping of S type is carried out.3 animals in In 1 feeding cage, ear indicates number to distinguish experimental rat.Stick Cage card mark cage number, strain, week old, number of animals, Test number tests group, during enter the room date and test.
1. the zootype experiment for causing ischemia apoplexy (MCAO)
Middle artery ischemia/reperfusion stream mode (Middle Cerebral Artery Occlusion, MCAO/ Reperfusion model)
By animal subject (in this example for 250-350 grams of male SD rat) with 2% isoflurane (isoflurane) in N2O/O2Gas anesthesia in (70%/30%).Right side general neck artery (right is isolated by neck Common carotid artery, right CCA), arteria carotis externa (external carotid artery, ECA) and interior neck Artery (internal carotid artery, ICA).
Along scalp midline incision, by nylon monofilament line, (front end covers the nylon monofilament of polysiloxanes (polysiloxane) Line (nylon monofilament)), it is inserted into via arteria carotis externa, extends to brain Wei Lishi ring along arteria carotis interna (circle of Willis) causes arteria cerebri media (middle cerebral artery) to block.Through lacking after an hour After blood, then nylon monofilament line removed, restores the re perfusion (reperfusion) of brain blood.It, will be big after 24 hours The brain taking-up of mouse is sliced, and every has thickness 2mm, totally seven, is analyzed with doing brain Embolization area.
Experimental design and grouping
Two batch experiments are carried out, four groups of progress of every batch of point, every group there are 5 rats, amounts to 40 rats.
It is to be tested using avoidance mode in one embodiment of the invention, as shown in Figure 1.Every group of animal subject is in reality Apply first 10 minutes of ishemic stroke zootype (MCAO) (min) administer respectively above-mentioned number AR-04-41S, AR-04-15S and Each 50mg/kg of the compound of AR-04-1822S.
It include the blank control group that any compound is performed the operation and do not administered without MCAO in above-mentioned avoidance mode experiment (sham), and MCAO operation is carried out, and replaces the solvent control group (Vehicle) of aforesaid compound with water.
As a result
I. neurobehavioral analysis and assessment
It is postoperative that neurobehavioral assessment in one embodiment of the invention carries out MCAO in each group rat respectively 0.5, rat was tested in 1.5 and 24 hours (hr), and is classified (score) according to following states.This analysis and assessment Purpose is the severity for assessing rat brain nerve damage.
0th grade: rat is lifted to about 20 to 30 centimetres of ground or more from tail, observes the state of rat forelimb performance stretching, extension, The state of rat forelimb performance is balanced can to stretch to the ground, does not occur other nerve damages, such as Fig. 2A, represents normal rat.
1st grade: rat is lifted to about 20 to 30 centimetres of ground or more from tail, observes the state of rat forelimb performance stretching, extension, Rat forelimb performance shrinks such as Fig. 2 B toward the opposite side of brain affected area.
2nd grade: rat being placed on the ground and imposes lateral thrust, rat is to brain affected area with the resistance of side-thrust Decline, experimental method such as Fig. 2 C.
3rd level: when moveing freely rat, rat continuous can not keep straight on to injured brain region opposite side pitch of the laps.
4th grade: because of serious nerve damage, paralysis or epilepsy is presented in rat four limbs.
0.5,1.5 and 24 hour neurobehavioral assessment result such as Fig. 3 institute after each control group and experimental group MCAO operation Show.(Student ' s t test) is examined to compare between the group and solvent control group that administer each compound whether have difference using T It is anisotropic.Significant difference is indicated if p value is less than or equal to 0.05.As shown in Figure 3, neural in 1.5 hours at least after MCAO operation It is impaired to become serious, 24 hours time points, administer the chemical combination such as number AR-04-15S, AR-04-1822S and AR-04-41S The group of object, neurotrosis have recovery to be inclined to, wherein the effect of group of administering AR-04-1822S and AR-04-41S has Statistical significant property, p value is less than 0.01.
II. brain infarct area is analyzed
24 hours after MCAO operation, the brain of rat is taken out, the oxygen containing normal saline solution (0.95% of low temperature is placed in Normal saline) in.The coronal section of each brain is cut into 7, every has thickness 2mm.Remove brain forward position 1mm. Then it is soaked with 1% 2,3,5 triphenyltetrazolium chlorid (2,3,5-triphenyltetrazolium chloride, TTC) Moisten brain tissue slice, reaction 30 minutes is carried out in 37 DEG C of insulating boxs.Slice is fixed in 4% formalin solution, to take the photograph Shadow system (MarcoPATH Digital Image System) record, as shown in Figure 4 A.Brain as shown in figs. 4 b and 4 c The percentage of infarct volume is calculated by image analysis software (ImageJ 1.42q).
Fig. 4 B provides the brain blocking part and infarct volume of each compound and control group in the embodiment according to Fig. 4 A Percentage, analyze from front end to 15mm range brain block region.Fig. 4 C is shown in the embodiment according to Fig. 4 A The total infarct volume of brain (Infarct Volume, %) that each compound and control group are administered to each rat, from front end to The area of the surface analysis infraction brain of 15mm.The present embodiment is examined using T.By Fig. 4 B and Fig. 4 C it is found that administering number AR- The group of 04-15S compound has effects that significant reduction infarct size from brain front end 7mm, 9mm and 11mm.Administering The group of number AR-04-1822S compound at brain front end 3mm, 5mm, 7mm, 9mm, 11mm and 13mm have it is significant The effect of reducing infarct size.Administer number AR-04-41S compound group apart from brain front end 3mm, 7mm, 9mm, Has effects that significant reduction infarct size at 11mm and 13mm.Among them, number AR-04-1822S compound is in distance Brain front end 7mm, 9mm provides obvious more preferable effect on reducing infarct size；Number AR-04-41S compound is also big in distance More preferable effect (p value is less than 0.001) is provided at the 7mm of brain front end.
As shown in Figure 4 C, the infarct volume of solvent control group (Vehicle) is more than 30%.Compared to solvent control group (Vehicle), all compound provides significant effect on reducing infraction below: (p value is less than number AR-04-15S 0.01), number AR-04-1822S (p value is less than 0.001) and number AR-04-15S (p value is less than 0.01).Among them, it compiles Number AR-04-41S, i.e., above-mentioned dehydroeburicoic acid have the effect of that best (infarct volume is less than on reducing infarct volume 10%).
III. weight is analyzed
Following table one show the equal rats before implementing middle artery ischemic/reperfusion mode operation (0hr) with perform the operation after 24 hours (changes of weight r) for 24 hours:
One changes of weight table of table
In Table 1, AVG refers to that average value, SEM refer to standard error (Standard Error of the mean), T- Test refers to that T is examined.See also Fig. 5.Fig. 5 shows that each control group and experimental group are in MCAO in one embodiment of the invention 24 hours changes of weight analysis charts after operation consent and operation.As shown in figure 5, after cerebral ischemia these rats weight loss, The group of the compound of middle administering number AR-04-1882S (p value is less than 0.05) and number AR-04-15S (p value is less than 0.05) Comparing solvent control group (Vehicle) has significant obstruction for weight loss.
In conclusion dehydroeburicoic acid (number: AR-04-41S), 4,7- dimethoxy -5- methyl-1,3- benzo two are disliked Cyclopentadienyl (number: AR-04-15S) and dehydrosulphurenic acid (number: AR-04-1822S) are subtracting for 24 hours after MCAO operation Significant effect is provided on few rat nerve injury, and is also reduced because of MCAO brain infarct volume caused by operation.Among them, The dehydroeburicoic acid (number: AR-04-41S) that dosage is 50mg/kg and the dehydrosulphurenic acid that dosage is 50mg/kg (are compiled Number: AR-04-1822S) there is statistical significant effect relative to solvent control group (Vehicle) on reducing neurotrosis. Dehydroeburicoic acid (number: AR-04-41S) that all dosage are 50mg/kg, 50mg/kg dehydrosulphurenic acid (number: AR-04-1822S it) dislikes cyclopentadienyl (number: AR-04-15S) with the 4,7- dimethoxy -5- methyl-1 of 50mg/kg, 3- benzo two and is subtracting Few rat relative to solvent control group (Vehicle) has statistical significant effect because of MCAO brain infarct volume caused by operation Fruit.
Although the present invention is disclosed with preferred embodiment, it is not intended to limit the present invention.The neck of technology belonging to any Those who have general knowledge in domain, without departing from the spirit and scope of the present invention, when can change and modify.Therefore this hair Bright protection scope is subject to view appended claims institute confining spectrum.

Claims (11)

1. formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) compound are in preparation for treating apoplexy and subtracting Purposes in the drug of few neurotrosis:
Wherein R1Represent O, α-OH or β-H；R2Represent H or OH；R3Represent O, α-H, β-OAc or H2；R4Represent H or OH；R5Represent H Or OH；R6Represent COOH or COO (CH2)n-CH3；R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represents singly-bound or double Key；N represents 0 to 3 integer；Or
Wherein R21Represent CH3, COOH or COO (CH2)n-CH3, n represents 0 to 3 integer；Each R22、R23And R24It can represent OCH3Or R22With R23O-CH can be formed together2-O；Or R23With R24O-CH can be formed together2-O。
2. purposes according to claim 1, wherein the compound is:
Wherein R1Represent O or α-OH；R2Represent H or OH；R3Represent O, β-OH or H2；R4Represent H or OH；Dotted line represents singly-bound or double Key.
3. purposes according to claim 1, wherein the compound is:
Wherein R1Represent O or α-OH；R2Represent H or OH；R3Represent O, β-OH or H2；R4Represent H or OH；Dotted line represents singly-bound or double Key R5Represent H or OH；R6Represent COOH or COOEt；R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represent singly-bound or Double bond.
4. purposes according to claim 1, wherein the compound is:
Wherein R1Represent O, α-OH or β-H；R3Represent O, α-H, β-OAc or H2；R5Represent H or OH；R6Represent COOMe.
5. purposes according to claim 1, wherein the compound is:
Wherein R7Represent H, OH or OAc；R8Represent CH3Or COOH；Dotted line represents singly-bound or double bond.
6. purposes according to claim 1, wherein the compound is:
7. purposes according to claim 1, wherein the formula (Ia) compound is:
8. purposes according to claim 1, wherein the formula (Ib) compound is:
9. purposes according to claim 1, wherein the formula (II) compound is
10. purposes according to claim 1, wherein the compound is
11. purposes according to claim 1, wherein the apoplexy is ishemic stroke.
CN201810600675.8A 2017-06-12 2018-06-12 Compounds for treating stroke and reducing nerve damage and uses thereof Pending CN109091483A (en)

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Application publication date: 20181228