TW201902474A - Compounds for treating stroke and reducing nerve damage and uses thereof - Google Patents

Abstract

The present invention provides a new method for treating stroke or reducing nerve injury. The method comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of the following: (Ia), (Ib), (Ic), (Id), (Ie), or (II); wherein R1 is O, [alpha]-OH or [beta]-H; R2 is H or OH; R3 is O, [alpha]-H, [beta]-OAc or H2; R4 is H or OH; R5 is H, or OH; R6 is COOH or COO(CH2)n-CH3; n is an integer from 0-3; R7 is H, OH or OAc; R8 is CH3 or COOH; R21 is CH3,COOH, or COO(CH2)n-CH3; n is an integer from 0-3; each of R22, R23, R24 is OCH3, or R22 and R23 together form a O-CH2-O; or R23 and R24 together form a O-CH2-O; the dotted line represents a single bond or a double bond.

Description

Compound for treating stroke and reducing nerve damage and use thereof

The present invention relates to compounds for treating stroke and reducing nerve damage and uses thereof.

Cerebrovascular accident (CVA), commonly known as stroke, refers to the rapid loss of brain function caused by abnormal blood supply to the brain. The most common factors are thrombosis, embolism, and bleeding. It is caused by the destruction of the blood supply to the brain, making the local cells of the brain unable to obtain sufficient nutrients and oxygen, resulting in impaired nerve function. Stroke can be divided into hemorrhage stroke and ischemia stroke. Ischemic stroke or hemorrhagic stroke can cause abnormal brain function. Hemorrhagic stroke is caused by intracerebral hemorrhage and usually has a higher mortality rate. Ischemic stroke is caused by cerebral ischemia caused by cerebral thrombosis and cerebral embolism. Mortality is usually low, but it is easy to cause neurobehavioral damage. Common stroke symptoms include the inability to move unilateral limbs or unilateral body sensation, inability to understand other people's speech, inability to speak, feeling spinning, and loss of unilateral vision. Stroke patients may also have long-term sequelae such as pneumonia and urinary incontinence.

High blood pressure is a major risk factor for stroke. Other factors include age, history of stroke, transient ischemic heart disease, diabetes, high cholesterol, smoking and atrial fibrillation. Therefore, the most common drugs for the treatment and prevention of stroke are anticoagulants (Warfarin TAB, COFaRin TAB, Dabigatran), antiplatelet drugs (such as Aspirin, Chlorine) Clopidogrel, Ticlopidine, Dipyridamole and Aggrenox), Cerebral circulation improving drugs (Pentoxifylline), Ginkgo biloba extract, Piracetam (Piracetam and Nicametate), anticoagulants (anticoagulants), antihypertensive drugs, statins (statins), etc.

In view of the side effects of the above-mentioned drugs, those skilled in the art are actively looking for alternative drugs with low biotoxicity, few side effects, and protection of brain nerve damage after stroke. For example, Chinese Patent No. CN 101406569 B discloses a pharmaceutical composition using a traditional Chinese medicine composition for treating cerebrovascular diseases. U.S. Patent No. 9333207 B2 discloses the use of 1-adamantylethyloxy-3-morpholino-2-propanol in the treatment of cerebrovascular disease and in the central nervous system. Neurodegenerative diseases. The Republic of China Patent No. I461204 discloses the efficacy of Antrodia camphorata in treating stroke. US Patent No. 8486460 B2 discloses a Chinese herbal medicine composition for reducing the possibility of stroke and a method for treating stroke.

There remains a need to develop new methods / medical compositions for the treatment of stroke without side effects and low toxicity.

The present invention provides a new method to treat stroke and reduce nerve damage. The method includes administering to a subject in need thereof a pharmaceutical combination comprising a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) Things: Formula (Ia); Formula (Ib); Formula (Ic); (Id); or Formula (Ie) wherein R ₁ represents O, α-OH or β-H; R ₂ represents H or OH; R ₃ represents O, α-H, β-OAc or H ₂ ; R ₄ represents H or OH; R ₅ Represents H or OH; R ₆ represents COOH or COO (CH ₂ ) n-CH3; R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; the dashed line represents a single or double bond; n represents 0 to 3 An integer; or Formula (II) wherein R ₂₁ represents CH ₃ , COOH or COO (CH ₂ ) n-CH ₃ ; n represents an integer from 0 to 3; each of R ₂₂ , R ₂₃ and R ₂₄ may represent OCH ₃ , or R ₂₂ and R ₂₃ may together form O-CH ₂ -O; or R ₂₃ and R ₂₄ may together form O-CH ₂ -O.

In one embodiment of the invention, the compound may be: Wherein R ₁ represents O or α-OH; R ₂ represents H or OH; R ₃ represents O, α-H, β-OH or H ₂ ; R ₄ represents H or OH; R ₇ represents H, OH or OAc; Represents a single or double bond.

In one embodiment of the invention, the compound may be: Wherein R ₁ represents O or α-OH; R ₂ represents H or OH; R ₃ represents O, α-H, β-OH or H ₂ ; R ₄ represents H or OH; dashed line represents single or double bond; R ₅ Represents H or OH; R ₆ represents COOH or COOEt; R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; and the dashed line represents a single or double bond.

In one embodiment of the invention, the compound may be: Wherein R ₁ represents O, α-OH or β-H; R ₃ represents O, α-H, β-OAc or H ₂ ; R ₅ represents H or OH; R ₆ represents COOMe.

In one embodiment of the invention, the compound may be: Wherein R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; the dashed line represents a single or double bond.

In one embodiment of the invention, the compound may be lanostane, as shown below:

In one embodiment of the present invention, the compound of formula (Ia) is dehydroeburicoic acid, as shown below:

In one embodiment of the present invention, the compound of formula (Ia) is dehydrosulphurenic acid (dehydrosulfurenic acid), as shown below:

In one embodiment of the invention, the compound of formula (II) is 4,7-dimethoxy-5-methyl-1,3-benzodioxo (4,7-dimethoxy-5-methyl-1 , 3-benzodioxole), as shown below:

In one embodiment of the present invention, the compound of formula (Ib) is cinnamolic acid A ((6R) -2-methyl-3-methylidene-6-[(4S, 5S, 10S, 13R, 14R17R) -4,10 , 13-trimethyl-3,11-dioxo-2,4,5,6,7,12,14,15,16,17-decahydro-1H-cyclopenta [a] phenanthren-17-yl] heptanoic acid), as follows Show:

In one embodiment of the present invention, the compound of formula (Ib) is cinnamolic 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] heptanoic acid) , As shown below:

In one embodiment of the invention, the compound of formula (Ib) is cinnamolic 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-methylideneheptanoic acid) as shown below:

In one embodiment of the invention, the compound of formula (Ib) is cinnamolic 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-methyl-3-methylideneheptanoic acid) as shown below:

In one embodiment of the present invention, the compound of formula (Ib) is cinnamolic acid K ((6R) -2-methyl-3-methylidene-6-[(4R, 10S, 13R, 14R, 17R) -3,4 , 7-trihydroxy-4,10,13-trimethyl-11-oxo-2,3,5,6,7,12,14,15,16,17-decahydro-1H-cyclopenta [a] phenanthren-17-yl ] heptanoic acid) as shown below:

In a preferred embodiment of the invention, the stroke is an ischemic stroke.

In another aspect, the present invention also provides a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (II) in the preparation of a compound for treating stroke and reducing nerve damage. Use in medicine.

In yet another aspect, the present invention provides a pharmaceutical composition for treating stroke and reducing nerve damage, comprising a therapeutically effective amount of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula ( Ie) or (II) compounds and one or more pharmaceutically acceptable carriers.

It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not restrictive of the invention.

Unless defined otherwise, all technical and scientific terms used herein have the meaning as commonly understood by a person having ordinary knowledge in the field of the invention.

The invention provides the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (II) in the preparation of a medicament for treating stroke and reducing nerve damage, wherein, R1 stands for O, α-OH or β-H; R2 represents H or OH; R3 representative of O, α-H, β- OAc or H _2; R4 represents H or OH; R5 represents H or OH; R6 Representative COOH Or COO (CH ₂ ) n-CH ₃ , n represents an integer from 0 to 3; R7 represents H, OH, or OAc; R8 represents CH ₃ or COOH; R21 represents CH ₃ , COOH, or COO (CH ₂ ) n-CH ₃ , N represents an integer from 0 to 3; each of R22, R23, and R24 may represent OCH ₃ , or R22 and R23 may form O-CH ₂ -O together; or R23 and R24 may form O-CH ₂ -O together; dashed line Represents a single or double bond.

In one embodiment of the invention, the compound may be:

In one embodiment of the invention, the compound may be:

In one embodiment of the invention, the compound may be: R = COOMe.

In one embodiment of the invention, the compound may be:

In a specific embodiment of the present invention, the compound may be lanostane, as shown below: .

In one embodiment of the invention, the compound of formula (II) may be:

In one embodiment of the invention, the compound of formula (Ia) may be: (Urethanumate); (Dehydrotoxamic acid); (3-epi-desmoateuric acid); (Dehydrosulfuric porous bacteric acid); (Urea-desmoateurate-methyl ester); ((20ξ) -3β, 15α, 16α-trihydroxy-24-methyllanosterol-7,9 (11), 24 (241) -triene-21-acid; 15α-hydroxydehydroturmoric acid); (Methyl 25-hydroxy-3 epidehydrotomoate (methyl)); (Dehydroporiaic acid); (15α-acetyldehydrosulfuric porous fungal acid); (15α-acetyldehydrosulphurenic acid); (dehydrosulphurenic acid); (29-hydroxydehydroporiaic acid ((3β, 16α) -3- (acetoxy) -16,29-dihydroxy-24-methylene lanosterol-7,9 (11) -diene-21- Acid); and (Dehydrodentate).

In one embodiment of the invention, the compound of formula (Ib) may be: (Antrodiacid A); (Antrodiacid B); (Cinnamolic acid C); (Antrodia H); and (Antrodiacid K).

In one embodiment of the present invention, the compound of formula (II) may be 4,7-dimethoxy-5-methyl-1,3-benzodioxo, as shown below: .

In the present invention, these compounds have been shown to be effective in the treatment of stroke, particularly ischemic stroke, and to reduce nerve damage. In particular, dehydroodontonic acid, 4,7-dimethoxy-5-methyl-1,3-benzodioxo, dehydrosulphurenic acid, and dehydrosulfuric acid, are used in the treatment of stroke and reduce nerve damage. Provides significant results.

Therefore, the present invention provides the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (II) in the preparation of a medicament for treating stroke and reducing nerve damage. .

In another aspect, the present invention provides a method for treating stroke and reducing nerve damage, the method comprising administering to an individual in need thereof a formula (Ia), (Ib), (Ic), ( Id), a pharmaceutical composition of a compound of formula (Ie) or formula (II).

As used herein, the term "therapeutically effective amount" refers to an amount of a compound or agent that results in the treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or reduces the rate of progression of a disease or disorder compared to a corresponding individual who has not yet received that amount. effect. The term also includes amounts within its scope that effectively enhance normal physiological functions.

For use in therapy, a therapeutically effective amount of a compound is formulated as a pharmaceutical composition for administration. Accordingly, the invention also provides a therapeutically effective amount of a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (II) and one or more pharmaceutically acceptable Carrier of pharmaceutical composition.

The term "pharmaceutically acceptable carrier" as used herein refers to an acceptable carrier, diluent or excipient that is compatible with the other ingredients of the formulation and is not harmful to the individual who is administered the pharmaceutical composition. Depending on the requirements of the pharmaceutical formulation, any carrier, diluent or excipient commonly known or used in the art can be used in the present invention.

According to the invention, the pharmaceutical composition may be adapted for administration by any suitable route, including but not limited to the oral, rectal, nasal, topical, vaginal or parenteral route. In a particular embodiment of the invention, the pharmaceutical composition is formulated for oral administration. Such formulations can be prepared by any method known in the medical field.

The invention is further illustrated by the following examples, which should be construed as illustrative only and not limiting the rest of the invention in any way. Without further elaboration, those skilled in the art can make full use of the present invention based on the description herein.

Preparation Example

Preparation of active ingredients: dehydrodentate acid and 4,7- Dimethoxy -5- methyl -1,3- Benzodioxo

100 grams (g) of Antrodia camphorata fruiting body was refluxed for 6 hours by heating and refluxing in methanol, and the extract was collected and concentrated under reduced pressure to obtain a total of 15 grams of Antrodia camphorata methanol extract. 15 g of methanol extract of Antrodia camphorata fruiting body was filled with silica dioxide, and the column was separated (3x12 cm) by gradient elution with eluent "n-hexane / ethyl acetate / methanol" to obtain dehydrogenated tooth holes Acid (No .: AR-04-41S), 4,7-dimethoxy-5-methyl-1,3-benzodioxo (No .: AR-04-15S), and dehydrosulfur colored porous bacteria Acid (No .: AR-04-1822S). Dehydrodentate acid (No .: AR-04-41S), has the following structural formula: ; 4,7-dimethoxy-5-methyl-1,3-benzodioxo (number: AR-04-15S), with the following structural formula: ; And dehydrosulfuric porous bacteric acid (No .: AR-04-1822S), which has the following structural formula:

Efficacy Examples

Experimental animal

A 7-week-old male SD rat purchased from Luxco Biotechnology was used in the experiment, which was acclimated and quarantined for 1 week. These rats were used for the evaluation of ischemic stroke.

Feeding environment

These rats were housed at the Biomedical Experimental Animal Station of the Industrial Research Institute. The light time in the breeding area is automatically controlled to be 12 hours light and 12 hours dark, room temperature: 23 ± 2 ° C, relative humidity: 40-70%. Animals have free access to adequate food and water. During the quarantine and test period, the clinical symptoms of the hospital are observed and recorded daily by veterinarians and test personnel to ensure the health of the experimental animals.

Animal observation

Clinical observations were made daily during the trial and the animals were recorded for other clinical symptoms or death. Observation of clinical symptoms was also performed on normal holidays. Death and all abnormal symptoms with varying degrees of severity were found and recorded in the animal clinical observation records. Dead animals must also be dissected to find possible causes of death.

Animal grouping and individual identification

One week after domestication of experimental animals, healthy rats were selected. After weighing, S-shaped grouping is performed. Three animals were housed in a cage, and ears were numbered to distinguish experimental rats. Paste the Cage card to indicate the cage number, strain, week age, animal number, test number, test group, date of admission and test period.

1. Used to trigger ischemic stroke ( MCAO ) Animal model experiment

Middle cerebral artery ischemia / Reperfusion mode ( Middle Cerebral Artery Occlusion, MCAO / Reperfusion model )

The test animals (250-350 grams of male SD rats in this example) were anesthetized with 2% isoflurane gas in N2O / O2 (70% / 30%). The right common carotid artery (right CCA), external carotid artery (ECA), and internal carotid artery (ICA) were isolated from the neck. Cut along the midline of the scalp, insert the nylon monofilament thread (nylon monofilament with polysiloxane on the front end), insert it through the external carotid artery, and extend it along the internal carotid artery to the brain Willie's ring (Circle of Willis), causing middle cerebral artery occlusion. After one hour of ischemia, the nylon monofilament thread was removed to restore reperfusion of brain blood. After 24 hours, the brains of the rats were taken out as sections, each having a thickness of 2 mm, and a total of seven slices were used for brain embolization area analysis.

Experiment design and grouping

Two batches of experiments were performed, each batch was divided into four groups, each group had 5 rats, a total of 40 rats. In one embodiment of the present invention, a preventive mode experiment is used, as shown in FIG. 1. Each group of test animals was administered with the compounds of AR-04-41S, AR-04-15S and AR-04-1822S 50 mg / min 10 minutes (min) before the ischemic stroke animal model (MCAO). kg. The above-mentioned preventive mode experiment includes a blank control group (sham) without performing MCAO surgery and not administering any compound, and a solvent control group (vehicle) that performs MCAO surgery and replaces the aforementioned compound with water.

result

I. Neurobehavior assessment analysis

The neurobehavioral assessment in one embodiment of the present invention was performed at 0.5, 1.5, and 24 hours (hr) after MCAO surgery in each group of rats, and the scores were scored according to the following states. The purpose of this assessment analysis is to assess the severity of nerve damage in the rat brain.

Level 0: Raise the rat from the tail to about 20 to 30 cm above the ground. Observe the state of the rat's forelimbs. The state of the rat's forelegs can be balanced to the ground without other nerve damage, as shown in Figure 2A. Represents normal rats.

Level 1: Raise the rat from the tail to about 20 to 30 cm above the ground, and observe the state of the rat's forelimbs stretching. The rat's forelimbs contract to the opposite side of the brain damaged area as shown in Figure 2B.

Level 2: Place the rat on the ground and apply lateral thrust. The rat's resistance to the ipsilateral thrust of the damaged area of the brain decreases. The experimental method is shown in Figure 2C.

Level 3: When the rat is allowed to move freely, the rat continues to circle to the opposite side of the damaged brain area and cannot go straight.

Level 4: Rats are experiencing paralysis or epilepsy due to severe nerve damage.

The neurobehavioral assessment results at 0.5, 1.5, and 24 hours after MCAO surgery in each control group and experimental group are shown in Figure 3. T test (Student's t test) was used to compare whether there was a difference between the group administered with each compound and the solvent control group. A p value of 0.05 or less indicates a significant difference. As shown in Figure 3, at least 1.5 hours after MCAO surgery, nerve damage became severe. At 24 hours, the compounds AR-04-15S, AR-04-1822S, and AR-04-41S were administered. In the group, nerve injury tended to recover. The efficacy of the groups administered AR-04-1822S and AR-04-41S was statistically significant, with a p-value of less than 0.01.

II. Analysis of cerebral infarction area

Twenty-four hours after MCAO surgery, the brains of the rats were removed and placed in low-temperature oxygenated physiological saline (0.95% normal saline). Coronal sections of each brain were cut into 7 pieces, each with a thickness of 2 mm. Remove the front 1 mm of the brain. Then the brain tissue sections were infiltrated with 1% 2,3,5-triphenyltetrazolium chloride (TTC) and reacted in a 37 ° C incubator for 30 minutes. The sections were fixed in a 4% formalin solution and recorded with a MarcoPATH Digital Image System, as shown in Figure 4A. The percentage of cerebral infarct volume as shown in Figures 4B and 4C was calculated by image analysis software (ImageJ 1.42q).

FIG. 4B provides analysis of cerebral infarcted areas ranging from 15 mm from the front end to the infarct site and infarct volume percentage of each compound and control group in the embodiment of FIG. 4A. Fig. 4C shows the total infarct volume (Infarct Volume,%) of the brain administered to each compound and control group for each rat in the embodiment of Fig. 4A, and the area of the infarcted brain is analyzed from the front end to 15 mm. This embodiment uses a T test. As can be seen from FIG. 4B and FIG. 4C, the group administered with the compound number AR-04-15S has a significant effect of reducing the infarct area at 7 mm, 9 mm, and 11 mm from the front of the brain. The group administered with the compound number AR-04-1822S had a significant reduction in infarct size at 3 mm, 5 mm, 7 mm, 9 mm, 11 mm, and 13 mm from the front of the brain. The group administered with compound number AR-04-41S had a significant reduction in infarct size at 3 mm, 7 mm, 9 mm, 11 mm, and 13 mm from the front of the brain. Among them, compound AR-04-1822S provides significantly better results in reducing infarct area at 7 mm and 9 mm from the front of the brain; compound AR-04-41S also provides better results at 7 mm from the front of the brain Power (p-value is less than 0.001).

As shown in FIG. 4C, the infarct volume of the vehicle control group (Vehicle) exceeded 30%. Compared to the vehicle control group (Vehicle), all of the following compounds provide significant effects in reducing infarcts: number AR-04-15S (p value less than 0.01), number AR-04-1822S (p value less than 0.001), and number AR-04-15S (p value is less than 0.01). Among them, the number AR-04-41S, the above-mentioned dehydrodentate acid, has the best effect in reducing the infarct volume (infarct volume is less than 10%).

III. Weight analysis

The following table 1 shows the body weight changes of these rats before (0 hr) and 24 hours (24 hr) after middle cerebral ischemia / reperfusion mode: Table 1 Table of weight changes In Table 1, AVG refers to the average, SEM refers to the Standard Error of the mean, and T-test refers to the T test. See also Figure 5. FIG. 5 shows an analysis chart of body weight changes of each control group and experimental group before and after MCAO surgery in one embodiment of the present invention. As shown in Figure 5, these rats lost weight after cerebral ischemia, in which the groups of compounds AR-04-1882S (p value less than 0.05) and AR-04-15S (p value less than 0.05) were administered Compared with the vehicle control group (vehicle), it has a significant obstacle to weight loss.

To sum up, dehydrodonatomic acid (No. AR-04-41S), 4,7-dimethoxy-5-methyl-1,3-benzodioxo (No. AR-04- 15S) and dehydrosulfuric acid (No. AR-04-1822S) provide significant effects in reducing nerve damage in rats 24 hours after MCAO surgery, and also reduce the volume of cerebral infarction caused by MCAO surgery. Among them, dehydrodentate acid (No. AR-04-41S) at a dose of 50 mg / kg and dehydrosulfopolyporous acid (No. AR-04-1822S) at a dose of 50 mg / kg Compared with the solvent control group (vehicle), it has a statistically significant effect in reducing nerve damage. All doses of 50 mg / kg of dehydrodentholic acid (No. AR-04-41S), 50 mg / kg of dehydrosulfuric acid (No. AR-04-1822S), and 50 mg / kg of 4,7-Dimethoxy-5-methyl-1,3-benzodioxo (No .: AR-04-15S) reduces the volume of cerebral infarction caused by MCAO in rats relative to the solvent control group (Vehicle) has a statistically significant effect.

Although the invention has been disclosed in a preferred embodiment, it is not intended to limit the invention. Any person with ordinary knowledge in the technical field can make changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the appended claims.

no

The above summary and the following detailed description of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, the presently preferred embodiments are shown in the drawings.

FIG. 1 is a flow chart showing the timing of administering a therapeutic compound 10 minutes before the initiation of ischemic stroke (MCAO operation) in one embodiment of the present invention. Among them, neurobehavioral assessment was performed 0.5, 1.5 and 24 hours after the operation.

2A to 2C are schematic diagrams of a method for determining a degree of nerve injury in a rat in a neurobehavior assessment analysis according to an embodiment of the present invention.

FIG. 3 is an analysis result of neurobehavioral assessment performed in each control group and experimental group at 0.5, 1.5, and 24 hours after MCAO operation in an embodiment of the present invention, where the data are expressed as mean ± standard deviation, and ** indicates p value <0.01, *** indicates p-value <0.001, and the number of samples is 3-5.

FIG. 4A is a cross-sectional view of the brain in one embodiment of the present invention. The brain is cut into seven pieces from the front end to 15 mm, each piece having a thickness of 2 mm, and a portion of the brain tip 1 mm is removed.

Fig. 4B is the percentage of infarcted area and infarct volume of each compound and the control group according to the embodiment of Fig. 4A. The area of cerebral infarction is analyzed from the range of the brain from the front end to 15 mm. The deviation indicates that * indicates p-value <0.05, ** indicates p-value <0.01, *** indicates p-value <0.001, and the number of samples is 3-5.

FIG. 4C is the total cerebral infarct volume (Infarct Volume,%) of each compound and the control group according to the embodiment of FIG. 4A. The analysis area of the cerebral infarction is the range from the front end of the brain to 15 mm. Standard deviation indicates that ** indicates p-value <0.01, *** indicates p-value <0.001, and the number of samples is 3-5.

FIG. 5 is an analysis chart of body weight changes of each control group and experimental group before and after MCAO surgery in one embodiment of the present invention, where the data are expressed as mean ± standard deviation, * indicates p value <0.05, ** * Indicates that the p-value is <0.001 and the number of samples is 3-5.

no

Claims (11)

Use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (II) in the preparation of a medicament for treating stroke and reducing nerve damage: Formula (Ia); Formula (Ib); Formula (Ic); Formula (Id); Formula (Ie); wherein R ₁ represents O, α-OH or β-H; R ₂ represents H or OH; R ₃ represents O, α-H, β-OAc or H ₂ ; R ₄ represents H or OH; R ₅ represents H or OH; R ₆ represents COOH or COO (CH ₂ ) n-CH ₃ ; R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; dashed lines represent single or double bonds; n represents 0 to An integer of 3; or Formula (II) wherein R ₂₁ represents CH ₃ , COOH or COO (CH ₂ ) n-CH ₃ , and n represents an integer from 0 to 3; each of R ₂₂ , R ₂₃ and R ₂₄ may represent OCH ₃ , or R ₂₂ and R ₂₃ may together form O-CH ₂ -O; or R ₂₃ and R ₂₄ may form together with the O-CH ₂ -O. Use according to claim 1, wherein the compound is selected from: Wherein R ₁ represents O or α-OH; R ₂ represents H or OH; R ₃ represents O, β-OH or H ₂ ; R 4 represents H or OH; and the dashed line represents a single or double bond. Use according to claim 1, wherein the compound is selected from: Wherein R ₁ represents O, α-OH or β-H; R ₂ represents H or OH; R ₃ represents O, β-OH or H ₂ ; R ₄ represents H ₂ ; dashed line represents single or double bond; R ₅ represents H or OH; R ₆ represents COOH or COOEt; R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; dashed lines represent single or double bonds. Use according to claim 1, wherein the compound is selected from: Wherein R ₁ represents O, α-OH or β-H; R ₃ represents O, α-H, β-OAc or H ₂ ; R ₅ represents H or OH; R ₅ represents COOMe. Use according to claim 1, wherein the compound is selected from: Wherein R ₇ represents H, OH or OAc; R ₈ represents CH ₃ or COOH; the dashed line represents a single or double bond. Use according to claim 1, wherein the compound is selected from: Use according to claim 1, wherein said compound of formula (Ia) is selected from: , , , , , , , , , , , with . Use according to claim 1, wherein said compound of formula (Ib) is selected from: , , , with . Use according to claim 1, wherein the compound of formula (II) is Use according to claim 1, wherein the compound is , or . Use according to claim 1, wherein the stroke is an ischemic stroke.