Compounds for preventing nerve damage and protecting nerves, methods for preparing the same, pharmaceuticals and uses thereof

Abstract

The present invention provides a novel compound capable of effectively preventing nerve damage and protecting nerves and a preparation method thereof; the structure of the novel compound is shown as follows. In addition, the present invention further provides a pharmaceutical composition containing the novel compound and its use for preparing a medicament for preventing nerve damage and protecting nerves. Among them, R, L<supgt;1< / supgt;, L<supgt;2< / supgt;, Y, Z, n1 and n2 are as defined in the specification.

Description

Technical Field

[0001] The present invention relates to a compound, a preparation method thereof, a pharmaceutical product and uses thereof, and particularly to a compound capable of being applied to prevent nerve damage and protect nerves, a preparation method thereof, a pharmaceutical product and uses thereof. Background Art

[0002] Diseases caused by neurodegeneration or injury are common diseases that long-term affect the quality of life of patients. However, there has always been a lack of effective and non-invasive treatment means. At present, for the prevention and treatment of nervous system diseases related to stroke, cerebral ischemia, brain injury, Alzheimer's disease (AD), Parkinson's disease (PD), and retinal diseases, etc., drugs with the efficacy of preventing nerve damage and protecting nerves are the main research focuses in related fields.

[0003] Nerve tissue is composed of nerve cells (neurons) and neuroglia. Since the regenerative ability of nerve cells is weak, how to promote the repair of nerve tissue and protect it from secondary injury after nerve tissue damage is an important topic in clinical treatment.

[0004] The molecular mechanisms of nerve cell damage include: calcium overload caused by a large influx of calcium ions, a large release of excitatory amino acids, direct damage to nerve cells by free radicals, and inflammation.

[0005] In recent years, okadaic acid (OKA) has often been used to study the nerve damage models established for neurodegenerative diseases and Alzheimer's disease. Okadaic acid is an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2 (PP2, also known as PP2A), and PP1 and PP2A can reduce the phosphorylation level of tau protein. Therefore, the effects of PP1 and PP2A can be inhibited by okadaic acid, thereby inducing the over-phosphorylation of tau protein to establish an Alzheimer's disease model, and using this to verify the efficacy of drugs for treating Alzheimer's disease.

[0006] Currently, the treatment drugs for dementia caused by Alzheimer's disease have different options according to the severity of symptoms. For mild to moderate dementia cases, the treatment drugs that can be selected include anti-acetylcholinesterase agents such as donepezil, rivastigmine, and galantamine; while for moderate to severe dementia cases, the treatment drugs that can be selected include the aforementioned donepezil and N-methyl-D-aspartic acid receptor antagonist (NMDA antagonist) - memantine.

[0007] On the other hand, ischemic stroke is a major cause of death and disability, but its treatment options are limited. Generally speaking, when a stroke or brain trauma causes ischemic brain injury, nerve cells will die within days to months after ischemia, followed by secondary brain damage caused by blood reperfusion. Specifically, when nerve tissue undergoes ischemia-reperfusion, a large amount of reactive oxygen species and calcium influx will be generated, thereby triggering an inflammatory mechanism that leads to cytokine activation and leukocyte infiltration into the ischemic area, causing an inflammatory reaction and damage to nerve tissue.

[0008] Currently, the drugs commonly used for ischemic stroke include platelet anti-aggregation agents with anti-thrombotic effects, such as clopidogrel, aspirin, ticlopidine, and dipyridamole; anticoagulants that help prevent thrombosis, reduce thrombus expansion, and generate embolism, such as heparin, low molecular weight heparin, and warfarin; thrombolytic drugs that help induce fibrinolysis, such as urokinase and recombinant tissue plasminogen activator (rtPA); drugs that prevent cerebral edema caused by severe stroke, such as mannitol and glycerol fructose; and drugs that avoid massive necrosis of nerve cells by controlling calcium channels, scavenging free radicals, and reducing the metabolic rate of brain cells in the ischemic area, such as piracetam and nimodipine.

[0009] However, the clinical effects of the above drugs used to prevent and treat nerve-related diseases are not yet ideal. Therefore, currently, both the industry and the clinic are in urgent need to search for and develop methods that can effectively prevent nerve damage and protect nerves, in order to provide patients with more diverse medical options. Summary of the Invention

[0010] In view of the deficiencies of the prior art, the present invention provides a novel compound, which has the efficacy of effectively preventing nerve damage and protecting nerves.

[0011] To achieve the above object, the present invention provides a compound represented by the following formula (I):

[0012]

[0013] Wherein,

[0014] R is hydrogen or an unsubstituted alkyl group with 1 to 6 carbon atoms;

[0015] L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms, and L 2 is an unsubstituted alkylene group with 1 to 6 carbon atoms or an unsubstituted arylene group with 6 to 18 carbon atoms in the ring;

[0016] Y is an unsubstituted alkylene group with 1 to 6 carbon atoms, an unsubstituted alkenylene group with 2 to 6 carbon atoms, an acyloxy group or an amide group;

[0017] Z is a hydroxyl group, a carboxyl group, an unsubstituted alkyl group with 1 to 6 carbon atoms, a benzenediol group, an unsubstituted ester group with 1 to 6 carbon atoms, an unsubstituted aryl group with 6 to 18 carbon atoms in the ring, 2-methoxybenzenesulfonamide, 2,3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothiophene; and

[0018] n1 and n2 are each independently 0 or 1.

[0019] In this specification, the "alkyl group with 1 to 6 carbon atoms" may be a straight-chain or branched-chain alkyl group, which means that the overall substituent has a total of 1 to 6 carbon atoms. For example, the alkyl group with 1 to 6 carbon atoms may be methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3) isopropyl (-CH(CH 3 ) 2 ) n-butyl (-CH 2 CH 2 CH 2 CH 3 ) isobutyl (-CH 2 CH(CH 3 ) 2 ) sec-butyl (-CH(CH 3 )CH 2 CH 3 ) or tert-butyl (-C(CH 3 ) 3 ) etc., but not limited thereto. Specifically, the alkyl group having 1 to 6 carbon atoms may be an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0020] In this specification, the "alkylene group having 1 to 6 carbon atoms" may be a methylene group (-CH 2 -), an ethylene group (-CH 2 CH 2 -) or -CH(CH 3 )-), a propylene group (-CH 2 CH 2 CH 2 -), -CH 2 CH(CH 3 )- or -C(CH 3 ) 2 ) or a butylene group (for example, -CH 2 CH 2 CH 2 CH 2 -), -CH 2 C(CH 3 ) 2 -) or -CH(CH 3 )CH 2 CH 2 ) etc., but not limited thereto. Specifically, the alkylene group having 1 to 6 carbon atoms may be an alkylene group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0021] In this specification, the "alkenylene group having 2 to 6 carbon atoms" means that the entire substituent has a total of 2 to 6 carbon atoms. For example, the alkenylene group having 2 to 6 carbon atoms may be a vinylene group (for example, -CH=CH-), a propenylene group (for example, -CH 2CH=CH- or -CH=C(CH 3 )-), butenylene group (e.g., -CH 2 CH=CHCH 2 - or -CH=CHCH 2 CH 2 -), etc., but not limited thereto. Specifically, the alkenylene group having 2 to 6 carbon atoms may be an alkenylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0022] In this specification, the "arylalkylene group having 6 to 18 carbon atoms in the ring" means that the ring structure in the overall substituent has a total of 6 to 18 carbon atoms. For example, the arylalkylene group having 6 to 18 carbon atoms in the ring may be a phenylene group (-C 6 H 4 -), a biphenylene group (-C 6 H 4 -C 6 H 4 -), or a naphthylene group (-C 10 H 6 -), etc., but not limited thereto. Specifically, the arylalkylene group having 6 to 18 carbon atoms in the ring may be an arylalkylene group having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms in the ring.

[0023] Specifically, in Chemical Formula (I), the phenylene group may be an ortho-phenylene group, a meta-phenylene group, or a para-phenylene group. Preferably, the phenylene group is a para-phenylene group.

[0024] Specifically, in Chemical Formula (I), the benzenediol group may be a pyrocatechin, a resorcinol, or a hydroquinone. Preferably, the benzenediol group is a pyrocatechin.

[0025] Preferably, Y is an unsubstituted ethylene group, an unsubstituted propylene group, an unsubstituted butylene group, an unsubstituted propenylene group, an acyloxy group, or an amide group.

[0026] Preferably, Z is a hydroxyl group, a carboxyl group, a methyl group, a pyrocatechin group, -COOCH 2 CH 3, unsubstituted phenyl, 2-methoxybenzenesulfonamido, 2,3-dimethyl-1-phenyl-5-pyrazolinone or 2-methyl-4-cyanothienyl.

[0027] Preferably, L 2 is unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene or unsubstituted phenylene.

[0028] Specifically, in Chemical Formula (I), Y can be represented as a*-Y-b*, and the a* and the b* represent different connection sites on both sides. Y is connected to L 1 via the a* and connected to L 2 via the b*, or connected to L 2 via the a* and connected to L 1 via the b*.

[0029] In some embodiments of the present invention, Y is acyloxy and is connected to L 1 via the oxygen atom through the a*, and connected to L 2 via the carbon atom through the b*. L 1 is unsubstituted alkylene with 1 to 6 carbon atoms and n1 is 0 or 1. L 2 is unsubstituted alkylene with 1 to 6 carbon atoms or unsubstituted arylene with 6 to 18 carbon atoms on the ring and n2 is 0 or 1. Z is hydroxyl or unsubstituted alkyl with 1 to 6 carbon atoms. R is hydrogen or unsubstituted alkyl with 1 to 6 carbon atoms. The compound in this embodiment is shown as the following formula (i):

[0030]

[0031] In some embodiments of the present invention, Y is acyloxy and is connected to L 1 via the oxygen atom through the a*, and connected to L 2 via the carbon atom through the b*. L 1 is unsubstituted alkyl with 1 to 6 carbon atoms and n1 is 1, n2 is 0. Z is unsubstituted alkyl with 1 to 6 carbon atoms. R is hydrogen. The compound in this embodiment is shown as the following formula (ii):

[0032]

[0033] In some embodiments of the present invention, Y is acyloxy and is connected to L 2 via the oxygen atom through the a*, and connected to L 1 via the carbon atom through the b*. L 1The alkylene group is unsubstituted and has 1 to 6 carbon atoms, n1 is 0 or 1, n2 is 0, Z is an unsubstituted alkyl group having 1 to 6 carbon atoms, a hydroquinone group, an unsubstituted aryl group having 6 to 18 carbon atoms in the ring, a 2-methoxybenzenesulfonamide group, a 2,3-dimethyl-1-phenyl-5-pyrazolone group, or a 2-methyl-4-cyanothiophene group, and R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms. The compounds in this embodiment are shown by the following formula (iii):

[0034]

[0035] In some embodiments of the present invention, Y is an acyloxy group and is connected to L via the oxygen atom through the a*, 2 and is connected to L via the carbon atom through the b*, 1 L 1 is an unsubstituted alkylene group having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 is an unsubstituted alkylene group having 1 to 6 carbon atoms and n2 is 1, Z is a hydroxyl group, a carboxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, a hydroquinone group, an unsubstituted ester group having 1 to 6 carbon atoms, an unsubstituted aryl group having 6 to 18 carbon atoms in the ring, a 2-methoxybenzenesulfonamide group, a 2,3-dimethyl-1-phenyl-5-pyrazolone group, or a 2-methyl-4-cyanothiophene group, and R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms. The compounds in this embodiment are shown by the following formula (iv):

[0036]

[0037] In some embodiments of the present invention, for the compound shown by the above formula (iv), L 1 is an unsubstituted alkylene group having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 is an unsubstituted arylene group having 6 to 18 carbon atoms in the ring and n2 is 1, Z is a hydroxyl group, a carboxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, or an unsubstituted ester group having 1 to 6 carbon atoms, and R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms.

[0038] In some embodiments of the present invention, Y is an acyloxy group and is connected to L via the oxygen atom through the a*, 2 and is connected to L via the carbon atom through the b*, 1 n1 is 0, L 2 is an unsubstituted alkylene group having 1 to 6 carbon atoms and n2 is 1, Z is an unsubstituted aryl group having 6 to 18 carbon atoms in the ring, and R is hydrogen. The compounds in this embodiment are shown by the following formula (v):

[0039]

[0040] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a*, 1 connected to L via the carbon atom through the b*, 2 L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n1 is 0 or 1, L 2 is an unsubstituted alkylene group with 1 to 6 carbon atoms or an unsubstituted arylene group with 6 to 18 carbon atoms in the ring and n2 is 0 or 1, Z is a hydroxyl group or an unsubstituted alkyl group with 1 to 6 carbon atoms, and R is hydrogen or an unsubstituted alkyl group with 1 to 6 carbon atoms. The compound in this embodiment is shown as the following formula (vi):

[0041]

[0042] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a*, 1 connected to L via the carbon atom through the b*, 2 L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n1 is 1, n2 is 0, Z is an unsubstituted alkyl group with 1 to 6 carbon atoms, and R is hydrogen. The compound in this embodiment is shown as the following formula (vii):

[0043]

[0044] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a*, 2 connected to L via the carbon atom through the b*, 1 L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n1 is 0 or 1, n2 is 0, Z is an unsubstituted alkyl group with 1 to 6 carbon atoms, a benzenediol group, an unsubstituted aryl group with 6 to 18 carbon atoms in the ring, a 2-methoxybenzenesulfonamide group, a 2,3-dimethyl-1-phenyl-5-pyrazolone group or a 2-methyl-4-cyanothiophene group, and R is hydrogen or an unsubstituted alkyl group with 1 to 6 carbon atoms. The compound in this embodiment is shown as the following formula (viii):

[0045]

[0046] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a*, 2 connected to L via the carbon atom through the b*, 1 n1 is 0, n2 is 0, and Z is a 2,3-dimethyl-1-phenyl-5-pyrazolone group or a 2-methyl-4-cyanothiophene group, and R is hydrogen. The compound in this embodiment is shown as the following formula (ix):

[0047]

[0048] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a*, 2 connected to L via the carbon atom through the b*, 1 L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n1 is 0 or 1, L 2 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n2 is 1, Z is a hydroxyl group, a carboxyl group, an unsubstituted alkyl group with 1 to 6 carbon atoms, a benzenediol group, an unsubstituted ester group with 1 to 6 carbon atoms, an unsubstituted aryl group with 6 to 18 carbon atoms in the ring, a 2-methoxybenzenesulfonamide group, a 2,3-dimethyl-1-phenyl-5-pyrazolone group or a 2-methyl-4-cyanothiophene group, and R is hydrogen or an unsubstituted alkyl group with 1 to 6 carbon atoms. The compound in this embodiment is shown by the following formula (x):

[0049]

[0050] In some embodiments of the present invention, for the compound shown by the above formula (x), L 1 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n1 is 0 or 1, L 2 is an unsubstituted arylene group with 6 to 18 carbon atoms in the ring and n2 is 1, Z is a hydroxyl group, a carboxyl group, an unsubstituted alkyl group with 1 to 6 carbon atoms or an unsubstituted ester group with 1 to 6 carbon atoms, and R is hydrogen or an unsubstituted alkyl group with 1 to 6 carbon atoms.

[0051] In some embodiments of the present invention, Y is an amide group and is connected to L via the nitrogen atom through the a* 2 connected to L via the carbon atom through the b*, 1 n1 is 0, L 2 is an unsubstituted alkylene group with 1 to 6 carbon atoms and n2 is 1, Z is a carboxyl group, a benzenediol group, an unsubstituted aryl group with 6 to 18 carbon atoms in the ring or a 2-methoxybenzenesulfonamide group, and R is hydrogen. The compound in this embodiment is shown by the following formula (xi):

[0052]

[0053] In some embodiments of the present invention, for the compound shown by the above formula (xi), n1 is 0, L 2 is an unsubstituted arylene group with 6 to 18 carbon atoms in the ring and n2 is 1, Z is a hydroxyl group or an unsubstituted ester group with 1 to 6 carbon atoms.

[0054] In some embodiments of the present invention, Y is an unsubstituted alkylene group with 1 to 6 carbon atoms or an unsubstituted alkenylene group with 2 to 6 carbon atoms, L1 is an unsubstituted alkylene group having 1 to 6 carbon atoms, n1 is 1, n2 is 0, Z is an unsubstituted alkyl group having 1 to 6 carbon atoms, and R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms.

[0055] Preferably, the novel compound may be any one of the following Compounds 1 to 15, but not limited thereto:

[0056]

[0057]

[0058] In addition, the present invention further provides a method for preparing the above-mentioned novel compound, which comprises the following steps: Step (a): providing a first reactant, which is a 4,7-dimethoxy-1,3-benzodioxole derivative; Step (b): providing a second reactant, which comprises a halogenated hydrocarbon compound, an acid anhydride compound, a phenol compound, an aromatic alcohol compound, an ester compound, a benzenesulfonamide derivative, an ester hydrochloride derivative, a phenol hydrochloride derivative, an antipyrine derivative or a thiophene derivative; and Step (c): reacting the first reactant with the second reactant to obtain the compound.

[0059] Preferably, the first reactant comprises 4,7-dimethoxy-5-methyl-6-iodo-1,3-benzodioxole, 4,7-dimethoxy-5-iodo-1,3-benzodioxole, 4,7-dimethoxy-5-hydroxymethyl-1,3-benzodioxole, 4,7-dimethoxy-5-aminomethyl-1,3-benzodioxole, 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole or 4,7-dimethoxy-5-acyl chloride-1,3-benzodioxole.

[0060] Preferably, the second reactant comprises 3,3-dimethylallyl bromide, 1-bromobutane, acetic anhydride, 4-aminophenol, phenylmethanol, ethyl p-aminobenzoate (also known as benzocaine), 5-[(R)-(2-Amino-propyl)]-2-methoxy-benzenesulfonamide, 4-aminobutyric acid methyl ester hydrochloride, β-alanine methyl ester hydrochloride, alanine methyl ester hydrochloride, 4-(2-aminoethyl)-1,2-benzenediol hydrochloride (also known as dopamine hydrochloride), 4-aminoantipyrine, or 2-amino-3-cyano-5-methylthiophene.

[0061] In some embodiments of the present invention, the first reactant comprises 4,7-dimethoxy-5-methyl-6-iodo-1,3-benzodioxole, 4,7-dimethoxy-5-iodo-1,3-benzodioxole, 4,7-dimethoxy-5-hydroxymethyl-1,3-benzodioxole, or 4,7-dimethoxy-5-aminomethyl-1,3-benzodioxole, the second reactant comprises a halogenated hydrocarbon compound or an acid anhydride compound, and the first reactant and the second reactant react under the conditions of a temperature of -80°C to 25°C and a reaction time of 2 hours to 150 hours. Preferably, the second reactant comprises 3,3-dimethylallyl bromide, 1-bromobutane, or acetic anhydride.

[0062] In some other embodiments of the present invention, the first reactant comprises 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole or 4,7-dimethoxy-5-acyl chloride-1,3-benzodioxole, the second reactant comprises a phenolic compound, an aromatic alcohol compound, an ester compound, a benzenesulfonamide derivative, an ester hydrochloride derivative, a phenol hydrochloride derivative, an antipyrine derivative or a thiophene derivative, and the first reactant and the second reactant react under the conditions of a temperature of 0°C to 60°C and a reaction time of 0.5 hour to 100 hours. Preferably, the second reactant comprises 4-aminophenol, benzyl alcohol, ethyl p-aminobenzoate, 5-[(R)-(2-aminopropyl)]-2-methoxybenzenesulfonamide, methyl 4-aminobutyrate hydrochloride, methyl β-alaninate hydrochloride, methyl alaninate hydrochloride, 4-(2-aminoethyl)-1,2-benzenediol hydrochloride, 4-aminoantipyrine or 2-amino-3-cyano-5-methylthiophene.

[0063] In some other embodiments of the present invention, the first reactant is 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole, the second reactant comprises an aromatic alcohol compound or an antipyrine derivative, and the first reactant and the second reactant react under the conditions of a temperature of 25°C to 60°C and a reaction time of 20 hours to 90 hours. Preferably, the second reactant comprises benzyl alcohol or 4-aminoantipyrine.

[0064] In some other embodiments of the present invention, the first reactant is 4,7-dimethoxy-5-acyl chloride-1,3-benzodioxole, and step (a) further comprises a step of pre-acylating 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole into 4,7-dimethoxy-5-acyl chloride-1,3-benzodioxole to obtain the first reactant; the second reactant comprises a phenolic compound, an ester compound, a benzenesulfonamide derivative, a phenol hydrochloride derivative or a thiophene derivative; the first reactant and the second reactant react under the conditions of a temperature of 0°C to 60°C and a reaction time of 0.5 hour to 100 hours. Preferably, the second reactant comprises 4-aminophenol, ethyl p-aminobenzoate, 5-[(R)-(2-aminopropyl)]-2-methoxybenzenesulfonamide, 4-(2-aminoethyl)-1,2-benzenediol hydrochloride or 2-amino-3-cyano-5-methylthiophene.

[0065] In other embodiments of the present invention, the first reactant is 4,7-dimethoxy-5-acyl chloride-1,3-benzenedioxole, the second reactant is an ester hydrochloride derivative, and step (c) further includes reacting the first reactant with the second reactant to obtain a methyl ester intermediate, and then subjecting the methyl ester intermediate to a hydrolysis reaction to obtain the compound, wherein the first reactant and the second reactant react under the conditions of a temperature of 0°C to 60°C and a reaction time of 0.5 hours to 80 hours. Preferably, the second reactant includes methyl 4-aminobutyrate hydrochloride, methyl 3-aminopropionate hydrochloride, or methyl alaninate hydrochloride.

[0066] In addition, the present invention further provides a medicament for preventing nerve damage and protecting nerves, which comprises the novel compound of the present invention described above and a pharmaceutically acceptable carrier.

[0067] In addition, the present invention further provides a use for preparing a medicament for preventing nerve damage and protecting nerves, wherein the medicament comprises the novel compound of the present invention described above and a pharmaceutically acceptable carrier.

[0068] Preferably, the nerve refers to brain nerve tissue.

[0069] Preferably, the prevention of nerve damage and the protection of nerves include the prevention and / or treatment of stroke and Alzheimer's disease.

[0070] In this specification, the efficacy of "preventing nerve damage" means that after pre-administering the novel compound of the present invention described above, when nerve damage occurs, it can effectively reduce the degree of nerve cell damage and death. The efficacy of "protecting nerves" means that when nerve damage occurs, administering the novel compound of the present invention described above can effectively reduce the degree of nerve cell damage and death.

[0071] According to the present invention, the "pharmaceutically acceptable carrier" may include pharmaceutically or food-acceptable excipients or additives, such as starch, corn starch, gelatin, gum arabic, food coloring, flavoring, flavor enhancer, preservative, etc. The administration route may include oral administration, transdermal administration, intraperitoneal administration, intravenous administration, nasal administration, or ophthalmic administration, etc.

[0072] According to the present invention, the dosage of the pharmaceutical composition can be determined by relevant medical personnel according to factors such as the patient's age, weight, health status, disease type, disease progression, affected part, etc., based on the common knowledge in the technical field. The pharmaceutical composition of the present invention can also be administered alone or in combination with other medicaments, and the administration course should be implemented by a physician or relevant person according to the routine methods in pharmacy.

[0073] In the specification, a range expressed as "small value to large value" means, unless otherwise specified, a range greater than or equal to the small value and less than or equal to the large value. For example, a temperature range of -80°C to 25°C means a range "greater than or equal to -80°C and less than or equal to 25°C". Description of the Drawings

[0074] Figure 1 For the effect of preventing nerve damage after administering the compounds of Examples 1 to 15 to rats.

[0075] Figure 2 For the staining results of different regions of the brain after administering the compounds of Examples 1 to 15 to rats.

[0076] Figure 3 For the evaluation results of neurobehavior after administering the compounds of Examples 1, 3 to 11 and 15 to rats.

[0077] Figure 4 For the experimental results of evaluating the efficacy of the compounds of Examples 1 to 15 in protecting nerves. Detailed Description of the Invention

[0078] The following lists several examples to illustrate the embodiments of the present invention. Those of ordinary skill in the art can easily understand the advantages and effects that the present invention can achieve through the content of this specification, and make various modifications and changes without departing from the spirit of the present invention to implement or apply the content of the present invention.

[0079] Example 1

[0080] Add 0.65 grams of 4,7-dimethoxy-5-methyl-6-iodo-1,3-benzodioxole and 3 milliliters of tetrahydrofuran into a 100-milliliter three-necked flask, cool it to -80°C in a dry nitrogen environment, then slowly add 1.5 milliliters of a 1.6 molar / liter n-butyllithium solution, and then slowly add a mixed solution of 2.35 milliliters of 3,3-dimethylallyl bromide (0.35 milliliters) and tetrahydrofuran (2 milliliters) and react for 70.5 hours. After the reaction is completed, add 5 milliliters of water and 5 milliliters of ethyl acetate and mix evenly, then retain the ethyl acetate layer of the upper solution and wash it twice with 5 milliliters of water, then dehydrate it with anhydrous sodium sulfate and filter the insoluble matter. Wash the insoluble matter three times with 5 milliliters of ethyl acetate and retain the washing solution. Subsequently, combine the solution dehydrated with anhydrous sodium sulfate and filtered and the washing solution, remove the solvent through a rotary evaporator, and then purify it by column chromatography (the column is filled with 80 grams of silica gel, the filling length is 15 centimeters, and the eluent is 100% heptane). After collecting the main product, 0.22 grams of a pale yellow liquid can be obtained, which is the compound of Example 1, and its HPLC purity is 97.1%.

[0081] The structure of the compound of Example 1 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=5.892(s,2H),5.015(t,1H),3.868(s,6H),3.279(d,2H),2.108(s,3H),1.760(s,3H),1.677(s,3H). The mass spectrometry analysis is: [M-C 4 H 7 + ; C 11 H 13 O 4 ; 209.18.

[0082] Example 2

[0083] 3.24 g of 4,7-dimethoxy-5-methyl-6-iodo-1,3-benzodioxole and 25 mL of tetrahydrofuran were added to a 100 mL three-necked flask, and the temperature was lowered to -80 °C in a dry nitrogen environment. Subsequently, 7 mL of a 1.6 mol / L n-butyllithium solution was slowly added, and then 2.2 mL of 1-bromobutane was slowly added and reacted for 3 hours. Then the temperature was adjusted to room temperature. Subsequently, 25 mL of water and 25 mL of ethyl acetate were added and mixed evenly. Then the ethyl acetate layer of the upper layer solution was retained and washed twice with 30 mL of water, and then dehydrated with anhydrous sodium sulfate and the insoluble substances were filtered. The insoluble substances were washed three times with 10 mL of ethyl acetate and the washing solutions were retained. Subsequently, the solution dehydrated with anhydrous sodium sulfate and filtered and the washing solutions were combined. After removing the solvent by a rotary evaporator, purification was carried out by column chromatography (the silica gel filled in the column was 60 g, the filling length was 12 cm, and the eluent was 100% heptane). After collecting the main product, the solvent was removed by a rotary evaporator to obtain 0.9 g of the compound of Example 2, and its HPLC purity was 96.82%.

[0084] The structure of the compound of Example 2 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=5.887(s,2H),3.886(s,3H),3.870(s,3H),2.548(t,2H),2.119(s,3H),1.409-1.379(m,4H),0.935(t,3H). The mass spectrometry analysis is: [M+H] + ; C 14 H 21 O 4 ; 253.21. ​

[0085] Example 3

[0086] After adding 0.2438 g of 4,7-dimethoxy-5-hydroxymethyl-1,3-benzodioxole, 5 mL of tetrahydrofuran, and 0.3 mL of triethylamine into a 100-mL three-necked flask, the temperature was lowered to 0 °C. Then, 0.45 mL of acetic anhydride was added, and the temperature was adjusted to room temperature and the reaction was carried out for 144.5 hours. After the reaction was completed, all the solvents were removed by a rotary evaporator, and the residue was dissolved in 10 mL of dichloromethane. Subsequently, it was washed once with 10 mL of saturated sodium bicarbonate aqueous solution, then washed once with 10 mL of water, and the organic layer was retained. The organic layer was dried over anhydrous sodium sulfate, and then all the solvents were removed by a rotary evaporator to obtain 0.288 g of an off-white powder, which is the compound of Example 3, and its HPLC purity is 92.58%.

[0087] The structure of the compound of Example 3 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=6.520(s,1H),5.980(s,2H),5.049(s,2H),3.923(s,3H),3.861(s,3H),2.078(s,3H). Mass spectrometry analysis is:[M-C 2 H 3 O 2 + ;C 10 H 11 O 4 ;195.14。

[0088] Example 4

[0089] ​0.5722 g of 4,7-dimethoxy-5-iodo-1,3-benzenedioxole and 4 mL of tetrahydrofuran were added to a 100 mL three-necked flask, and the temperature was lowered to -80 °C under a dry nitrogen environment. Subsequently, 1.5 mL of a 1.6 M n-butyllithium solution was added and mixed evenly for 4 minutes. Then, a mixed solution of 3.35 mL of 3,3-dimethylallyl bromide (0.35 mL) and tetrahydrofuran (3 mL) was added and the reaction was carried out for 2.5 hours. After the reaction was completed, the temperature was adjusted to 0 °C, 10 mL of water and 10 mL of ethyl acetate were added for extraction once. Then, the organic layer was retained, washed once with 10 mL of water, dried over anhydrous sodium sulfate, and the solvent was removed by a rotary evaporator to obtain 0.438 g of a dark brown liquid with a wet weight. Subsequently, purification was carried out by column chromatography (the silica gel filled in the column was 29.1 g, the filling length was 6 cm, and the eluent was a solution of ethyl acetate:heptane = 1:50). After collecting the main product, 66.3 mg of the compound of Example 4 was obtained, and its HPLC purity was 96.50%.

[0090] The structure of the compound of Example 4 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=6.297(s,1H),5.935(s,2H),5.229(t,1H),3.871(s,3H),3.850(s,3H),3.244(d,2H),1.729(s,3H),1.716(s,3H). The mass spectrometry analysis was: [M-C 4 H 7 + ;C 10 H 11 O 4 ;195.15。

[0091] Example 5

[0092] ​1.0054 g of 4,7-dimethoxy-5-aminomethyl-1,3-benzodioxole was added to a 100 mL three-necked flask and placed in a dry nitrogen environment. After adding 10 mL of tetrahydrofuran and 1.5 mL of triethylamine, the temperature was lowered to 0 °C, and then 0.5 mL of acetic anhydride was added and reacted for 17 hours. After the reaction was completed, 10 mL of methanol was added and all the solvents were removed by a rotary evaporator. Then, the residue was dissolved in 30 mL of dichloromethane, washed once with 30 mL of saturated sodium bicarbonate aqueous solution, once with 30 mL of water, and finally once with 30 mL of brine, and the organic layer was retained. The organic layer was dehydrated with anhydrous sodium sulfate and then all the solvents were removed by a rotary evaporator to obtain 1.157 g of a pale yellow powder. Then, column chromatography (the silica gel filled in the column was 50.1 g, the filling length was 11 cm, and the eluent was a solution of ethyl acetate:heptane from 1:10 to 2:1) was used for purification. After collecting the main product, all the solvents were removed by a rotary evaporator to obtain 0.944 g of the compound of Example 5, and its HPLC purity was 89.59%.

[0093] The structure of the compound of Example 5 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=6.479(s,1H),5.959(s,2H),5.890(br,1H,NH),4.324(d,2H),3.942(s,3H),3.843(s,3H),1.969(s,3H). The mass spectrometry analysis is:[M+H] + ;C 12 H 16 NO 5 ;254.23,[M+Na] + ;276.16。

[0094] Example 6

[0095] Add 0.509 g of 4,7-dimethoxy-5-carboxylic acid-1,3-phenylene dioxole, 1.3 mL of dichloromethane and 2 drops of dimethylformamide into a 100 mL three-necked flask. Subsequently, add 0.34 mL of oxalyl chloride and mix evenly at room temperature for reaction for 1 hour. Then, remove the excess oxalyl chloride and the solvent through a rotary evaporator to obtain an acyl chloride. Place the acyl chloride into a 100 mL single-necked flask, and sequentially add 5 mL of dichloromethane, 2.5 mL of dichloromethane solution (which already contains 0.508 g of 5-[(R)-(2-aminopropyl)]-2-methoxybenzenesulfonamide), and 1.3 mL of triethylamine. After mixing evenly at room temperature for reaction for 19.5 hours, add 10 mL of water and 10 mL of ethyl acetate, and retain the organic layer after mixing evenly. Then, remove the solvent through a rotary evaporator to obtain 0.9 g of an off-white needle-like solid. Then, mix the off-white needle-like solid with 17.5 mL of heptane and stir at room temperature for 5 minutes. Then, filter to obtain 0.589 g of a white powder, which is the compound of Example 6, and its HPLC purity is 96.5%.

[0096] The structure of the compound of Example 6 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=7.789(d,1H,NH),7.742(s,1H),7.438(d,1H),7.387(s,1H),6.985(d,1H),6.045(s,2H),5.095(s,2H,NH 2 ),4.396(m,1H),3.983(s,3H),3.933(s,3H),3.885(s,3H),2.921-2.789(m,2H),1.215(d,3H). The mass spectrometry analysis is: [M+H] + ;C 20 H 25 N 2 O 8 S;453.30,[M+Na] + ;475.26。

[0097] Example 7

[0098] 1.1447 g of 4,7 - dimethoxy - 5 - carboxylic acid - 1,3 - benzodioxole, 2 mL of toluene and 2 drops of dimethylformamide were added to a 500 - mL single - necked flask. Then, 0.75 mL of thionyl chloride was added and the mixture was heated to 60 °C for reaction for 1.5 h. After the reaction was completed, all the solvents were removed by a rotary evaporator and the residue was dissolved in 20 mL of tetrahydrofuran. Subsequently, all the solvents were removed again by a rotary evaporator to obtain an acyl chloride. The acyl chloride was mixed with 20 mL of tetrahydrofuran and cooled to 0 °C. Then, 0.8076 g of methyl 4 - aminobutyrate hydrochloride and 3 mL of triethylamine were added. Subsequently, the temperature was adjusted to room temperature for reaction for 19 h. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added and mixed evenly, and the organic layer was retained. The aqueous layer was extracted once with 20 mL of ethyl acetate, and the organic layer was retained and combined with the previously retained organic layer. Then, all the solvents were removed by a rotary evaporator. The residue was dissolved in 20 mL of ethyl acetate, washed once with 20 mL of water, and then washed once with 20 mL of brine, and the organic layer was retained. The organic layer was dehydrated with anhydrous sodium sulfate and then all the solvents were removed by a rotary evaporator to obtain 1.404 g of a methyl ester intermediate (yellow liquid) with an HPLC purity of 86.32%.

[0099] 0.7962 g of the methyl ester intermediate, 8 mL of tetrahydrofuran and 8 mL of methanol were added to a 100 - mL two - necked flask and cooled to 0 °C. Then, 8 mL of an aqueous lithium hydroxide solution (which already contained 0.3744 g of lithium hydroxide) was added and mixed evenly. Subsequently, the temperature was adjusted to room temperature for reaction for 67 h. After the reaction was completed, it was cooled to 0 °C and 25 mL of ethyl acetate was added. The pH value was adjusted to 3.28 with a 1 - molar / liter hydrochloric acid aqueous solution. Subsequently, the temperature was adjusted to room temperature and the upper organic solution was retained. The lower layer solution was extracted once with 25 mL of ethyl acetate, and the upper organic solution was retained and combined with the previously retained organic solution. Then, it was dehydrated with anhydrous sodium sulfate and all the solvents were removed by a rotary evaporator to obtain a yellow liquid, which was dried under vacuum to obtain 0.746 g of a yellow needle - shaped solid, which was the compound of Example 7 with an HPLC purity of 95.47%.

[0100] The structure of the compound of Example 7 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=8.074(br,1H,NH),7.431(s,1H),6.060(s,2H),4.024(s,3H),3.899(s,3H),3.530(m,2H),2.450(t,2H),1.953(m,2H). Mass spectrometry analysis was: [M + H]+ ; C 14 H 18 NO 7 ; 312.16, [M+Na] + ; 334.18。

[0101] Example 8

[0102] 0.6818 g of 4,7-dimethoxy-5-carboxylic acid-1,3-phenylene dioxole, 20 mL of toluene and 5 drops of dimethylformamide were added to a 500 mL single-necked flask, and then 0.55 mL of thionyl chloride was added and heated to 60 °C for reaction for 1 hour. After the reaction was completed, the excess thionyl chloride and the solvent were removed by a rotary evaporator. The residue was dissolved in 20 mL of tetrahydrofuran, and then the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was uniformly mixed with 20 mL of tetrahydrofuran and cooled to 0 °C. Then, 10.9 mL of dopamine hydrochloride solution (prepared by dissolving 0.5713 g of dopamine hydrochloride and 0.9 mL of triethylamine in 10 mL of tetrahydrofuran) was added and reacted at 0 °C for 30 minutes. Then, the temperature was adjusted to room temperature and the reaction was continued for 46 hours. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added and uniformly mixed, and the upper layer solution was retained; the lower layer solution was extracted again with 20 mL of ethyl acetate, and the upper layer solution was retained and combined with the previously retained upper layer solution. Then, all the solvents were removed by a rotary evaporator. The residue was first washed once with 10 mL of hydrochloric acid aqueous solution with a molar concentration of 0.1 mol / L, then washed once with 10 mL of water, and finally washed once with 10 mL of brine. Subsequently, water was removed with anhydrous sodium sulfate and the solvent was removed by a rotary evaporator to obtain a product with a wet weight of about 1.05 g. Then, it was first purified by column chromatography (30 g of silica gel was filled in the column, the filling length was 6 cm, and the eluent was a solution of ethyl acetate:heptane from 1:10 to 5:1), and the main compound with a wet weight of 0.653 g was collected. Then, it was purified by reverse column chromatography (28.3 g of octadecylsilane silica gel was filled in the column, the filling length was 4.5 cm, and the eluent was a solution of acetonitrile:water 1:1), and 0.224 g of the main compound was collected, which was the compound of Example 8, and its HPLC purity was 98.76%.

[0103] The structure of the compound of Example 8 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,DMSO-d 6): δ = 8.735 (s, 1H, OH), 8.641 (s, 1H, OH), 7.999 (t, 1H, NH), 7.051 (s, 1H), 6.645 (d, 1H), 6.614 (s, 1H), 6.469 (d, 1H), 6.071 (s, 2H), 3.780 (s, 3H), 3.768 (s, 3H), 3.424 (m, 2H), 2.627 (t, 2H). Mass spectrometry: [M + H] + ; C 18 H 20 NO 7 ; 362.28, [M + Na] + ; 384.27.

[0104] Example 9

[0105] 1.1297 g of 4,7 - dimethoxy - 5 - carboxylic acid - 1,3 - benzodioxole, 20 mL of toluene and 2 drops of dimethylformamide were added to a 500 - mL single - necked flask, then 0.8 mL of thionyl chloride was added and the mixture was heated to 60 °C for reaction for 1 hour. Then, the excess thionyl chloride and the solvent were removed by a rotary evaporator. The residue was dissolved in 20 mL of tetrahydrofuran, and then the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was uniformly mixed with 20 mL of tetrahydrofuran and cooled to 0 °C. Then, 0.5529 g of 4 - aminophenol and 1.4 mL of triethylamine were added. After reacting at 0 °C for 30 minutes, the temperature was adjusted to room temperature and the reaction was continued for 22 hours. After the reaction was completed, 20 mL of water was added and the mixture was uniformly mixed. The upper organic solution was retained; the lower layer solution was extracted once with 20 mL of ethyl acetate, and the upper organic solution was retained and combined with the previously retained upper organic solution. Then, the combined organic solution was washed once with 20 mL of water, then washed once with 20 mL of brine, dehydrated with anhydrous sodium sulfate, and the solvent was removed by a rotary evaporator to obtain a product with a wet weight of about 1.6163 g. Subsequently, column chromatography (the silica gel filled in the column was 39.9 g, the filling length was 8 cm, and the eluent was a solution of ethyl acetate:heptane from 1:10 to 5:1) was used for purification, and 1.077 g of the main compound was collected, which was the compound of Example 9, and its HPLC purity was 95.98%.

[0106] The structure of the compound of Example 9 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR (500 MHz, DMSO - d 6): δ = 9.790 (s, 1H, OH), 9.220 (s, 1H, NH), 7.468 (d, 2H), 6.961 (s, 1H), 6.710 (d, 2H), 6.095 (s, 2H), 3.915 (s, 3H), 3.809 (s, 3H). Mass spectrometry: [M + H] + ; C 16 H 16 NO 6 ; 318.15, [M + Na] + ; 340.15.

[0107] Example 10

[0108] After adding 0.5669 g of 4,7 - dimethoxy - 5 - carboxylic acid - 1,3 - benzodioxole, 15 mL of toluene and 3 drops of dimethylformamide into a 250 - mL single - necked flask, 0.4 mL of thionyl chloride was added and the mixture was heated to 60 °C for reaction for 1 hour. After the reaction was completed, the excess thionyl chloride and the solvent were removed by a rotary evaporator and the residue was dissolved in 15 mL of 2 - methyltetrahydrofuran. Subsequently, all the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was mixed with 15 mL of tetrahydrofuran and cooled to 0 °C. Then, 0.5051 g of β - alanine methyl ester hydrochloride and 1.4 mL of triethylamine were added. After reacting at 0 °C for 30 minutes, the temperature was adjusted to room temperature and the reaction was continued for 2 days and 23 hours. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added and mixed evenly. The upper layer solution was retained. The upper layer solution was first washed once with 20 mL of water, then washed once with 20 mL of brine, dried over anhydrous sodium sulfate, and then the solvent was removed by a rotary evaporator to obtain a yellow powder with a wet weight of about 0.5639 g. Subsequently, purification was carried out by column chromatography (the silica gel filled in the column was 31 g, the filling length was 6 cm, and the eluent was a solution of ethyl acetate:heptane from 1:10 to 1:2), and 0.409 g of methyl ester intermediate was collected, and its HPLC purity was 99.34%.

[0109] 0.376 g of the methyl ester intermediate, 4 mL of tetrahydrofuran, and 4 mL of methanol were added to a 250 mL single-necked flask and cooled to 0 °C. Subsequently, 4 mL of an aqueous lithium hydroxide solution (which already contained 0.1915 g of lithium hydroxide) was slowly added. Then, the temperature was adjusted to room temperature and the reaction was carried out for 79 hours. After the reaction was completed, the organic solvent was removed by a rotary evaporator. Then, the remaining aqueous solution was mixed with 20 mL of dichloromethane and cooled to 0 °C. Subsequently, the pH value was adjusted to 1.75 with a hydrochloric acid aqueous solution with a molar concentration of 1 mol / L. Then, the temperature was adjusted to room temperature and the lower layer solution was retained. The upper layer solution was extracted twice with 40 mL of ethyl acetate each time, and the upper layer solution was retained and then combined with the retained lower layer solution. Then, it was washed twice with 40 mL of water each time and the organic solution was retained. Then, it was dehydrated with anhydrous sodium sulfate and the solvent was removed by a rotary evaporator to obtain 0.346 g of a white powder, which was the compound of Example 10 with an HPLC purity of 96.10%.

[0110] The structure of the compound of Example 10 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR(500MHz,CD 3 OD):δ=7.255(s,1H),6.057(s,2H),3.997(s,3H),3.858(s,3H),3.633(m,2H),2.608(t,2H). The mass spectrometry analysis was: [M+H] + ;C 13 H 16 NO 7 ;298.15,[M+Na] + ;320.13。

[0111] Example 11

[0112] 1.1356 g of 4,7-dimethoxy-5-carboxy-1,3-phenylene dioxole, 20 mL of toluene and 2 drops of dimethylformamide were added to a 250 mL single-necked flask, and then 0.8 mL of thionyl chloride was added and heated to 60 °C for reaction for 1 hour. After the reaction was completed, the excess thionyl chloride and the solvent were removed by a rotary evaporator, and the residue was dissolved in 20 mL of 2-methyltetrahydrofuran. Subsequently, the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was mixed with 20 mL of tetrahydrofuran and cooled to 0 °C. Then, 0.9445 g of methyl alaninate hydrochloride and 3 mL of triethylamine were added and reacted for 30 minutes, and then the temperature was adjusted to room temperature and reacted for another 27 hours. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added and mixed evenly, and the upper layer solution was retained. Subsequently, the upper layer solution was washed once with 20 mL of water, then washed once with 20 mL of brine, dehydrated with anhydrous sodium sulfate, and then the solvent was removed by a rotary evaporator to obtain a yellow liquid with a wet weight of about 1.272 g. Then, it was purified by column chromatography (the column was filled with 31 g of silica gel, the filling length was 6 cm, and the eluent was a solution of ethyl acetate:heptane from 1:10 to 1:2) to collect the main compound to obtain 1.02 g of a methyl ester intermediate with an HPLC purity of 97.07%.

[0113] 1.02 g of the methyl ester intermediate, 10 mL of tetrahydrofuran and 10 mL of methanol were added to a 250 mL single-necked flask and cooled to 0 °C. Then, 10 mL of an aqueous lithium hydroxide solution (which already contained 0.44 g of lithium hydroxide) was slowly added, and then the temperature was adjusted to room temperature and reacted for 24 hours. After the reaction was completed, the organic solvent was removed by a rotary evaporator, and the remaining aqueous solution was mixed with 20 mL of dichloromethane and cooled to 0 °C. Then, the pH value was adjusted to 4.6 with a hydrochloric acid aqueous solution with a molar concentration of 1 mol / L, and then the temperature was adjusted to room temperature and the lower layer solution was retained; the upper layer solution was extracted once with 20 mL of ethyl acetate and the upper layer solution was retained and then combined with the retained lower layer solution. After the solvent was removed by a rotary evaporator, a grayish-white powder with a wet weight of 0.965 g was obtained. Then, it was dissolved in 20 mL of ethyl acetate, washed once with 20 mL of water, then washed once with 20 mL of brine, and the organic solution was retained and the solvent was removed by a rotary evaporator to obtain 0.752 g of a grayish-white powder, which was the compound of Example 11 with an HPLC purity of 98.21%.

[0114] The structure of the compound of Example 11 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,DMSO-d 6): δ = 12.8 (br, 1H, COOH), 8.446 (d, 1H, NH), 7.102 (s, 1H), 6.110 (s, 2H), 4.416 (m, 1H), 3.911 (s, 3H), 3.795 (s, 3H), 1.374 (d, 3H). Mass spectrometry: [M+H] + ; C 13 H 16 NO 7 ; 298.15, [M+Na] + ; 320.13.

[0115] Example 12

[0116] 1.13 g of 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole, 5.5 mL of benzyl alcohol and 3 drops of concentrated sulfuric acid were added to a 50 mL two-necked flask, and then heated to 60 °C for reaction for 28 hours. After the reaction was completed, 50 mL of water was added and the lower layer solution was retained. Then the solvent was removed by a rotary evaporator to obtain a dark brown liquid. Subsequently, purification was carried out by column chromatography (the silica gel filled in the column was 45 g, the filling length was 9 cm, and the eluent was a solution of ethyl acetate:heptane from 1:20 to 1:10). After collecting the main product, the solvent was removed by a rotary evaporator to obtain a colorless transparent liquid with a wet weight of 1.8668 g. After drying under vacuum, 1.352 g of white powder was obtained, which was the compound of Example 12, and its HPLC purity was 98.40%.

[0117] The structure of the compound of Example 12 is shown in Table 1 below, and its 1H NMR spectrum is as follows: 1 H NMR (500 MHz, CDCl 3 ): δ = 7.461 - 7.329 (m, 5H), 7.110 (s, 1H), 6.054 (s, 2H), 5.343 (s, 2H), 3.897 (s, 3H), 3.873 (s, 3H). Mass spectrometry: [M+H] + ; C 17 H 17 O 6 ; 317.14, [M+Na] + ; 339.13.

[0118] Example 13

[0119] After adding 0.57 g of 4,7-dimethoxy-5-carboxylic acid-1,3-phenylene dioxole, 0.51 g of 4-aminoantipyrine, 10 mL of tetrahydrofuran and 5 mL of water into a 100-mL two-necked flask, 0.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added and the reaction was carried out at room temperature for 74 hours. After the reaction was completed, tetrahydrofuran was removed by a rotary evaporator. Then the remaining aqueous solution was extracted once with 20 mL of ethyl acetate, and the ethyl acetate layer was retained and washed three times with 20 mL of water first, then dehydrated with anhydrous sodium sulfate and all the solvents were removed by a rotary evaporator to obtain 0.80 g of a dark orange liquid, which is the compound of Example 13, and its HPLC purity is 97.58%.

[0120] The structure of the compound of Example 13 is shown in Table 1 below, and its proton nuclear magnetic resonance spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=9.445(s,1H,NH),7.475-7.419(m,5H),7.302-7.274(m,1H),6.078(s,2H),4.125(s,3H),3.914(s,3H),3.039(s,3H),2.387(s,3H). The mass spectrometry analysis is: [M+H] + ;C 21 H 22 N 3 O 6 ;412.34,[M+Na] + ;434.32。

[0121] Example 14

[0122] After adding 0.57 g of 4,7-dimethoxy-5-carboxy-1,3-benzenedioxole, 10 mL of toluene and 1 drop of dimethylformamide into a 100 mL single-necked flask, 0.4 mL of thionyl chloride was added and the mixture was heated to 60 °C for reaction for 1.5 hours. After the reaction was completed, the excess thionyl chloride and the solvent were removed by a rotary evaporator and the residue was dissolved in 10 mL of 2-methyltetrahydrofuran. Subsequently, the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was placed in a 250 mL single-necked flask, 10 mL of 2-methyltetrahydrofuran was added, and the temperature was cooled to 0 °C. Then, 0.35 g of 2-amino-3-cyano-5-methylthiophene and 1.8 mL of triethylamine were added, and the temperature was adjusted to room temperature for reaction for 96 hours. After the reaction was completed, 10 mL of water and 10 mL of ethyl acetate were added, and the aqueous solution in the lower layer was retained. Then, it was extracted three times with 20 mL of ethyl acetate. The aqueous layer was retained and then extracted three times with 20 mL of dichloromethane, and the dichloromethane layer solution was retained. Subsequently, it was dehydrated with anhydrous sodium sulfate and then the solvent was removed by a rotary evaporator to obtain 0.47 g of a yellow powder, which was the compound of Example 14 with an HPLC purity of 90.82%.

[0123] The structure of the compound of Example 14 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=11.420(s,1H,NH),7.517(s,1H),6.640(s,1H),6.110(s,2H),4.267(s,3H),3.904(s,3H),2.416(s,3H). The mass spectrometry analysis was: [M+H] + ;C 16 H 15 N 2 O 5 S;347.14,[M+Na] + ;369.15.

[0124] Example 15

[0125] After adding 0.57 g of 4,7-dimethoxy-5-carboxylic acid-1,3-phenylene dioxole, 10 mL of toluene and 1 drop of dimethylformamide into a 250 mL single-necked flask, 0.42 mL of thionyl chloride was added and the mixture was heated to 60 °C for reaction for 1.5 hours. After the reaction was completed, the excess thionyl chloride and the solvent were removed by a rotary evaporator and the residue was dissolved in 10 mL of 2-methyltetrahydrofuran. Subsequently, the solvent was removed by a rotary evaporator to obtain an acyl chloride. The acyl chloride was placed in a 250 mL single-necked flask, then 10 mL of 2-methyltetrahydrofuran was added and the temperature was lowered to 0 °C. Subsequently, 0.42 g of benzocaine and 0.8 mL of triethylamine were added and the temperature was adjusted to room temperature for reaction for 22 hours. After the reaction was completed, 10 mL of water was added and the mixture was extracted three times with 10 mL of ethyl acetate, and the ethyl acetate layer was retained. The aqueous layer was further extracted three times with 10 mL of dichloromethane, and the dichloromethane layer was retained and combined with the retained ethyl acetate layer. Then, water was removed with anhydrous sodium sulfate and the solvent was removed by a rotary evaporator to obtain a 0.98 g off-white powder. After dissolving it in 50 mL of dichloromethane, it was washed three times with 25 mL of water and water was removed with anhydrous sodium sulfate. Subsequently, the solvent was removed by a rotary evaporator to obtain 0.92 g of an off-white powder, which was the compound of Example 15 with an HPLC purity of 93.0%.

[0126] The structure of the compound of Example 15 is shown in Table 1 below, and its nuclear magnetic resonance hydrogen spectrum is as follows: 1 H NMR(500MHz,CDCl 3 ):δ=10.074(s,1H,NH),8.044(d,2H),7.727(d,2H),7.515(s,1H),6.109(s,2H),4.371(q,2H),4.131(s,3H),3.931(s,3H),1.398(t,3H). The mass spectrometry analysis was: [M+H] + ;C 19 H 20 NO 7 ;347.30,[M+Na] + ;396.35。

[0127] Table 1: Structures of the compounds of Examples 1 to 15.

[0128]

[0129]

[0130] Test Example 1: Evaluation of the efficacy of preventing nerve damage

[0131] In this test example, the compounds of Examples 1 to 15 were dissolved in a solvent to prepare the test solutions of Examples 1 to 15 (with a concentration of 10 mg / mL). Among them, the solvent was composed of dimethyl sulfoxide (DMSO), cremophor EL (CrEL), and water, and the contents were 10% by volume, 20% by volume, and 70% by volume in sequence. In addition to the experimental group, a simple solvent was used as the blank group, and the group that only underwent the following surgical procedures without being blocked and ischemic with a nylon monofilament was used as the sham operation group (Sham group) without administering the compound or solvent.

[0132] In this test example, a transient focal Middle Cerebral Artery Occlusion / Reperfusion model (MCAO / R model) was used to simulate ischemic stroke to evaluate the subsequent nerve damage. Specifically, male Sprague Dawley rats (SD rats) were anesthetized with 2% isoflurane, and then the right common carotid artery, external carotid artery, and internal carotid artery were isolated from the neck.

[0133] Subsequently, a nylon monofilament with a length of about 22 mm, numbered 4 / 0, and with the front end covered with polysiloxane was inserted through the external carotid artery and extended along the internal carotid artery to the circle of Willis in the brain to cause middle cerebral artery occlusion and ischemia. After 1 hour of occlusion and ischemia, the nylon monofilament was removed to restore blood circulation in the brain, enabling blood reperfusion in the previously ischemic brain area.

[0134] After 24 hours of blood reperfusion, the rats were sacrificed and their brains were removed and placed in cold saline with a concentration of 0.95%. Then, the first 1 mm of the brain tip was removed, and the brain was cut into seven coronal tissue slices with a thickness of 2 mm. Subsequently, the tissue slices were infiltrated with 2,3,5-triphenyltetrazolium chloride (TTC) at a concentration of 1% and reacted at room temperature (about 25°C to 27°C) for 30 minutes. Then, the tissue slices were fixed in a 4% formalin solution, and then photographed and recorded using a MacroPATH Digital Imaging System, and the infarct volume percentage was calculated using ImageJ 1.52a image analysis software to represent the degree of nerve damage. The infarct volume percentage was obtained by summing up the product of the infarct area ratio of each tissue slice and the thickness of each slice. Among them, the infarct area ratio was obtained according to the following formula: (B - A) / B × 100%, where A is the non-damaged area in the right damaged cerebral hemisphere and B is the total area of the left non-damaged cerebral hemisphere.

[0135] Herein, for the groups of Examples 1 to 15, 10 minutes before performing the MCAO / R model, the test solutions of Examples 1 to 15 were administered to the rats once by intraperitoneal injection (i.p.). The administered dose was calculated according to the weight of the rats, 50 mg per kilogram (50 mg / kg), and the administered volume was 5 ml / kg; the blank group was also administered the solvent to the rats once by intraperitoneal injection, and the administered volume was also 5 ml / kg.

[0136] The total infarct volume percentages (the sum of the volume percentages of the seven brain tissue slices) of Examples 1 to 15, the blank group, and the Sham group are listed in Table 2 below and as Figure 1 shown, while the TTC staining results of the brain tissue slices of Examples 1 to 15, the blank group, and the Sham group at seven different positions are as Figure 2 shown. For the experimental groups of Examples 1 to 15 and the blank group, 5 animal experiments were conducted for each (n = 5), and 3 animal experiments were conducted for the Sham group (n = 3).

[0137] Table 2: Total infarct volume percentages of Examples 1 to 15, the blank group, and the Sham group.

[0138]

[0139]

[0140] *: p value < 0.05, **: p value < 0.01, ***: p value < 0.001.

[0141] As can be seen from the results in Table 2, after simulating ischemic stroke and reperfusing the blood for 24 hours, the total infarction volume percentage of the blank group was 40.48%, indicating that a large range of nerve damage indeed occurred after simulating stroke via the aforementioned MCAO / R model; while the total infarction volume percentage of the Sham group was only 1.79%, which was statistically significantly different from the blank group (p value < 0.001), indicating that the nerves were not damaged, suggesting that the surgical operation during the experiment did not affect the experimental results of the total infarction volume percentage.

[0142] Referring to the results of Examples 1 to 15 again, compared with the total infarction volume percentage of the blank group, Examples 1 to 15 all showed lower total infarction volume percentages (ranging from about 14.52% to 35.67%). In addition, further analysis was performed using the Student's T - test statistical method, and the results showed that Examples 3, 4, 6, 7, 9 to 11, and 15 were all statistically significantly different from the blank group. Among them, the p values of Examples 3, 4, and 6 were less than 0.05, the p values of Examples 7, 10, 11, and 15 were less than 0.01, and the p value of Example 9 was less than 0.001; and from Figure 1 the results can also clearly show that the total infarction volume percentages of the groups of Examples 1 to 15 were lower than that of the blank group. Thus, it can be seen that the total infarction volume percentage was indeed reduced after pre - administering the novel compound of the present invention, indicating a reduction in the degree of nerve damage and thus achieving the effect of preventing nerve damage.

[0143] Looking again Figure 2 , the seven - column staining results from top to bottom were brain tissue sections at 3 mm, 5 mm, 7 mm, 9 mm, 11 mm, 13 mm, and 15 mm from the boundary 1 mm in front of the excised brain front end respectively. According to the principle of TTC staining, if it appears white in the brain tissue section, it indicates that the nerves in that part have been damaged. From the staining results of the blank group, it can be observed that the right half of the seven - column brain tissue sections all showed obvious white, indicating that the nerves in different parts were indeed damaged. Looking at the staining results of Examples 1 to 15 again, it can be observed that the phenomenon of white appearance on the right side of the brain tissue sections in different parts was not as obvious as that of the blank group. Thus, it can also be confirmed that the novel compound of the present invention indeed has the effect of preventing nerve damage.

[0144] Test Example 2: Neurological Behavior Assessment

[0145] This experiment was conducted simultaneously with Test Example 1. Therefore, the preparation of the test solution, the blank group, and the Sham group were all exactly the same as those in Test Example 1. Specifically, in this test example, the groups of Examples 1, 3 to 11, and 15 were selected. At the time points of 0.5 hour, 1.5 hours, and 24 hours after blood reperfusion in the MCAO / R model, the severity of nerve deficits in rats was evaluated according to the grading criteria specified by Bederson to assess the neurobehavior. Among them, the methods for behavioral assessment and nerve defect grading are as follows: Grade 0 indicates no occurrence of nerve deficits; Grade 1 indicates that the forelimb of the rat contracts towards the contralateral side of the brain damaged area; Grade 2 indicates a decrease in the resistance of the rat to the ipsilateral thrust of the brain damaged area; Grade 3 indicates that the rat spontaneously circles towards the contralateral side of the damaged brain area and is unable to walk straight; and Grade 4 indicates severe nerve damage, with the limbs showing weakness and paralysis or having epileptic phenomena.

[0146] The results of Examples 1, 3 to 11, and 15, the blank group, and the Sham group are listed in Table 3 below and Figure 3 in.

[0147] Table 3: Neurobehavioral assessment results of Examples 1, 3 to 11, and 15, the blank group, and the Sham group.

[0148]

[0149] As can be seen from the results in Table 3, at the time points of 0.5 hour, 1.5 hours, and 24 hours after blood reperfusion, the neurobehavioral assessment results of the blank group were all 2.8, approaching the situation of Grade 3, indicating that the neurobehavior was indeed affected. Looking at the results of Examples 1, 3 to 11, and 15 again, compared with the blank group, Examples 1, 3 to 11, and 15 all showed preferred neurobehavioral assessment results (all lower than 2.8). Among them, at the time point of 24 hours after reperfusion, Examples 1, 3 to 11, and 15 showed better neurobehavioral assessment results. In particular, the neurobehavioral assessment results of Examples 3, 4, 7, 9, and 11 were better than the situation of Grade 2. In addition, from Figure 3 the results, it can also be seen that at 24 hours after blood reperfusion, the neurobehavioral assessment results of Examples 1, 3 to 11, and 15 were indeed better than those of the blank group. Thus, it can be seen that after administering the novel compound of the present invention, the nerve damage condition can indeed be improved after a relatively long time.

[0150] Test Example 3: Evaluation of the efficacy of protecting nerves

[0151] In this test example, the compounds of Examples 1 to 15 were dissolved in DMSO to prepare the test solutions for Examples 1 to 15. Okadaic acid was used as a nerve injury inducer to simulate the situation of nerve cell damage. Then, the protective effect of the test substances on nerve cells was evaluated through a cell viability reagent (cell counting kit, CCK-8, purchased from Dojindo Laboratories, Japan).

[0152] Specifically, this test selected the mouse neuroblastoma cell line - Neuro-2a cells ( CCL-131 TM ) and subcultured them in MEM medium containing 10% (v / v) fetal bovine serum (FBS) under the conditions of an incubator with 5% carbon dioxide and a temperature of 37°C. Subsequently, the Neuro-2a cells were seeded in a 96-well culture plate at a cell density of 5×10 3 / well, where the volume of the medium was 100 μl and it contained okadaic acid at a concentration of 120 nM. Then, 0.1 μl of the pre-prepared test solutions of Examples 1 to 15 with a concentration 1000 times higher were added to the medium, so that the concentrations of the test solutions in the media of each group were as shown in Table 4 below. Subsequently, co-treatment was carried out for 24 hours, and then the cell viability of each group was analyzed using the CCK-8 reagent. Among them, the group containing only okadaic acid without adding the test solution was used as the control group, and the analysis results of the cell viability of each group are listed in Table 4 below. The concentrations of okadaic acid and the test solutions of Examples 1 to 15 in the medium are also listed in Table 4 below, where the concentration unit of the test solutions of Examples 1 to 15 is expressed in micrograms per milliliter (μg / ml). Each group was subjected to 3 to 4 repeated tests.

[0153] Table 4: Analysis results of cell viability of Examples 1 to 15 and the control group.

[0154]

[0155]

[0156] *: p value < 0.05, **: p value < 0.01, ***: p value < 0.001.

[0157] As can be seen from the results in Table 4, the control group is a group treated with okadaic acid only, so serious nerve cell damage and death occurred, resulting in a cell survival rate of only 28.88%; and the groups co-treated with compounds containing Examples 1 to 15 all had significantly higher cell survival rates than the control group (34.18% to 67.27%), among which Example 5 had the highest cell survival rate. Further analysis using the statistical method of Student's T-test showed that Examples 1 to 3, 5 to 7, 9 and 12 to 14 were statistically significantly different from the control group, among which the p value of Examples 12 to 14 was less than 0.05, and the p value of Examples 1 to 3, 5 to 7 and 9 was less than 0.01. In addition, the analysis results of the cell survival rates of each group are presented in a chart as follows Figure 4 As shown, it can be clearly seen that the cell survival rates of Examples 1 to 15 are all higher than those of the control group. Therefore, it can be seen that the treatment of the novel compound of the present invention at the same time as nerve damage occurs does increase the cell survival rate, which means that the degree of nerve cell damage and death is effectively slowed down to achieve the effect of protecting nerves.

[0158] In summary, the present invention provides a novel compound and a method for preparing the same. The novel compound has the efficacy of preventing nerve damage and protecting nerves, and can therefore be used to prevent or improve diseases caused by nerve damage, thereby providing patients with another highly potential and effective treatment method.

Claims

1. A compound, characterized in that, the compound is represented by formula (I): wherein, R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms; L 1 is an unsubstituted alkylene group having 1 to 6 carbon atoms, L 2 is an unsubstituted alkylene group having 1 to 6 carbon atoms or an unsubstituted arylene group having 6 to 18 carbon atoms in the ring; Y is acyloxy or amido; Z is a carboxyl group, an unsubstituted ester group having 1 to 6 carbon atoms, an unsubstituted aryl group having 6 to 18 carbon atoms in the ring, and n1 is 0, n2 is 0 or 1; wherein, when Y is acyloxy, Z is an unsubstituted aryl group having 6 to 18 carbon atoms in the ring; When Y is an amide group and Z is a carboxyl group, an unsubstituted ester group having 1 to 6 carbon atoms, 2. The compound according to claim 1, characterized in that, Z is a carboxyl group, -COOCH 2 CH 3 an unsubstituted phenyl group, 3. The compound according to claim 1, characterized in that, L 2 is an unsubstituted methylene group, an unsubstituted ethylene group, an unsubstituted propylene group or an unsubstituted phenylene group.

4. The compound according to claim 1, characterized in that, the compound is one of the following compounds 6, compound 7, compound 8, compound 10 to compound 15:

5. A compound, characterized in that, the compound is represented by formula (I): wherein, R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms; L 1 is an unsubstituted alkylene group having 1 to 6 carbon atoms, and L 2 is an unsubstituted arylene group having 6 to 18 carbon atoms in the ring; Y is amido; Z is hydroxyl; and n1 is 0, n2 is 1.

6. The compound according to claim 5, characterized in that, the compound is represented by the following compound 9:

7. A compound, characterized in that, the compound is represented by formula (vii): Among them, L 1 is an alkylene group that is unsubstituted and has 1 to 6 carbon atoms; and Z is an unsubstituted alkyl group having 1 to 6 carbon atoms.

8. The compound according to claim 7, characterized in that, the compound is represented by the following compound 5:

9. A compound, characterized in that, the compound is represented by formula (i): wherein, R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms; L 1 is an unsubstituted alkylene group having 1 or 2 carbon atoms, L 2 is an unsubstituted alkylene group having 1 to 6 carbon atoms or an unsubstituted arylene group having 6 to 18 carbon atoms in the ring; Z is hydroxyl or an unsubstituted alkyl group having 1 to 6 carbon atoms; and n1 is 1, n2 is 0.

10. The compound according to claim 9, characterized in that, the compound is represented by the following compound 3:

11. A method for preparing a compound, characterized in that, the method for preparing the compound is the method for preparing the compounds according to claims 4, 6, 8 and 10, which comprises the following steps: Step (a): providing a first reactant, the first reactant being 4,7-dimethoxy-5-hydroxymethyl-1,3-benzodioxole, 4,7-dimethoxy-5-aminomethyl-1,3-benzodioxole, 4,7-dimethoxy-5-carboxylic acid-1,3-benzodioxole or 4,7-dimethoxy-5-acyl chloride-1,3-benzodioxole; Step (b): providing a second reactant, the second reactant being acetic anhydride, 4-aminophenol, benzyl alcohol, ethyl p-aminobenzoate, 5-[(R)-(2-aminopropyl)]-2-methoxybenzenesulfonamide, methyl 4-aminobutyrate hydrochloride, methyl β-alaninate hydrochloride, methyl alaninate hydrochloride, 4-(2-aminoethyl)-1,2-benzenediol hydrochloride, 4-aminoantipyrine or 2-amino-3-cyano-5-methylthiophene; and Step (c): reacting the first reactant with the second reactant to obtain the compound.

12. The method according to claim 11, characterized in that, The first reactant is 4,7-dimethoxy-5-acyl chloride-1,3-benzenedioxole, and step (a) further includes a step of pre-acyl chlorinating 4,7-dimethoxy-5-carboxylic acid-1,3-benzenedioxole to 4,7-dimethoxy-5-acyl chloride-1,3-benzenedioxole to obtain the first reactant.

13. The preparation method according to claim 11, characterized in that the first reactant is 4,7-dimethoxy-5-acyl chloride-1,3-benzenedioxole, the second reactant is methyl 4-aminobutyrate hydrochloride, methyl β-alaninate hydrochloride or methyl alaninate hydrochloride, and step (c) further includes reacting the first reactant with the second reactant to obtain a methyl ester intermediate, and then subjecting the methyl ester intermediate to a hydrolysis reaction to obtain the compound.

14. A pharmaceutical for preventing nerve damage and protecting nerves, characterized in that it comprises the compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 10 for preparing a pharmaceutical for preventing nerve damage and protecting nerves.

16. The use according to claim 15, characterized in that the prevention of nerve damage and protection of nerves include preventing and / or treating stroke and Alzheimer's disease.

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