CN116143746A - Compound for preventing nerve injury and protecting nerve, its preparation method, medicinal products and application - Google Patents
Compound for preventing nerve injury and protecting nerve, its preparation method, medicinal products and application Download PDFInfo
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- CN116143746A CN116143746A CN202111385314.4A CN202111385314A CN116143746A CN 116143746 A CN116143746 A CN 116143746A CN 202111385314 A CN202111385314 A CN 202111385314A CN 116143746 A CN116143746 A CN 116143746A
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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Abstract
The present invention provides a novel compound capable of effectively preventing nerve damage and protecting nerves and a method for preparing the same; the structure of the novel compounds is shown below. In addition, the invention also provides a pharmaceutical composition containing the novel compound and application of the pharmaceutical composition in preparing medicines for preventing nerve damage and protecting nerves.
Therein, R, L 1 、L 2 Y, Z, n1 and n2 are as defined in the specification.
Description
Technical Field
The present invention relates to a compound, a method for producing the same, a pharmaceutical and uses thereof, and more particularly, to a compound which can be used for preventing nerve damage and protecting nerves, a method for producing the same, a pharmaceutical and uses thereof.
Background
Diseases caused by neurodegeneration or injury are common diseases that affect the quality of life of patients for a long period of time, however, effective and non-invasive treatments have been lacking. At present, drugs having effects of preventing nerve damage and protecting nerves are the main research focus in the related fields for preventing and treating diseases related to nervous system diseases such as stroke, cerebral ischemia, brain injury, alzheimer's Disease (AD), parkinson's Disease (PD), retinal disease and the like.
The nerve tissue consists of nerve cells (neuron) and glia (neuroglia). Since nerve cells have a weak regeneration ability, how to promote repair of nerve tissue after it is damaged and to protect it from secondary damage is an important issue in clinical treatment.
Molecular mechanisms of neuronal cell damage include: calcium overload caused by large amount of calcium ion inflow, large amount of excitatory amino acid release, direct injury of nerve cell by free radicals (inflammation).
In recent years, okadaic acid (okaaic acid, OKA) is often used for studying a nerve damage model established by neurodegenerative diseases and alzheimer's disease. Okadaic acid is an inhibitor of protein phosphatase 1 (protein phosphatase, PP 1) and protein phosphatase 2 (protein phosphatase, PP2, also referred to as PP 2A), whereas PP1 and PP2A can reduce the phosphorylation level of tau protein, so that the effect of PP1 and PP2A can be inhibited by okadaic acid, thereby inducing hyperphosphorylation of tau protein to build up a model of alzheimer's disease, and thus to verify the efficacy of the drug for treating alzheimer's disease.
At present, the treatment drugs for senile dementia caused by Alzheimer's disease are selected differently according to the severity of symptoms. Therapeutic agents that may be selected in the light-moderate misshapen individual are anti-acetylcholinesterase agents such as Donepezil (Donepezil), rivastigmine (Rivastigmine), galantamine (Galantamine); among the therapeutic agents that may be selected in moderately severe to severely ill individuals are donepezil and the N-methyl-D-aspartate receptor antagonist (NMDA antagonit) -Memantine (Memantine).
Ischemic stroke (ischemia stroke), on the other hand, is the leading cause of death and disability, but its treatment options are limited. In general, when a stroke or brain trauma causes ischemic brain injury, brain nerves die several days to months after ischemia, with secondary damage to the brain caused by blood reperfusion (reperfusion). Specifically, when ischemia-reperfusion occurs in brain nerve tissue, a large amount of reactive oxygen species and calcium influx are generated, thereby triggering inflammatory mechanisms to cause activation of cytokines (cytokine) and infiltration of leukocytes into the ischemic area, causing inflammatory reactions and injuries to brain nerve tissue.
Currently, drugs commonly used for ischemic stroke include platelet anti-aggregation agents having antithrombotic action, such as Clopidogrel (Clopidogrel), aspirin (Aspirin), ticlopidine (Ticlopidine), and Dipyridamole (Dipyridamole); anticoagulants that help prevent thrombosis, reduce thrombosis expansion, and embolization, such as heparin, low molecular heparin, and Warfarin (Warfarin); thrombolytic agents that help induce fibrinolysis, such as Urokinase (Urokinase) and tissue plasminogen activator (rtPA); a medicament for preventing cerebral edema caused by severe stroke, such as Mannitol (Mannitol) and glycerofructose (glychol); and drugs such as Piracetam (Piracetam) and Nimodipine (Nimodipine) that prevent massive necrosis of brain nerve cells by controlling calcium ion channels, scavenging free radicals, and reducing the metabolic rate of brain cells in ischemic areas.
However, the above-mentioned drugs for preventing and treating nerve-related diseases have not been satisfactory in clinical effect, so that there is still an urgent need to find and develop methods for effectively preventing nerve damage and protecting nerves in the industry or clinically, so as to provide patients with more medical options.
Disclosure of Invention
In view of the drawbacks of the prior art, the present invention provides a novel compound having the efficacy of effectively preventing nerve damage and protecting nerves.
To achieve the object, the present invention provides a compound represented by the 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 an unsubstituted alkylene group having 1 to 6 carbon atoms, an unsubstituted alkenylene group having 2 to 6 carbon atoms, an acyloxy group or an amid group;
z is hydroxy (hydroxyl group), carboxyl (carboxyl group), unsubstituted alkyl group having 1 to 6 carbon atoms, benzenediol group, unsubstituted ester group having 1 to 6 carbon atoms (ester group), unsubstituted aryl group having 6 to 18 carbon atoms in the ring (aryl group), 2-methoxybenzenesulfonamide group (2-methoxybenzenesulfonamide), 2,3-dimethyl-1-phenyl-5-pyrazolone group (2, 3-dimethyl-1-phenyl-5-pyrazolone group) or 2-methyl-4-cyanothienyl group (2-methyl-4-cyanothiophene group); and
n1, n2 are each independently 0 or 1.
In the present specification, the "alkyl group having 1 to 6 carbon atoms" may be a straight-chain or branched alkyl group, which means that the entire substituent has a total number of 1 to 6 carbon atoms. For example, an alkyl group having 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 is 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.
In the present specification, the "alkylene group having 1 to 6 carbon atoms" may be methylene group (CH) 2 (-) ethylene group, -CH 2 CH 2 -or-CH (CH) 3 ) (-) propylene group, -CH 2 CH 2 CH 2 -、-CH 2 CH(CH 3 ) -or-C (CH) 3 ) 2 (-) or butylene groups, e.g. -CH 2 CH 2 CH 2 CH 2 -、-CH 2 C(CH 3 ) 2 -or-CH (CH) 3 )CH 2 CH 2 (-) and the like, but is 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.
In the context of the present description,the "alkenyl group having 2 to 6 carbon atoms" means that the entire substituent has a total number of 2 to 6 carbon atoms. For example, an alkenylene group having 2 to 6 carbon atoms may be a vinylene group (e.g., -CH=CH-), a propenylene group (propenylene group, e.g., -CH) 2 Ch=ch-or-ch=c (CH 3 ) -), butenyl (groups, e.g. -CH 2 CH＝CHCH 2 -or-ch=chch 2 CH 2 (-) and the like, but is not limited thereto. Specifically, the alkenyl group having 2 to 6 carbon atoms may be an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
In the present specification, the "arylene group having 6 to 18 carbons on the ring" means that the ring structure in the overall substituent has 6 to 18 carbons in total. For example, the arylene group having 6 to 18 carbon atoms in the ring may be a phenylene group (phenylene group, -C) 6 H 4 (-) biphenylene (biphenylene group, -C) 6 H 4 -C 6 H 4 (-) or naphthylene (naphthylene group, -C) 10 H 6 (-), but is not limited thereto. Specifically, the arylene group having 6 to 18 carbon atoms in the ring may be an arylene group having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the ring.
Specifically, in the chemical formula (I), the phenylene group may be an o-phenylene group (ortho-phenylene group), a meta-phenylene group (meta-phenylene group), or a para-phenylene group (para-phenylene group). Preferably, the phenylene group is a p-phenylene group.
Specifically, in the chemical formula (I), the benzenediol group may be a catechol group (pyrocatechn), a resorcinol group (resorcinol), or a hydroquinone group (hydroquinone). Preferably, the benzenediol group is a catechol group.
Preferably, Y is unsubstituted ethylene, unsubstituted propylene, unsubstituted butylene, unsubstituted propylene, acyloxy, or amido.
Preferably, Z is hydroxy, carboxy, methyl, catechol, -COOCH 2 CH 3 Unsubstituted phenyl, 2-methoxybenzenesulfonamido, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl。
Preferably, L 2 Is unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene or unsubstituted phenylene.
Specifically, in formula (I), Y may be represented by a-Y-b, where a and b represent two different linking sites, and Y is a linking site between a and L 1 Is connected and connected with L through b 2 Linked, or via the a and L 2 Is connected and connected with L through b 1 And (5) connection.
In some embodiments of the invention, Y is acyloxy and is represented by an oxygen atom through the a and L groups 1 Is connected with L by carbon atom through b 2 Connection, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 Is unsubstituted alkylene having 1 to 6 carbon atoms or unsubstituted arylene having 6 to 18 carbon atoms in the ring and n2 is 0 or 1, Z is hydroxy or unsubstituted alkyl having 1 to 6 carbon atoms, and R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms. The compounds in this embodiment are represented by the following formula (i):
In some embodiments of the invention, Y is acyloxy and is represented by an oxygen atom through the a and L groups 1 Is connected with L by carbon atom through b 2 Connection, L 1 Is an unsubstituted alkyl 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. The compounds in this embodiment are of formula (ii):
in some embodiments of the invention, Y is acyloxy and is represented by an oxygen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 Connection, L 1 Is an unsubstituted alkylene having 1 to 6 carbon atomsAnd n1 is 0 or 1, n2 is 0, Z is an unsubstituted alkyl group having 1 to 6 carbon atoms, a benzenediol 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-cyanothienyl group, and R is hydrogen or an unsubstituted alkyl group having 1 to 6 carbon atoms. The compounds in this embodiment are represented by the following formula (iii):
in some embodiments of the invention, Y is acyloxy and is represented by an oxygen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 Connection, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 Is unsubstituted alkylene having 1 to 6 carbon atoms and n2 is 1, Z is hydroxy, carboxy, unsubstituted alkyl having 1 to 6 carbon atoms, benzenediol, unsubstituted ester having 1 to 6 carbon atoms, unsubstituted aryl having 6 to 18 carbon atoms in the ring, 2-methoxybenzenesulfonamido, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl, R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms. The compounds in this embodiment are represented by the following formula (iv):
in some embodiments of the invention, a compound of formula (iv) above, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 Is unsubstituted aryl having 6 to 18 carbon atoms in the ring and n2 is 1, Z is hydroxy, carboxy, unsubstituted alkyl having 1 to 6 carbon atoms or unsubstituted ester having 1 to 6 carbon atoms, R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms.
In some embodiments of the invention, Y is acyloxy and is represented by an oxygen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 And n1 is 0,L 2 is unsubstituted alkylene having 1 to 6 carbon atoms, n2 is 1, Z is unsubstituted aryl having 6 to 18 carbon atoms in the ring, and R is hydrogen. The compounds in this embodiment are represented by the following formula (v):
In some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 1 Is connected with L by carbon atom through b 2 Connection, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 Is unsubstituted alkylene having 1 to 6 carbon atoms or unsubstituted arylene having 6 to 18 carbon atoms in the ring and n2 is 0 or 1, Z is hydroxy or unsubstituted alkyl having 1 to 6 carbon atoms, and R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms. The compounds in this embodiment are represented by the following formula (vi):
in some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 1 Is connected with L by carbon atom through b 2 Connection, L 1 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. The compounds in this embodiment are represented by the following formula (vii):
in some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 Connection, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms, n1 is 0 or 1, n2 is 0, Z is unsubstituted alkyl having 1 to 6 carbon atoms, benzenediol, unsubstituted carbon atoms in the ring Aryl having a number of 6 to 18, 2-methoxybenzenesulfonamido, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl, R is hydrogen or unsubstituted alkyl having a carbon number of 1 to 6. The compounds in this embodiment are represented by the following formula (viii):
in some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 In the connection, n1 is 0, n2 is 0, Z is 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyano thienyl, and R is hydrogen. The compounds in this embodiment are represented by the following formula (ix):
in some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 Connection, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1, L 2 Is unsubstituted alkylene having 1 to 6 carbon atoms and n2 is 1, Z is hydroxy, carboxy, unsubstituted alkyl having 1 to 6 carbon atoms, benzenediol, unsubstituted ester having 1 to 6 carbon atoms, unsubstituted aryl having 6 to 18 carbon atoms in the ring, 2-methoxybenzenesulfonamido, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl, R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms. The compounds in this embodiment are represented by the following formula (x):
In some embodiments of the invention, a compound of formula (x) above, L 1 Is unsubstituted alkylene having 1 to 6 carbon atoms and n1 is 0 or 1,L 2 is unsubstituted aryl having 6 to 18 carbon atoms in the ring and n2 is 1, Z is hydroxy, carboxy, unsubstituted alkyl having 1 to 6 carbon atoms or unsubstituted ester having 1 to 6 carbon atoms, R is hydrogen or unsubstituted alkyl having 1 to 6 carbon atoms.
In some embodiments of the invention, Y is an amide group and is represented by a nitrogen atom through the a and L groups 2 Is connected with L by carbon atom through b 1 Connection, n1 is 0, L 2 Is unsubstituted alkylene having 1 to 6 carbon atoms, n2 is 1, Z is carboxyl, benzenediol, unsubstituted aryl having 6 to 18 carbon atoms in the ring or 2-methoxybenzenesulfonamide, and R is hydrogen. The compounds in this embodiment are represented by the following formula (xi):
in some embodiments of the invention, a compound of formula (xi) above, n1 is 0, L 2 Is an unsubstituted arylene group having 6 to 18 carbon atoms in the ring and n2 is 1, Z is a hydroxy group or an unsubstituted ester group having 1 to 6 carbon atoms.
In some embodiments of the invention, Y is an unsubstituted alkylene group having 1 to 6 carbon atoms or an unsubstituted alkenylene group having 2 to 6 carbon atoms, L 1 Is unsubstituted and C1-6 alkylene, n1 is 1, n2 is 0, Z is unsubstituted and C1-6 alkyl, R is hydrogen or unsubstituted and C1-6 alkyl.
Preferably, the novel compound may be any one of the following compounds 1 to 15, but is not limited thereto:
in addition, the present invention provides a process for preparing the novel compounds described above, which comprises the steps of: step (a): providing a first reactant which is 4,7-dimethoxy-1, 3-benzene dioxygen singultus (4, 7-dimethoxy-1, 3-benzodioole) derivative; step (b): providing a second reactant, wherein the second reactant comprises halogenated hydrocarbon compounds, acid anhydride compounds, phenol compounds, aromatic alcohol compounds, ester compounds, benzenesulfonamide derivatives, ester hydrochloride derivatives, phenol hydrochloride derivatives, antipyrine derivatives or thiophene derivatives; step (c): reacting the first reactant with the second reactant to obtain the compound.
Preferably, the first reactant comprises 4, 7-dimethoxy-5-methyl-6-iodo-1, 3-benzenediol, 4, 7-dimethoxy-5-hydroxymethyl-1, 3-benzenediol, 4, 7-dimethoxy-5-aminomethyl-1, 3-benzenediol, 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediol, or 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenediol.
Preferably, the second reactant comprises 3,3-dimethylallyl bromide (3, 3-dimethylallyl bromide), 1-bromobutane (1-bromobutane), acetic anhydride (acetic anhydride), 4-aminophenol (4-aminophenol), benzyl alcohol (phenylmethyl alcohol), ethyl p-aminobenzoate (also known as benzocaine), 5- [ (R) - (2-aminopropyl) ] -2-methoxybenzenesulfonamide (5- [ (R) - (2-Amino-propyl) ] -2-methoxy-benzenesulfonamide), 4-aminobutyric acid methyl ester hydrochloride (4-aminobutyric acid methyl ester hydrochloride), beta-propanethide methyl ester hydrochloride (beta-alanine methyl ester hydrochloride), propylamine methyl ester hydrochloride (alanine methyl ester hydrochloride), 4- (2-aminoethyl) -1, 2-benzenedicarboxylic acid hydrochloride (4- (2-aminoethyl) -1,2-benzenediol hydrochloride, dopamine hydrochloride), 4-Amino-3-aminopyridine hydrochloride (4-Amino-2-methoxy-benzenesulfonamide), or 4-Amino-3-Amino-thiophene hydrochloride (4-aminobutyric acid methyl ester hydrochloride).
In some embodiments of the invention, the first reactant comprises 4, 7-dimethoxy-5-methyl-6-iodo-1, 3-benzenediol, 4, 7-dimethoxy-5-hydroxymethyl-1, 3-benzenediol, or 4, 7-dimethoxy-5-aminomethyl-1, 3-benzenediol, the second reactant comprises a halogenated hydrocarbon compound or an anhydride compound, and the first reactant and the second reactant are reacted at a temperature of-80 ℃ to 25 ℃ for a reaction time of 2 hours to 150 hours. Preferably, the second reactant comprises 3,3-dimethylallyl bromide, 1-bromobutane or acetic anhydride.
In other embodiments of the present invention, the first reactant comprises 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediol-in-singultus or 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenediol-in-singultus, the second reactant comprises 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 the first reactant and the second reactant are reacted at a temperature of 0 ℃ to 60 ℃ for a reaction time of 0.5 hours 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 beta-alaninate hydrochloride, methyl propylamine hydrochloride, 4- (2-aminoethyl) -1, 2-benzenebiphenol hydrochloride, 4-aminoantipyrine, or 2-amino-3-cyano-5-methylthiophene.
In other embodiments of the present invention, the first reactant is 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediol, the second reactant comprises an aromatic alcohol compound or an antipyrine derivative, and the first reactant and the second reactant are reacted at a temperature of 25 ℃ to 60 ℃ for a reaction time of 20 hours to 90 hours. Preferably, the second reactant comprises benzyl alcohol or 4-aminoantipyrine.
In other embodiments of the present invention, the first reactant is 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenediol, and the step (a) further comprises the step of pre-chlorinating 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediol into 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenediol, to obtain the first reactant; the second reactant comprises a phenol 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 condition that the temperature is 0 ℃ to 60 ℃ and the reaction time is 0.5 hours to 100 hours. Preferably, the second reactant comprises 4-aminophenol, ethyl p-aminobenzoate, 5- [ (R) - (2-aminopropyl) ] -2-methoxybenzenesulfonamide, 4- (2-aminoethyl) -1, 2-benzenediphenol hydrochloride or 2-amino-3-cyano-5-methylthiophene.
In other embodiments of the present invention, the first reactant is 4, 7-dimethoxy-5-acyl chloride-1, 3-benzene dioxygen singultus, the second reactant is ester hydrochloride derivative, and the step (c) further comprises a step of reacting the first reactant with the second reactant to obtain a methyl ester intermediate, and then subjecting the methyl ester intermediate to hydrolysis reaction to obtain the compound, wherein the first reactant and the second reactant react at a temperature of 0 ℃ to 60 ℃ for a reaction time of 0.5 to 80 hours. Preferably, the second reactant comprises methyl 4-aminobutyrate hydrochloride, methyl beta-alanine hydrochloride or methyl propylamine hydrochloride.
In addition, the present invention provides a pharmaceutical product for preventing nerve damage and protecting nerves, which comprises the novel compound of the present invention as described above and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides a use for the preparation of a medicament for preventing nerve damage and protecting nerves, wherein the medicament comprises the novel compound of the present invention as described above and a pharmaceutically acceptable carrier.
Preferably, the nerve refers to brain nerve tissue.
Preferably, the preventing nerve damage and protecting nerves comprises preventing and/or treating stroke and Alzheimer's disease.
In the present specification, the "efficacy of preventing nerve damage" means that the novel compounds of the present invention are capable of effectively reducing the damage and death degree of nerve cells when nerve damage occurs after administration of the compounds. The "nerve-protecting" effect means that administration of the novel compounds of the present invention described above while nerve damage occurs is effective in reducing the degree of damage and death of nerve cells.
According to the present invention, the "pharmaceutically acceptable carrier" may include pharmaceutically or food acceptable excipients or additives, such as starch, corn starch, gelatin, acacia, food color, spices, flavoring agents, preservatives, and the like. The route of administration may include oral, transdermal, intraperitoneal, intravenous, nasal, or ocular administration, among others.
According to the present invention, the pharmaceutical composition can be administered according to the age, weight, health condition, disease type, disease progress, affected part and the like of the patient, and the relevant medical staff can determine the administration dosage according to common knowledge in the technical field. The pharmaceutical compositions of the present invention may also be administered alone or in combination with other agents, the course of which is according to the pharmaceutical routine of the physician or the relevant person.
In the specification, a range expressed by "small value to large value" means that the range is greater than or equal to the small value to less than or equal to the large value unless otherwise specified. For example: the temperature is-80 ℃ to 25 ℃, which means that the range is' greater than or equal to-80 ℃ and less than or equal to 25 ℃.
Drawings
Fig. 1 is the effect on the prevention of nerve damage following administration of the compounds of examples 1 to 15 to rats.
Fig. 2 shows the results of staining of different areas of the brain after administration of the compounds of examples 1 to 15 to rats.
Fig. 3 is the evaluation result of neural behavior after administration of the compounds of examples 1, 3 to 11 and 15 to rats.
Fig. 4 is the result of an experiment evaluating the efficacy of the compounds of examples 1 to 15 for protecting nerves.
Detailed Description
The following examples are given by way of illustration of the embodiments of the present invention and their advantages and effects will be readily apparent to those skilled in the art from the teachings of the present invention and various modifications and alterations may be made to practice or use the teachings of the present invention without departing from the spirit thereof.
Example 1
0.65 g of 4, 7-dimethoxy-5-methyl-6-iodo-1, 3-benzenediox and 3 ml of tetrahydrofuran are added to a 100 ml three-necked flask, cooled to-80℃under dry nitrogen, then 1.5 ml of n-butyllithium solution having a volume molar concentration of 1.6 mol/liter is slowly added, followed by a further slow addition of a mixed solution of 2.35 ml of 3, 3-dimethylallylbromide (0.35 ml) and tetrahydrofuran (2 ml) and reaction is carried out for 70.5 hours. After the reaction was completed, 5 ml of water and 5 ml of ethyl acetate were added and uniformly mixed, then the ethyl acetate layer of the upper layer solution was retained and washed twice with 5 ml of water, then water was removed with anhydrous sodium sulfate and insoluble matters were filtered, and the insoluble matters were washed three times with 5 ml of ethyl acetate and the washing liquid was retained, then the above-mentioned dehydrated and filtered solution with anhydrous sodium sulfate and washing liquid were combined, and after the solvent was removed by a rotary thickener, purification was performed by column chromatography (column packed with 80 g of silica gel, a packing length of 15 cm, and a washing liquid of 100% concentration of heptane) to obtain 0.22 g of pale yellow liquid after collecting the main product, namely, the compound of example 1, whose HPLC purity was 97.1%.
The structures of the compounds of example 1 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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 was: [ M-C 4 H 7 ] + ；C 11 H 13 O 4 ；209.18。
Example 2
3.24 g of 4, 7-dimethoxy-5-methyl-6-iodo-1, 3-benzenediox-ing singultus and 25 ml of tetrahydrofuran are added into a three-necked flask of 100 ml, cooled to-80 ℃ under dry nitrogen, then 7 ml of n-butyllithium solution with a volume molar concentration of 1.6 mol/liter is slowly added, then 2.2 ml of 1-bromobutane is slowly added and reacted for 3 hours, the temperature is adjusted to room temperature, then 25 ml of water and 25 ml of ethyl acetate are added and uniformly mixed, then the ethyl acetate layer of the upper layer solution is retained and washed twice with 30 ml of water, then, the insoluble matter was removed with anhydrous sodium sulfate and filtered, and the insoluble matter was washed three times with 10 ml of ethyl acetate and the washing liquid was retained, then, the solution removed with anhydrous sodium sulfate and filtered was combined with the washing liquid, and after the solvent was removed by a rotary thickener, purification was performed by column chromatography (column was filled with 60 g of silica gel, the filling length was 12 cm, and the washing liquid was 100% heptane), and after collecting the main product, the solvent was removed by a rotary thickener, 0.9 g of the compound of example 2 was obtained, which had an HPLC purity of 96.82%.
The structures of the compounds of example 2 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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 was: [ M+H ]] + ；C 14 H 21 O 4 ；253.21。
Example 3
After adding 0.2438 g of 4, 7-dimethoxy-5-hydroxymethyl-1, 3-benzenediox, 5 ml of tetrahydrofuran and 0.3 ml of triethylamine to a 100 ml three-necked flask, the temperature was lowered to 0℃and then 0.45 ml of acetic anhydride was added, the temperature was adjusted to room temperature and the reaction was carried out for 144.5 hours. After the completion of the reaction, the whole solvent was removed by a rotary thickener and the residue was dissolved with 10 ml of methylene chloride, followed by washing with 10 ml of saturated aqueous sodium bicarbonate solution once, followed by washing with 10 ml of water once again and leaving the organic layer, and after removing the water from the organic layer with anhydrous sodium sulfate, the whole solvent was removed by a rotary thickener to obtain 0.288 g of an off-white powder, i.e., the compound of example 3, having an HPLC purity of 92.58%.
The structures of the compounds of example 3 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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). The mass spectrometry analysis was: [ M-C 2 H 3 O 2 ] + ；C 10 H 11 O 4 ；195.14。
Example 4
0.5722 g of 4, 7-dimethoxy-5-iodo-1, 3-benzenediox and 4 ml of tetrahydrofuran are introduced into a three-necked flask of 100 ml and cooled to-80℃under dry nitrogen, followed by 1.5 ml of n-butyllithium solution having a volume molar concentration of 1.6 mol/l and uniformly mixed for 4 minutes, followed by 3.35 ml of a mixed solution of 3, 3-dimethylallylbromide (0.35 ml) and tetrahydrofuran (3 ml) and reaction for 2.5 hours. After the reaction was completed, the temperature was adjusted to 0 ℃ and 10 ml of water and 10 ml of ethyl acetate were added to conduct extraction once, then the organic layer was retained and washed once with 10 ml of water, then anhydrous sodium sulfate was used to remove water and the solvent was removed by a rotary thickener to obtain a dark brown liquid having a wet weight of 0.438 g, which was then purified by column chromatography (column packed with 29.1 g of silica gel and a packing length of 6 cm, ethyl acetate: heptane was used as a 1:50 solution), to obtain 66.3 mg of the compound of example 4 after collecting the main product, which had an HPLC purity of 96.50%.
The structures of the compounds of example 4 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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。
Example 5
1.0054 g of 4, 7-dimethoxy-5-aminomethyl-1, 3-benzenedioxiat was added to a 100 ml three-necked flask and placed in a dry nitrogen atmosphere, and after adding 10 ml of tetrahydrofuran and 1.5 ml of triethylamine, the temperature was lowered to 0℃and then 0.5 ml of acetic anhydride was added to carry out the reaction for 17 hours. After the reaction was completed, 10 ml of methanol was added and all solvents were removed by a rotary thickener, then after dissolving the residue with 30 ml of dichloromethane, the residue was washed once with 30 ml of saturated aqueous sodium bicarbonate solution, once with 30 ml of water, and finally washed once with 30 ml of brine and the organic layer was remained. The organic layer was dehydrated with anhydrous sodium sulfate and then all solvents were removed by a rotary thickener to give 1.157 g of pale yellow powder, followed by column chromatography (column filled with 50.1 g of silica gel and a filling length of 11 cm, ethyl acetate: heptane was used as a solution of 1:10 to 2:1), and after collecting the main product, all solvents were removed by a rotary thickener to give 0.944 g of the compound of example 5 having an HPLC purity of 89.59%.
The structures of the compounds of example 5 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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 was: [ M+H ]] + ；C 12 H 16 NO 5 ；254.23,[M+Na] + ；276.16。
Example 6
0.509 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzene dioxygen singultus, 1.3 ml of dichloromethane and 2 drops of dimethylformamide are added into a three-necked bottle of 100 ml, then 0.34 ml of oxalyl chloride is added and uniformly mixed at room temperature for reaction for 1 hour, and then the excessive oxalyl chloride and solvent are removed by a rotary thickener to obtain monoacyl chloride. The acid chloride was placed in a 100 ml single-necked flask, and 5 ml of methylene chloride, 2.5 ml of methylene chloride solution (containing 0.508 g of 5- [ (R) - (2-aminopropyl) ] -2-methoxybenzenesulfonamide) and 1.3 ml of triethylamine were added in this order, and after uniformly mixing and reacting at room temperature for 19.5 hours, 10 ml of water and 10 ml of ethyl acetate were added and the organic layer was left after uniform mixing, and then the solvent was removed by a rotary thickener to obtain 0.9 g of an off-white needle-like solid. The off-white needle solid was then mixed with 17.5 ml of heptane and stirred at room temperature for 5 minutes, followed by filtration to give 0.589 g of white powder, the compound of example 6, having an HPLC purity of 96.5%.
The structures of the compounds of example 6 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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(d3H). The mass spectrometry analysis was: [ M+H ]] + ；C 20 H 25 N 2 O 8 S；453.30,[M+Na] + ；475.26。
Example 7
1.1447 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox, 2 ml of toluene and 2 drops of dimethylformamide are added to a 500 ml single-necked flask, and then 0.75 ml of thionyl chloride is added thereto and the mixture is heated to 60℃to carry out a reaction for 1.5 hours. After the completion of the reaction, the whole solvent was removed by a rotary thickener and the residue was dissolved in 20 ml of tetrahydrofuran, followed by removing the whole solvent by a rotary thickener to obtain monoacyl chloride. The acid chloride was mixed with 20 ml of tetrahydrofuran and cooled to 0 ℃, followed by addition of 0.8076 g of methyl 4-aminobutyrate hydrochloride and 3 ml of triethylamine, followed by reaction at room temperature for 19 hours. After the reaction was completed, 20 ml of water and 20 ml of ethyl acetate were added and uniformly mixed to leave an organic layer, and the aqueous layer was extracted once with 20 ml of ethyl acetate again to leave an organic layer and combined with the organic layer which had previously been left, and then after all the solvent was removed by a rotary concentrator, the residue was dissolved with 20 ml of ethyl acetate, and then washed once with 20 ml of water and then with 20 ml of brine to leave an organic layer. After the organic layer was dehydrated with anhydrous sodium sulfate, all solvents were removed by a rotary concentrator to obtain 1.404 g of a methyl ester intermediate (yellow liquid) having an HPLC purity of 86.32%.
0.7962 g of the methyl ester intermediate, 8 ml of tetrahydrofuran and 8 ml of methanol were added to a double flask of 100 ml and cooled to 0℃and then 8 ml of an aqueous lithium hydroxide solution (which had 0.3744 g of lithium hydroxide contained therein) was added and mixed uniformly, followed by adjusting the temperature to room temperature for reaction for 67 hours. After the reaction is completed, the temperature is reduced to 0 ℃ and 25 milliliters of ethyl acetate is added, then the pH value is adjusted to 3.28 by using a hydrochloric acid aqueous solution with the volume molar concentration of 1 mol/liter, and then the temperature is adjusted to room temperature and the upper organic solution is reserved; the lower solution was extracted once more with 25 ml of ethyl acetate, the upper organic solution was retained and combined with the previously retained organic solution, then the entire solvent was removed by a rotary thickener after removal of water with anhydrous sodium sulfate to give a yellow liquid, which was dried under vacuum to give 0.746 g of a yellow needle-like solid, i.e., the compound of example 7 having an HPLC purity of 95.47%.
The structures of the compounds of example 7 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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). The mass spectrometry analysis was: [ M+H ] ] + ；C 14 H 18 NO 7 ；312.16,[M+Na] + ；334.18。
Example 8
0.6818 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzene dioxy singultus, 20 ml of toluene and 5 drops of dimethylformamide are added into a 500 ml single-necked bottle, 0.55 ml of thionyl chloride is added and heated to 60 ℃ for reaction for 1 hour, after the reaction is completed, the redundant thionyl chloride and solvent are removed by a rotary thickener, the remainder is dissolved in 20 ml of tetrahydrofuran, and then the solvent is removed by the rotary thickener to obtain monoacyl chloride. The acid chloride was uniformly mixed with 20 ml of tetrahydrofuran and cooled to 0 ℃, followed by addition of 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) and reaction at 0 ℃ for 30 minutes, and then the temperature was adjusted to room temperature and the reaction was further carried out for 46 hours. After the reaction is completed, 20 ml of water and 20 ml of ethyl acetate are added and uniformly mixed, and then an upper layer solution is reserved; the lower solution was extracted once with 20 ml of ethyl acetate and the upper solution was retained and combined with the previously retained upper solution, after all the solvent was removed by a rotary thickener, the remainder was washed once with 10 ml of an aqueous hydrochloric acid solution having a molar concentration of 0.1 mol/l, once with 10 ml of water, finally with 10 ml of brine, then with anhydrous sodium sulfate to remove water and remove the solvent by a rotary thickener, to obtain a product having a wet weight of about 1.05 g, and then column chromatography (column packed with 30 g of silica gel having a packing length of 6 cm, ethyl acetate: heptane of 1:10 to 5:1) was used for purification, and a main compound having a wet weight of 0.653 g was collected, and reverse column chromatography (column packed with 28.3 g of carbon-eighteen silica gel having a packing length of 4.5 cm, and bank wash with acetonitrile: water: 1:1) was used for purification, and 0.224 g of the main compound was collected, i.e., the compound having a purity of 98.76% in the example of HPLC.
The structures of the compounds of example 8 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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). The mass spectrometry analysis was: [ M+H ]] + ；C 18 H 20 NO 7 ；362.28,[M+Na] + ；384.27。
Example 9
1.1297 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox, 20 ml of toluene and 2 drops of dimethylformamide are added to a 500 ml single-necked flask, 0.8 ml of thionyl chloride is added and heated to 60 ℃ for reaction for 1 hour, then excess thionyl chloride and solvent are removed by a rotary thickener, and the residue is dissolved in 20 ml of tetrahydrofuran, and then the solvent is removed by a rotary thickener to obtain monoacyl chloride. The acyl chloride is uniformly mixed with 20 ml of tetrahydrofuran, cooled to 0 ℃, 0.5529 g of 4-aminophenol and 1.4 ml of triethylamine are added, the reaction is carried out for 30 minutes at 0 ℃, and the temperature is adjusted to room temperature for further 22 hours. After the reaction was completed, 20 ml of water was added and the upper organic solution was retained after uniform mixing; the lower solution was extracted once more with 20 ml of ethyl acetate and the upper organic solution was retained and combined with the previously retained upper organic solution, after which the combined organic solution was washed once with 20 ml of water, once with 20 ml of brine, then with anhydrous sodium sulfate to remove water, and the solvent was removed by a rotary concentrator to give a product having a wet weight of about 1.6163 g, after which column chromatography (column packed with 39.9 g of silica gel with a packing length of 8 cm) was used to purify the extract using ethyl acetate: heptane of 1:10 to 5:1 solution) and 1.077 g of the main compound was collected as the compound of example 9, which had an HPLC purity of 95.98%.
The structures of the compounds of example 9 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 1 H NMR(500MHz,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). The mass spectrometry analysis was: [ M+H ]] + ；C 16 H 16 NO 6 ；318.15,[M+Na] + ；340.15。
Example 10
0.5669 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediol singultus, 15 ml of toluene and 3 drops of dimethylformamide are added to a 250 ml single-necked flask, and then 0.4 ml of thionyl chloride is added thereto and heated to 60℃to carry out the reaction for 1 hour. After the reaction was completed, excess thionyl chloride and solvent were removed by a rotary thickener and the residue was dissolved in 15 ml of 2-methyltetrahydrofuran, followed by removal of all solvent by a rotary thickener to obtain monoacyl chloride. The acid chloride was mixed with 15 ml of tetrahydrofuran and cooled to 0 ℃, followed by the addition of 0.5051 g of beta-methyl propylamine hydrochloride and 1.4 ml of triethylamine, and after 30 minutes at 0 ℃, the temperature was adjusted to room temperature and the reaction was further carried out for 2 days for 23 hours. After the reaction was completed, 20 ml of water and 20 ml of ethyl acetate were added, and the upper solution was uniformly mixed and retained, and then the upper solution was washed once with 20 ml of water, and then washed once with 20 ml of brine, and then dehydrated with anhydrous sodium sulfate, and then the solvent was removed by a rotary thickener to obtain a yellow powder having a wet weight of about 0.5639 g, and then purified by column chromatography (column packed with 31 g of silica gel and a packing length of 6 cm, and the solution of ethyl acetate: heptane was 1:10 to 1:2), and 0.409 g of methyl ester intermediate was collected, the HPLC purity of which was 99.34%.
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℃followed by slow addition of 4 ml of an aqueous lithium hydroxide solution containing 0.1915 g of lithium hydroxide, followed by adjustment of the temperature to room temperature for 79 hours of reaction. After the reaction was completed, the organic solvent was removed by a rotary thickener, and then the aqueous residue was mixed with 20 ml of methylene chloride and cooled to 0 ℃, followed by adjusting the pH to 1.75 with an aqueous hydrochloric acid solution having a volume molar concentration of 1 mol/liter, and then adjusting the temperature to room temperature and keeping a layer solution; the upper solution was extracted twice with 40 ml of ethyl acetate and the upper solution was retained and combined with the retained lower solution, then the organic solution was retained after washing twice with 40 ml of water, and then water was removed with anhydrous sodium sulfate and the solvent was removed by a rotary thickener to give 0.346 g of a white powder, i.e., the compound of example 10 having an HPLC purity of 96.10%.
The structures of the compounds of example 10 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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。
Example 11
1.1356 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox, 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 thereto and heated to 60℃to carry out a reaction for 1 hour. After the reaction was completed, excess thionyl chloride and solvent were removed by a rotary thickener and the residue was dissolved in 20 ml of 2-methyltetrahydrofuran, followed by removal of the solvent by a rotary thickener to obtain monoacyl chloride. The acid chloride was mixed with 20 ml of tetrahydrofuran and cooled to 0 ℃, followed by the addition of 0.9445 g of methyl propylamine hydrochloride and 3 ml of triethylamine for reaction for 30 minutes, and then the temperature was adjusted to room temperature for further reaction for 27 hours. After the reaction was completed, 20 ml of water and 20 ml of ethyl acetate were added, and the upper solution was uniformly mixed and remained, then the upper solution was washed once with 20 ml of water, then washed once with 20 ml of brine, and then dehydrated with anhydrous sodium sulfate, then the solvent was removed by a gyratory concentrator to obtain a yellow liquid having a wet weight of about 1.272 g, and then column chromatography (column packed with 31 g of silica gel and a packing length of 6 cm, and a solution of ethyl acetate: heptane of 1:10 to 1:2 was used as a wash solution) was used to purify the yellow liquid, and the main compound was collected to obtain 1.02 g of methyl ester intermediate having an HPLC purity of 97.07%.
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℃followed by slow addition of 10 ml of an aqueous lithium hydroxide solution (which already contained 0.44 g of lithium hydroxide), followed by reaction at room temperature for 24 hours. After the reaction was completed, the organic solvent was removed by a rotary thickener, and then the aqueous residue solution was mixed with 20 ml of methylene chloride and cooled to 0 ℃, followed by adjusting the pH to 4.6 with an aqueous hydrochloric acid solution having a volume molar concentration of 1 mol/liter, and then adjusting the temperature to room temperature and keeping a layer solution; the upper solution was extracted once with 20 ml of ethyl acetate and the upper solution was retained and combined with the retained lower solution, and then the solvent was removed by a rotary thickener to give an off-white powder having a wet weight of 0.965 g, which was then dissolved in 20 ml of ethyl acetate, washed once with 20 ml of water, washed once with 20 ml of brine, and the organic solution was retained and the solvent was removed by a rotary thickener to give 0.752 g of the off-white powder, which was the compound of example 11 having an HPLC purity of 98.21%.
The structures of the compounds of example 11 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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). The mass spectrometry analysis was: [ M+H ]] + ；C 13 H 16 NO 7 ；298.15,[M+Na] + ；320.13。
Example 12
1.13 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox singultus, 5.5 ml of benzyl alcohol and 3 drops of concentrated sulfuric acid were added to a 50 ml double-necked flask, and the mixture was heated to 60℃to carry out the reaction for 28 hours. After the reaction was completed, 50 ml of water was added and the lower layer solution was kept, and then the solvent was removed by a rotary thickener to obtain a dark brown liquid, which was then purified by column chromatography (column packed with 45 g of silica gel and 9 cm of packing length, ethyl acetate: heptane was used as the solution of 1:20 to 1:10), and after the main product was collected, the solvent was removed by a rotary thickener to obtain a colorless transparent liquid having a wet weight of 1.8668 g, and then dried under vacuum to obtain 1.352 g of a white powder, which was the compound of example 12, having an HPLC purity of 98.40%.
The structures of the compounds of example 12 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 1 H NMR(500MHz,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). The mass spectrometry analysis was: [ M+H ]] + ；C 17 H 17 O 6 ；317.14,[M+Na] + ；339.13。
Example 13
After adding 0.57 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenedioxirane, 0.51 g of 4-aminoantipyrine, 10 ml of tetrahydrofuran and 5 ml of water to a 100 ml double-necked flask, 0.8 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide was further added to the flask and reacted at room temperature for 74 hours. After the reaction was completed, tetrahydrofuran was removed by a rotary thickener, 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, then dehydrated with anhydrous sodium sulfate and all solvents were removed by a rotary thickener to obtain 0.80 g of a deep orange liquid, i.e., the compound of example 13 having an HPLC purity of 97.58%.
The structures of the compounds of example 13 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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 was: [ M+H ]] + ；C 21 H 22 N 3 O 6 ；412.34,[M+Na] + ；434.32。
Example 14
After 0.57 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox, 10 ml of toluene and 1 drop of dimethylformamide were added to a 100 ml single-necked flask, 0.4 ml of thionyl chloride was further added and the mixture was heated to 60℃to conduct a reaction for 1.5 hours. After the completion of the reaction, excess thionyl chloride and solvent were removed by a rotary thickener and the residue was dissolved in 10 ml of 2-methyltetrahydrofuran, followed by removal of the solvent by a rotary thickener to obtain monoacyl chloride. The acid chloride was placed in a 250 ml single-necked flask, and after adding 10 ml of 2-methyltetrahydrofuran, the temperature was lowered to 0 ℃, and 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 to conduct the reaction for 96 hours. After the completion of the reaction, 10 ml of water and 10 ml of ethyl acetate were added and the lower aqueous solution was retained, followed by extraction with 20 ml of ethyl acetate three times, the retained aqueous layer was extracted with 20 ml of dichloromethane three times and the dichloromethane layer solution was retained, followed by dehydration with anhydrous sodium sulfate and then removal of the solvent by a rotary thickener to obtain 0.47 g of a yellow powder, i.e., the compound of example 14 having an HPLC purity of 90.82%.
The structures of the compounds of example 14 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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。
Example 15
After 0.57 g of 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenediox, 10 ml of toluene and 1 drop of dimethylformamide were added to a 250 ml single-necked flask, 0.42 ml of thionyl chloride was further added and the mixture was heated to 60℃to conduct a reaction for 1.5 hours. After the completion of the reaction, excess thionyl chloride and solvent were removed by a rotary thickener and the residue was dissolved in 10 ml of 2-methyltetrahydrofuran, followed by removal of the solvent by a rotary thickener to obtain monoacyl chloride. The acid chloride was placed in a 250 ml single-necked flask, followed by addition of 10 ml of 2-methyltetrahydrofuran and cooling to 0℃followed by addition of 0.42 g of benzocaine and 0.8 ml of triethylamine and reaction was carried out for 22 hours after the temperature was adjusted to room temperature. After the completion of the reaction, 10 ml of water was added and 10 ml of ethyl acetate was extracted three times to leave an ethyl acetate layer, and the aqueous layer was extracted three times with 10 ml of dichloromethane, and then the dichloromethane layer was left and combined with the remaining ethyl acetate layer, followed by removal of the solvent by a rotary thickener after removal of the water with anhydrous sodium sulfate to give an off-white powder having a wet weight of 0.98 g, which was dissolved in 50 ml of dichloromethane, followed by washing three times with 25 ml of water and removal of the water with anhydrous sodium sulfate, followed by removal of the solvent by a rotary thickener to give 0.92 g of an off-white powder, which was the compound of example 15 having an HPLC purity of 93.0%.
The structures of the compounds of example 15 are shown in table 1 below, with nuclear magnetic resonance hydrogen spectra of: 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。
Table 1: structures of the compounds of examples 1 to 15.
Test example 1: efficacy assessment for preventing nerve damage
The test example uses the compounds of examples 1 to 15 dissolved in a solvent as the test solutions of examples 1 to 15 (the concentration is 10 mg/ml), wherein the solvent consists of dimethyl sulfoxide (dimethyl sulfoxide, DMSO), castor oil polyoxyethylene ether (CrEL) and water, and the contents are respectively 10 volume percent, 20 volume percent and 70 volume percent in sequence; in addition to the experimental group, a group in which a simple solvent was used as a blank group, and no compound or solvent was administered, only the following surgical operation was performed, and no occlusion ischemia was performed with a nylon monofilament thread was used as a Sham group.
This test example simulates ischemic cerebral stroke using a transient in-local cerebral arterial ischemia/reperfusion animal model (transient focal Middle Cerebral Artery Occlusion/Reperfusion model, MCAO/R model) to assess the subsequent neurological damage. Specifically, male history-daoshan rats (Sprague Dawley rat, SD rat) were selected and anesthetized with 2% isoflurane (isofiurane), followed by separation of the right common carotid (right common carotid artery), external carotid (external carotid artery) and internal carotid (internal carotid artery) from the neck.
Subsequently, a nylon monofilament wire (nylon monofilament) having a length of about 22 millimeters (mm), a number of 4/0, and a front end covered with polysiloxane (polysiloxane) was inserted through the external carotid artery and then extended along the internal carotid artery all the way to the Willis ring portion (circle of Willis) of the brain to cause occlusion ischemia of the middle cerebral artery (middle cerebral artery), and after 1 hour of occlusion ischemia, the nylon monofilament wire was removed to restore blood circulation to the brain even if the previously ischemic brain region was subjected to blood reperfusion.
After 24 hours of blood reperfusion, the rat was sacrificed and the brain was removed and placed in saline (sample) at low temperature and 0.95% concentration, then the front end of the brain was removed at 1mm, and then the brain was cut into seven brain tissue slices with a thickness of 2mm in the form of coronal sections, and then the brain tissue slices were infiltrated with 2,3,5-triphenyltetrazolium chloride (2, 3,5-triphenyltetrazolium chloride, TTC) at a concentration of 1% and reacted at room temperature (about 25 ℃ to 27 ℃) for 30 minutes, and then the brain tissue slices were fixed in formalin solution at a concentration of 4%, and then the infarct volume percentage was recorded by photographing with MacroPATH Digital Imaging System photographic system and calculated using ImageJ 1.52a image analysis software to represent the case of nerve damage. The infarct volume percentage is obtained by multiplying the respective infarct area ratio of the brain tissue slice by the thickness of each slice and then adding up the respective infarct area ratios, wherein the infarct area ratio is obtained according to the following formula: (B-ase:Sub>A)/bx 100%, wherein ase:Sub>A is the undamaged arease:Sub>A in the right damaged brain hemisphere and B is the total arease:Sub>A of the left undamaged brain hemisphere.
The group of examples 1 to 15 herein was that the test solutions of examples 1 to 15 were administered to rats in a single administration by intraperitoneal injection (intraperitoneal injection, i.p.) for the first 10 minutes of the MCAO/R model, the administered dose being 50 milligrams (50 milligrams per kilogram) per kilogram and the administered volume being 5 milliliters per kilogram, calculated as the weight of the rats; the solvent was also administered to rats in a single dose by intraperitoneal injection, and the volume of the solvent was 5 ml/kg.
The total infarct volume percentages (sum of the volume percentages of seven brain tissue sections) for examples 1-15, blank, and Sham groups are listed in table 2 below and shown in fig. 1, while TTC staining results for brain tissue sections at seven different locations for examples 1-15, blank, and Sham groups are shown in fig. 2. Each of the experimental groups and the blank groups of examples 1 to 15 was subjected to 5 animal experiments (n=5), and the Sham group was subjected to 3 animal experiments (n=3).
Table 2: examples 1 to 15, blank, and Sham groups.
* : p-value less than 0.05: p-value is less than 0.01: the p value is less than 0.001.
As can be seen from the results of table 2, after the ischemic stroke was simulated and the blood was reperfusion for 24 hours, the total infarct volume percentage of the blank group was 40.48%, showing that a wide range of nerve damage did occur after the stroke was simulated via the MCAO/R model described above; whereas the total infarct volume percentage of Sham group was only 1.79%, which showed statistically significant differences (p-value less than 0.001) compared to the blank group, indicating that the nerves were not damaged, indicating that the surgical procedure during the experiment did not affect the experimental results of the total infarct volume percentage.
Referring again to the results of examples 1-15, examples 1-15 all showed lower total infarct volume percentages (between about 14.52% and 35.67%) compared to the total infarct volume percentages of the blank, except that further analysis by Student's T-test showed statistically significant differences for examples 3, 4, 6, 7, 9-11 and 15 compared to the blank, wherein examples 3, 4 and 6 had p-values less than 0.05, examples 7, 10, 11 and 15 had p-values less than 0.01 and example 9 had p-values less than 0.001; it is also evident from the results of FIG. 1 that the total infarct volume percentages for the groups of examples 1 to 15 are lower than for the blank. It follows that the pre-administration of the novel compounds of the present invention does indeed reduce the percentage of total infarct volume, representing a reduction in the extent of nerve damage and thus the efficacy of preventing nerve damage.
Looking again at FIG. 2, seven columns of staining results from top to bottom are, in order, brain tissue sections 3mm, 5mm, 7mm, 9mm, 11mm, 13mm and 15mm from the boundary of the front end of the brain which has been resected, respectively, and it can be judged that if white appears in the brain tissue sections, it means that the nerves of the portion have been damaged, according to the principle of TTC staining. From the results of the staining in the blank, the right half of the seven rows of brain tissue sections showed significant whiteness, showing that the nerves in the different locations were indeed damaged, and from the results of the staining in examples 1 to 15, the phenomenon that the right side of the brain tissue sections in the different locations showed whiteness was less significant than that in the blank, thus also confirming that the novel compounds of the present invention were indeed effective in preventing nerve damage.
Test example 2: neural behavior assessment
The test was performed simultaneously with the test example 1, so that the test solution was prepared, and the blank and Sham groups were all identical to the test example 1. Specifically, the test examples were selected from the group of examples 1, 3 to 11 and 15, and the severity of neurological deficit was evaluated at the time points of 0.5 hour, 1.5 hour and 24 hours after reperfusion of blood of the MCAO/R model according to the classification criteria specified by Bederson to evaluate neurological behavior, wherein the behavioral evaluation and neurological deficit classification methods were as follows: grade 0 indicates that no neurological deficit occurs, grade1 indicates that the rat forelimb contracts toward the contralateral (contralateral) side of the brain-damaged area, grade 2 indicates that the rat's resistance to ipsilateral thrust is reduced, grade 3 indicates that the rat spontaneously circles on the contralateral side of the damaged brain area, fails to proceed straight, and Grade 4 indicates severe neurological impairment, the limbs appear to be paralyzed or epileptic.
The results of examples 1, 3 to 11 and 15, blank and Sham are set forth in table 3 below and in fig. 3.
Table 3: results of neural behavior evaluation of examples 1, 3 to 11 and 15, blank and Sham groups.
As can be seen from the results in table 3, at the time points of 0.5 hours, 1.5 hours and 24 hours after blood reperfusion, the neural behavior evaluation results of the blank group were all 2.8 close to Grade 3, indicating that the neural behavior was indeed affected; comparing the results of examples 1, 3 to 11 and 15 with the blank, examples 1, 3 to 11 and 15 all showed preferred neurobehavioral assessment results (all lower than 2.8), wherein at the time point 24 hours after reperfusion, examples 1, 3 to 11 and 15 showed better neurobehavioral assessment results, especially for examples 3, 4, 7, 9 and 11, which were superior to Grade 2; furthermore, it can be seen from the results of fig. 3 that the neural behavior evaluation results of examples 1, 3 to 11 and 15 were indeed better than those of the blank group after 24 hours of blood reperfusion. It follows that the nerve damage condition can indeed be improved over a longer period of time by administration of the novel compounds of the present invention.
Test example 3: efficacy assessment of protecting nerves
The test example uses the compounds of examples 1 to 15 dissolved in DMSO as the test solutions of examples 1 to 15, and okadaic acid as a nerve damage inducing substance to simulate the damage of nerve cells, and then the protective effect of the test substance on nerve cells was evaluated through a cell viability reagent (cell counting kit, CCK-8, available from Dojindo corporation, japan).
Specifically, the test selects a mouse neuroblastoma cell line-Neuro-2 a cell
And subcultured in MEM medium containing 10 volume percent of fetal bovine serum (fetal bovine serum, FBS) in an incubator containing 5% carbon dioxide at 37℃followed by 5X 10 of Neuro-2a cells 3 Cell density of/well was inoculated into 96-well culture plates in which the volume of the medium was 100. Mu.l and okadaic acid was contained at a concentration of 120 nM by volume molar concentration (nM), then 0.1. Mu.l of the test solutions of examples 1 to 15, which had been prepared in advance at a concentration 1000 times, were added to the medium, the test solution concentrations in each group of the culture media were as shown in Table 4 below, followed by co-treatment for 24 hours, and then each group of the cell viability was analyzed with CCK-8 reagent, wherein the group containing okadaic acid alone without the test solution was used as a control group, and the analysis results of the cell viability of each group of the cells are shown in Table 4 below. The concentrations of okadaic acid and the test solutions of examples 1 to 15 in the medium are also shown in Table 4 below, wherein the concentration units of the test solutions of examples 1 to 15 are expressed in micrograms/milliliter (μg/ml). Each group was subjected to 3 to 4 replicates.
Table 4: results of cell viability analyses of examples 1 to 15 and control group.
* : p-value less than 0.05: p-value is less than 0.01: the p value is less than 0.001.
As can be seen from the results of table 4, the control group was the group treated with okadaic acid only, and thus serious damage and death of nerve cells occurred, resulting in a cell viability of only 28.88%; the co-treated groups with the compounds of examples 1 to 15 all had significantly higher cell viability (34.18% to 67.27%) than the control group, with example 5 having the highest cell viability, and further analyzed by Student's T-test, which showed statistically significant differences between examples 1 to 3, 5 to 7, 9 and 12 to 14 compared to the control group, wherein examples 12 to 14 had p values of less than 0.05 and examples 1 to 3, 5 to 7 and 9 had p values of less than 0.01. In addition, the results of the analysis of cell viability for each group are shown graphically in FIG. 4, which also shows that the cell viability for examples 1-15 is higher than that for the control group. From this, it can be seen that the treatment of the novel compounds of the present invention while the occurrence of nerve damage does increase the cell viability, representing an effective reduction in the damage and death of nerve cells to achieve the effect of protecting the nerve.
In summary, the present invention provides a novel compound and a preparation method thereof, wherein the novel compound has effects of preventing nerve damage and protecting nerves, and thus can be applied to preventing or improving diseases caused by nerve damage, and further provides another potential and effective treatment method for patients.
Claims (13)
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 unsubstituted alkylene 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 an unsubstituted alkylene group having 1 to 6 carbon atoms, an unsubstituted alkenylene group having 2 to 6 carbon atoms, an acyloxy group or an amido group;
z is hydroxy, carboxy, unsubstituted alkyl having 1 to 6 carbon atoms, benzenediol, unsubstituted ester having 1 to 6 carbon atoms, unsubstituted aryl having 6 to 18 carbon atoms in the ring, 2-methoxybenzenesulfonamide, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl; and
n1, n2 are each independently 0 or 1.
2. The compound of claim 1, wherein Y is unsubstituted ethylene, unsubstituted propylene, unsubstituted butylene, unsubstituted propylene, acyloxy, or amido.
3. The compound of claim 1 wherein Z is hydroxy, carboxy, methyl, catechol, -COOCH 2 CH 3 Unsubstituted phenyl, 2-methoxybenzenesulfonamido, 2, 3-dimethyl-1-phenyl-5-pyrazolone or 2-methyl-4-cyanothienyl.
4. The compound of claim 1, wherein L 2 Is unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene or unsubstituted phenylene.
5. The compound of claim 1, wherein the compound is represented by one of the following compounds 1 to 15:
6. a process for the preparation of a compound according to claim 1, comprising the steps of:
step (a): providing a first reactant, wherein the first reactant is a 4, 7-dimethoxy-1, 3-benzene dioxygen singultus derivative;
step (b): providing a second reactant, wherein the second reactant comprises halogenated hydrocarbon compounds, anhydride compounds, phenol compounds, aromatic alcohol compounds, ester compounds, benzenesulfonamide derivatives, ester hydrochloride derivatives, phenol hydrochloride derivatives, antipyrine derivatives or thiophene derivatives; and
Step (c): reacting the first reactant with the second reactant to obtain the compound.
7. The method of claim 6, wherein the first reactant comprises 4, 7-dimethoxy-5-methyl-6-iodo-1, 3-benzenedioxid, 4, 7-dimethoxy-5-hydroxymethyl-1, 3-benzenedioxid, 4, 7-dimethoxy-5-aminomethyl-1, 3-benzenedioxid, 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenedioxid, or 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenedioxid.
8. The method of claim 6, wherein the second reactant comprises 3, 3-dimethylallyl bromide, 1-bromobutane, acetic anhydride, 4-aminophenol, benzyl alcohol, ethyl p-aminobenzoate, 5- [ (R) - (2-aminopropyl) ] -2-methoxybenzenesulfonamide, methyl 4-aminobutyrate hydrochloride, methyl β -alanate hydrochloride, methyl propylate hydrochloride, 4- (2-aminoethyl) -1, 2-benzenediol hydrochloride, 4-aminoantipyrine, or 2-amino-3-cyano-5-methylthiophene.
9. The method of claim 6, wherein the first reactant is 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenedioxido, and step (a) further comprises the step of pre-chlorinating 4, 7-dimethoxy-5-carboxylic acid-1, 3-benzenedioxido to 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenedioxido to obtain the first reactant.
10. The method of claim 6 wherein the first reactant is 4, 7-dimethoxy-5-acyl chloride-1, 3-benzenediox, the second reactant is an ester hydrochloride derivative, and step (c) further comprises the step of reacting the first reactant with the second reactant to provide a methyl ester intermediate, and thereafter, hydrolyzing the methyl ester intermediate to provide the compound.
11. A pharmaceutical product for preventing nerve damage and protecting nerves, comprising a compound of any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
12. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the prevention of nerve damage and for the protection of nerves.
13. The use according to claim 12, wherein the prevention of nerve damage and the protection of nerves comprises the prevention and/or treatment of stroke and alzheimer's disease.
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