CN114478410B - Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof - Google Patents
Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof Download PDFInfo
- Publication number
- CN114478410B CN114478410B CN202210337251.3A CN202210337251A CN114478410B CN 114478410 B CN114478410 B CN 114478410B CN 202210337251 A CN202210337251 A CN 202210337251A CN 114478410 B CN114478410 B CN 114478410B
- Authority
- CN
- China
- Prior art keywords
- derivative
- compound
- disubstituted phenyl
- hydrazine
- triazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a disubstituted phenyl-1, 2, 4-triazole derivative and preparation and application thereof, belonging to the technical field of biological medicine, and the structural formula is shown as formula I, wherein R is 1 Is H, OH, CH 2 OH、F、Cl、Br、CF 3 、CCl 3 、NO 2 、NH 2 、C 1 ‑C 4 Alkyl radical, C 1 ‑C 4 Alkoxy radical, C 1 ‑C 4 Dialkylamino, C 1 ‑C 4 Acyl radical, C 1 ‑C 4 One of ester groups; r 2 Is H,OH、CH 2 OH、F、Cl、Br、CF 3 、CCl 3 、NO 2 、NH 2 、C 1 ‑C 4 Alkyl radical, C 1 ‑C 4 Alkoxy radical, C 1 ‑C 4 Dialkylamino radical, C 1 ‑C 4 Acyl radical, C 1 ‑C 4 One of ester groups; the disubstituted phenyl-1, 2, 4-triazole derivative has good oxidation resistance and good neuroprotective effect, is expected to become a potential candidate drug,
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a disubstituted phenyl-1, 2, 4-triazole derivative and preparation and application thereof.
Background
The neurodegenerative disease is a neuronal injury disease with degenerative change of nerve cells, and comprises cerebral apoplexy, alzheimer disease, parkinson disease, amyotrophic lateral sclerosis and the like. A large number of researches show that when a nervous system is damaged and stimulated, an oxidative stress pathway of a nerve cell is abnormal, so that the level of reactive oxygen Radicals (ROS) or reactive nitrogen radicals (NOS) in the cell is too high, further biomacromolecules such as DNA, RNA, proteins and lipids in the cell are damaged, and finally the nerve cell is killed. Among them, side effects caused by oxidative stress are important causes and pathological features leading to neurodegenerative diseases. Therefore, designing compounds with an effect against oxidative stress is an effective strategy for treating neurodegenerative diseases.
At present, a plurality of neurodegenerative diseases have no specific medicine, and the main problem existing in the field is that the animal experiment effect is good but the clinical effect is poor in the development process of a plurality of medicines. Therefore, there is an urgent need to develop a novel medicament for preventing and treating neuronal damage with good clinical effects. Researches show that the oxadiazole compound has good oxidation resistance and can play a role in protecting nerves in vivo and in vitro. Triazole is a biological electron isostere of oxadiazole, has biological activity similar to that of oxadiazole, can introduce a series of drug active groups on the ring change of triazole to enhance the antioxidation and blood brain barrier permeability of triazole, and plays a better neuroprotective activity in the development of nervous system drugs.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the disubstituted phenyl-1, 2, 4-triazole derivative and the preparation and application thereof, and the disubstituted phenyl-1, 2, 4-triazole derivative has good oxidation resistance and good neuroprotective effect.
In order to achieve the purpose, the invention adopts the technical scheme that:
a disubstituted phenyl-1, 2, 4-triazole derivative has a structural formula shown in formula I:
wherein R is 1 Is H, OH, CH 2 OH、F、Cl、Br、CF 3 、CCl 3 、NO 2 、NH 2 、C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Dialkylamino radical, C 1 -C 4 Acyl radical, C 1 -C 4 One of ester groups;
R 2 is H, OH, CH 2 OH、F、Cl、Br、CF 3 、CCl 3 、NO 2 、NH 2 、C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Dialkylamino radical, C 1 -C 4 Acyl radical, C 1 -C 4 One of ester groups;
R 3 is C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxy, C 1 -C 6 Halo, C 1 -C 6 Polyhaloalkyl, C 1 -C 6 Nitro radical, C 1 -C 6 Carboxy, C 1 -C 6 Amino group, C 1 -C 6 Hydrazine radical, C 1 -C 4 Substituted amino, C 1 -C 4 Ether radical, C 1 -C 4 Keto group, C 1 -C 4 Ester group and heteroaryl.
The inventor of the invention finds that the disubstituted phenyl-1, 2, 4-triazole derivative has good oxidation resistance and good nerve protection effect, can obviously resist oxidative stress reaction, protects nerve cells from oxidative stress damage caused by sodium nitroprusside, and improves the survival rate of the cells and the form of the nerve cells in a large number of researches.
As a preferred embodiment of the present invention, the heteroaryl group is one of a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a triazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group, a naphthyl group, a benzothiazolyl group, a benzothienyl group, a benzofuryl group, a purinyl group.
As a preferred embodiment of the present invention, said R 1 Is CF 3 ，R 2 Is H, R 3 Is CH (CH) 3 ) 2 、C(CH 3 ) 3 、CH(CH 2 ) 4 、(CH 2 ) 2 OH、CH 2 CF 3 、CH 2 COOH、CH 2 COOCH 2 CH 3 Pyridyl, pyrazinyl, naphthyl and benzothiazolyl.
Especially when R is 1 、R 2 、R 3 Compared with the existing 3, 5-disubstituted phenyl triazole, the derivative has better neuroprotective activity, and can remarkably reduce the dosage, namely, the good neuroprotective activity can be achieved under the condition of low dosage.
The invention also provides a preparation method of the disubstituted phenyl-1, 2, 4-triazole derivative, which comprises the following steps:
adding an o-hydroxybenzoic acid derivative and an o-hydroxybenzamide derivative into a solvent A, adding pyridine, adding thionyl chloride while stirring, heating and refluxing, removing the solvent and residual thionyl chloride, and recrystallizing to obtain an oxazine intermediate;
and adding the oxazine intermediate and the hydrazine derivative into a solvent B, heating and refluxing, removing part of the solvent, crystallizing, and recrystallizing to obtain the disubstituted phenyl-1, 2, 4-triazole derivative.
According to the invention, the disubstituted phenyl-1, 2, 4-triazole derivative with good oxidation resistance and good neuroprotective effect is prepared by taking the o-hydroxybenzoic acid derivative, the o-hydroxybenzamide derivative and the hydrazine derivative as raw materials, and the disubstituted phenyl-1, 2, 4-triazole derivative has a novel structure, a simple preparation method and a wide application prospect.
As a preferred embodiment of the present invention, the o-hydroxybenzoic acid derivative is 2-hydroxy-4- (trifluoromethyl) benzoic acid; the o-hydroxybenzamide derivative is 2-hydroxybenzamide.
As a preferred embodiment of the present invention, the hydrazine derivative is at least one of isopropyl hydrazine, tert-butyl hydrazine, para-fluorophenylhydrazine hydrochloride, cyclopentanedihydrazine, hydroxyethylhydrazine, trifluoroethylhydrazine, ethyl hydrazinoacetate, hydrazinoacetic acid, hydrazinopyridine, hydrazinopyrazine, hydrazinonaphthalene, hydrazinobenzothiazole.
As a preferred embodiment of the present invention, the solvent a is at least one of toluene, xylene, diphenyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide; the solvent B is at least one of ethanol, propanol, isopropanol, tert-butanol, tetrahydrofuran, dioxane, butanone, acetonitrile, ethyl acetate, chloroform, 1-dichloroethane and pyridine.
As a preferred embodiment of the present invention, the ratio of the amount of the substance of the o-hydroxybenzoic acid derivative to the amount of the substance of the o-hydroxybenzamide derivative is 1: (0.9-3); the material ratio of the o-hydroxybenzoic acid derivative to thionyl chloride is 1g: (1-5) ml; the mass ratio of the oxazine intermediate to the hydrazine derivative is 1: (0.9-3).
The invention also provides application of the disubstituted phenyl-1, 2, 4-triazole derivative or pharmaceutically acceptable salt thereof in preparing a medicament for preventing and treating neuron injury.
The invention also provides a medicament for preventing and treating neuron injury, which takes the disubstituted phenyl-1, 2, 4-triazole derivative or pharmaceutically acceptable salt thereof as a main active ingredient.
The invention has the beneficial effects that: (1) The disubstituted phenyl-1, 2, 4-triazole derivative is prepared from an o-hydroxybenzoic acid derivative, an o-hydroxybenzamide derivative and a hydrazine derivative, and has a novel structure and a simple preparation method. (2) The disubstituted phenyl-1, 2, 4-triazole derivative can obviously resist oxidative stress reaction, protect nerve cells against oxidative stress damage caused by sodium nitroprusside, and improve the survival rate of the nerve cells and the shape of the nerve cells; meanwhile, the compound can obviously reduce cerebral embolism volume in animal rat MCAO experiments, resists ischemia reperfusion injury, has good neuroprotective effect, and (3) the compound has good fat solubility and oil-water distribution coefficient, is easy to pass through a blood brain barrier, and preferably compound LD 50 >1000mg/kg, low toxicity and good market development prospect. (4) Because oxidative stress is an important pathological characteristic of diseases such as cerebral apoplexy, cerebral injury, spinal cord injury, alzheimer disease, amyotrophic lateral sclerosis and the like, the compound has excellent antioxidant stress effect and blood brain barrier penetration effect, and can be applied to the preparation of medicaments for preventing and treating neurodegenerative diseases such as cerebral apoplexy, cerebral injury, spinal cord injury, alzheimer disease, amyotrophic lateral sclerosis and the like.
Drawings
FIG. 1 is a graph showing the protective effect of di-substituted phenyltriazole derivatives described in examples 1-11 on nitroprusside-induced PC12 cell damage.
FIG. 2 is a comparison of the cell survival rates of the disubstituted phenyl-1, 2, 4-triazole derivatives of the present invention with the existing 3, 5-disubstituted phenyl-1, 2, 4-triazole derivatives and 1,3, 5-trisubstituted phenyl triazole derivatives.
FIG. 3 is a graph of the neurological scores of rats with Compound 5.
Fig. 4 is a plot of Longa scores for cerebral ischemia in rats with compound 5.
FIG. 5 is a TTC staining pattern of cerebral ischemia in rats of Compound 5.
FIG. 6 is a graph showing the effect of compound 5 on SOD and MAD content in serum of animals.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Example 1
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is shown as compound 1 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH(CH 3 ) 2 ) Shown in the specification:
synthesis of Compound 1:
(1) Synthesis of an oxazine intermediate: adding 3.09g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.92g of 2-hydroxybenzamide into a flask, adding 25mL of dimethylbenzene and 100 mu L of pyridine, adding 3mL of thionyl chloride at room temperature while stirring, heating and refluxing for 5h, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using absolute ethyl alcohol to obtain an oxazine intermediate;
(2) Synthesis of Compound 1: adding 0.9g of oxazine intermediate and 0.1g of isopropyl hydrazine into a flask, adding 10mL of absolute ethyl alcohol, heating and refluxing for reaction for 9 hours, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using ethyl alcohol to obtain the compound 1.
Structure confirmation data for compound 1: a white solid, which is a solid, 1 H NMR(400MHz，DMSO-d6)δ11.51(s，1H)，10.39(s，1H)，8.20(d，J＝8.3Hz，1H)，7.49–7.41(m，2H)，7.36–7.29(m，2H)，7.07(d，J＝8.4Hz，1H)，7.01(t，J＝7.5Hz，1H)，4.48(p，J＝6.5Hz，1H)，1.47(s，3H)，1.45(s，3H)。
example 2
A disubstituted phenyl-1, 2, 4-triazole derivative with structural formula shown in compound 2 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝C(CH 3 ) 3 ) Shown in the specification:
synthesis of Compound 2:
(1) Synthesis of an oxazine intermediate: adding 2.0g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.3g of 2-hydroxybenzamide into a flask, adding 25mL of DMF and 150 mu L of pyridine, adding 2.5mL of thionyl chloride at room temperature while stirring, heating and refluxing for 7h, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using absolute ethyl alcohol to obtain an oxazine intermediate;
(2) Synthesis of Compound 2: adding 1.0g of oxazine intermediate and 0.1g of tert-butylhydrazine into a flask, adding 10mL of absolute ethyl alcohol, heating and refluxing for 7h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing with methanol to obtain a compound 2.
Structure confirmation data for compound 2: a white solid, which is a solid, 1 H NMR(400MHz，Chloroform-d)δ8.12(d，J＝8.2Hz，1H)，7.36–7.28(m，3H)，7.17(d，J＝8.2Hz，1H)，7.02(t，J＝7.5Hz，1H)，6.89(d，J＝8.1Hz，1H)，1.61(s，9H)。
example 3
A disubstituted phenyl-1, 2, 4-triazole derivative with a structural formula shown as a compound 3 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH(CH 2 ) 4 ) Shown in the figure:
synthesis of Compound 3:
(1) Synthesis of an oxazine intermediate: adding 1.9g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.2g of 2-hydroxybenzamide into a flask, adding 25mL of DMSO and 160 mu L of pyridine, adding 1.8mL of thionyl chloride at room temperature while stirring, heating and refluxing for 5h, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction solution to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using acetonitrile to obtain an oxazine intermediate;
(2) Synthesis of Compound 3: adding 1.0g of oxazine intermediate and 0.1g of p-fluorophenylhydrazine hydrochloride into a flask, adding 10mL of acetonitrile, heating and refluxing for 8h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction solution to room temperature after the reaction is finished, and recrystallizing by using acetonitrile to obtain a compound 3.
Structure confirmation data for compound 3: a white solid, which is a solid, 1 H NMR(400MHz，Chloroform-d)δ10.28(s，2H)，8.21(d，J＝8.1Hz，1H)，7.59(d，J＝7.9Hz，1H)，7.48(t，J＝7.8Hz，1H)，7.34(s，1H)，7.28(d，J＝4.4Hz，1H)，7.21(d，J＝8.3Hz，1H)，7.07(t，J＝7.6Hz，1H)，5.16(p，J＝6.9Hz，1H)，2.32–2.24(m，4H)，2.15–2.07(m，2H)，1.89–1.80(m，2H)。
example 4
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is a compound 4 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH 2 CH 2 OH) is shown in the specification:
synthesis of Compound 4:
(1) Synthesis of an oxazine intermediate: adding 2.2g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.6g of 2-hydroxybenzamide into a flask, adding 25mL of diphenyl ether and 150 mu L of pyridine, adding 2.2mL of thionyl chloride at room temperature while stirring, heating and refluxing for 4h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using ethyl acetate to obtain an oxazine intermediate;
(2) Synthesis of Compound 4: 1.0g of oxazine intermediate and 0.2g of hydroxyethylhydrazine were added to the flask, 10mL of ethyl acetate was added, and the reaction was heated under reflux for 8h and monitored by thin layer chromatography. After the reaction is finished, the reaction solution is naturally cooled to room temperature and recrystallized by ethyl acetate to obtain a compound 4.
Structure confirmation data for compound 4: a white solid, which is a solid, 1 H NMR(500MHz，DMSO-d6)δ11.52(s，1H)，10.37(s，1H)，8.19(d，J＝8.3Hz，1H)，7.49(d，J＝8.0Hz，1H)，7.44(t，J＝8.6Hz，1H)，7.35–7.29(m，2H)，7.07(d，J＝8.3Hz，1H)，7.01(d，J＝7.5Hz，1H)，4.89(s，1H)，4.22(t，J＝5.7Hz，2H)，3.79(t，J＝5.7Hz，2H)。
example 5
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is a compound 5 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH 2 CF 3 ) Shown in the figure:
synthesis of Compound 5:
(1) And (3) synthesis of an oxazine intermediate: 2.1g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.7g of 2-hydroxybenzamide were placed in a flask, 25mL of xylene and 100. Mu.L of pyridine were added, 2mL of thionyl chloride was added under stirring at room temperature, and the mixture was refluxed for 6 hours, and the reaction was monitored by thin layer chromatography. After the reaction is finished, naturally cooling the reaction liquid to room temperature, separating out solids, filtering, taking a filter cake, and recrystallizing with tert-butyl alcohol to obtain an oxazine intermediate;
(2) Synthesis of Compound 5: adding 1.0g of oxazine intermediate and 0.1g of trifluoroethylhydrazine into a flask, adding 10mL of tert-butyl alcohol, heating and refluxing for 10h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using tert-butyl alcohol to obtain a compound 5.
Structure of Compound 5And (3) confirming data: a white solid, which is a solid, 1 H NMR(500MHz，Chloroform-d)δ9.80(s，2H)，8.19(d，J＝8.1Hz，1H)，7.54(d，J＝7.7Hz，1H)，7.50(t，J＝7.7Hz，1H)，7.33(s，1H)，7.24(d，J＝6.9Hz，1H)，7.17(d，J＝8.0Hz，1H)，7.08(t，J＝7.5Hz，1H)，5.01(q，J＝7.7Hz，2H)。
example 6
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is shown as compound 6 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH 2 COOH) is shown:
synthesis of Compound 6:
(1) And (3) synthesis of an oxazine intermediate: adding 2.0g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.5g of 2-hydroxybenzamide into a flask, adding 25mL of DMF and 300 mu L of pyridine, stirring at room temperature while adding 2.4mL of thionyl chloride, heating and refluxing for 8 hours, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using isopropanol to obtain an oxazine intermediate;
(2) Synthesis of Compound 6: adding 1.0g of oxazine intermediate and 0.2g of hydrazino acetic acid into a flask, adding 10mL of isopropanol, heating and refluxing for 10h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction solution to room temperature after the reaction is finished, and recrystallizing with acetone to obtain the compound 6.
Structural confirmation data for compound 6: a white solid, a solid which is, 1 H NMR(500MHz，DMSO-d6)δ13.24(s，1H)，11.34(s，1H)，10.62(s，1H)，8.18(d，J＝8.0Hz，1H)，7.47(d，J＝7.2Hz，1H)，7.44(d，J＝7.3Hz，1H)，7.37–7.28(m，2H)，7.08(d，J＝8.2Hz，1H)，7.01(t，J＝7.5Hz，1H)，5.13(s，2H)。
example 7
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is shown as a compound 7 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 ＝CH 2 COOCH 2 CH 3 ) Shown in the figure:
synthesis of compound 7:
(1) Synthesis of an oxazine intermediate: adding 1.9g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.4g of 2-hydroxybenzamide into a flask, adding 25mL of N-methylpyrrolidone and 150 mu L of pyridine, adding 1.9mL of thionyl chloride while stirring at room temperature, heating and refluxing for 6 hours, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using pyridine to obtain an oxazine intermediate.
(2) Synthesis of compound 7: adding 1.0g of oxazine intermediate and 0.15g of hydrazino ethyl acetate into a flask, adding 10mL of pyridine, heating and refluxing for 8 hours, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using ethyl acetate to obtain a compound 7.
Structural confirmation data for compound 7: a white solid, which is a solid, 1 H NMR(500MHz，DMSO-d6)δ11.29(s，1H)，10.61(s，1H)，8.17(d，J＝8.2Hz，1H)，7.51–7.43(m，2H)，7.37–7.31(m，2H)，7.07(d，J＝8.2Hz，1H)，7.01(t，J＝7.5Hz，1H)，5.21(s，2H)，4.10(q，J＝7.1Hz，2H)，1.13(t，J＝7.1Hz，3H)。
example 8
A disubstituted phenyl-1, 2, 4-triazole derivative with a structural formula shown as a compound 8 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 = pyridyl) shown:
synthesis of compound 8:
(1) And (3) synthesis of an oxazine intermediate: adding 2.0g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.9g of 2-hydroxybenzamide into a flask, adding 25mL of DMF and 200 mu L of pyridine, adding 2.3mL of thionyl chloride at room temperature while stirring, heating and refluxing for 5 hours, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction solution to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using isopropanol to obtain an oxazine intermediate;
(2) Synthesis of compound 8: adding 1.0g of oxazine intermediate and 0.3g of 2-hydrazinopyridine into a flask, adding 10mL of isopropanol, heating and refluxing for 10 hours, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using methanol to obtain a compound 8.
Structure confirmation data for compound 8: a white solid, a solid which is, 1 H NMR(500MHz，Chloroform-d)δ10.79(s，1H)，10.08(s，1H)，8.62(dd，J＝4.9，1.8Hz，1H)，8.25(d，J＝8.1Hz，1H)，8.03(td，J＝7.8，1.8Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.55(dd，J＝7.5，4.8Hz，1H)，7.38(td，J＝7.8，1.5Hz，1H)，7.34(d，J＝1.6Hz，1H)，7.29–7.25(m，1H)，7.14(d，J＝8.1Hz，1H)，6.98(dd，J＝8.0，1.6Hz，1H)，6.75(t，J＝7.5Hz，1H)。
example 9
A disubstituted phenyl-1, 2, 4-triazole derivative with a structural formula shown as a compound 9 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 = pyrazinyl) is represented by:
synthesis of compound 9:
(1) Synthesis of an oxazine intermediate: adding 2.1g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.7g of 2-hydroxybenzamide into a flask, adding 20mL of dimethylbenzene and 180 mu L of pyridine, adding 2.5mL of thionyl chloride at room temperature while stirring, heating and refluxing for 7h, monitoring the reaction by using a thin layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out a solid, filtering, taking a filter cake, and recrystallizing by using tetrahydrofuran to obtain an oxazine intermediate;
(2) Synthesis of compound 9: adding 1.0g of oxazine intermediate and 0.4g of 2-hydrazinopyrazine into a flask, adding 10mL of tetrahydrofuran, heating and refluxing for 6h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction solution to room temperature after the reaction is finished, and recrystallizing with tetrahydrofuran to obtain the compound 9.
Structure confirmation data for compound 9: a white solid, which is a solid, 1 H NMR(500MHz，Chloroform-d)δ10.05(s，2H)，9.03(s，1H)，8.82(d，J＝2.3Hz，1H)，8.59(s，1H)，8.25(d，J＝8.1Hz，1H)，7.40(t，J＝8.0Hz，1H)，7.35(s，1H)，7.28(d，J＝8.2Hz，1H)，7.13(d，J＝8.3Hz，1H)，6.99(d，J＝8.1Hz，1H)，6.78(t，J＝7.6Hz，1H)。
example 10
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is a compound 10 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 = naphthyl) is represented by:
synthesis of compound 10:
(1) Synthesis of an oxazine intermediate: adding 2.1g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.7g of 2-hydroxybenzamide into a flask, adding 25mL of DMSO and 240 mu L of pyridine, adding 3mL of thionyl chloride at room temperature while stirring, heating and refluxing for 6h, monitoring the reaction by using a thin layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using isopropanol to obtain an oxazine intermediate;
(2) Synthesis of compound 10: adding 1.0g of oxazine intermediate and 0.5g of 2-hydrazinonaphthalene into a flask, adding 10mL of isopropanol, heating and refluxing for reaction for 11h, monitoring the reaction by using thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using propanol to obtain the compound 10.
Structural confirmation data for compound 10: a white solid, which is a solid, 1 H NMR(500MHz，Chloroform-d)δ11.40(s，1H)，9.95(s，1H)，8.25(d，J＝8.2Hz，1H)，8.04(d，J＝8.4Hz，2H)，7.99(d，J＝8.0Hz，1H)，7.92(d，J＝7.9Hz，1H)，7.70–7.60(m，2H)，7.52(dd，J＝8.6，2.1Hz，1H)，7.36–7.24(m，3H)，7.14(d，J＝8.3Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.56(t，J＝7.7Hz，1H)。
example 11
A disubstituted phenyl-1, 2, 4-triazole derivative, the structural formula of which is a compound 11 (R) 1 ＝CF 3 ，R 2 ＝H，R 3 = benzothiazolyl):
synthesis of compound 11:
(1) Synthesis of an oxazine intermediate: adding 2.1g of 2-hydroxy-4- (trifluoromethyl) benzoic acid and 1.8g of 2-hydroxybenzamide into a flask, adding 20mL of dimethylbenzene and 170 mu L of pyridine, adding 2.3mL of thionyl chloride at room temperature while stirring, heating and refluxing for 9h, monitoring the reaction by using a thin-layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, separating out solids, filtering, taking a filter cake, and recrystallizing by using dioxane to obtain an oxazine intermediate;
(2) Synthesis of compound 11: adding 1.0g of oxazine intermediate and 0.8g of 2-hydrazinobenzothiazole into a flask, adding 10mL of dioxane, heating and refluxing for reaction for 8h, monitoring the reaction by using thin layer chromatography, naturally cooling the reaction liquid to room temperature after the reaction is finished, and recrystallizing by using dioxane to obtain the compound 11.
Structure confirmation data for compound 11: a white solid, a solid which is, 1 H NMR(500MHz，Chloroform-d)δ11.40(s，1H)，9.95(s，1H)，8.25(d，J＝8.2Hz，1H)，8.04(d，J＝8.4Hz，2H)，7.99(d，J＝8.0Hz，1H)，7.92(d，J＝7.9Hz，1H)，7.70–7.60(m，2H)，7.52(dd，J＝8.6，2.1Hz，1H)，7.36–7.24(m，3H)，7.14(d，J＝8.3Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.56(t，J＝7.7Hz，1H)。
to further demonstrate the effect of the present invention, the following test methods were provided:
1. study of protective effects of compounds 1-11 on sodium nitroprusside-induced PC12 cell damage:
1.1 establishment of a model for inducing PC12 cell damage by nitroprusside (SNP): placing rat adrenal pheochromocytoma cells (PC 12 cells) in DMEM medium containing 5% fetal calf serum and 5% horse serum, and 5% CO at 37 deg.C 2 Culturing in the environment of (1), after the cells grow in an adherent manner for a period of time, digesting with trypsin, adding a culture medium to dilute, calculating the number of the cells by using a cell counting plate, then inoculating PC12 cells into a 96-well plate at the density of 5000 cells/well, adding the culture medium to culture for 24h, discarding the old culture medium, adding a new culture medium into a control group to continue culturing, adding culture media containing different SNP concentrations (200, 300, 400, 500 and 600 mu M) into an experimental group to culture, measuring the cell survival rate by using an MTT method after 12h, and determining the cell survival rate = OD Each concentration of /OD control *100%, repeating the experimental results for more than three times, and taking the average value as the final cell survival rate.
1.2 study of the protective Effect of Compounds 1-11: dissolving the positive drug edaravone and the compounds 1-11 in DMSO respectively to prepare 10mM stock solution, diluting the edaravone to 100, 50 and 25 μ M with culture medium, diluting the test concentration of the drug (compounds 1-11) to 10, 5 and 1 μ M with culture medium, inoculating PC12 cells into 96-well plate at 5000 cells/well density, adding culture medium, and making into 5% CO at 37 deg.C 2 Culturing for 24h under the environment of (1), removing the old culture medium, adding a blank culture medium into a control group and a model group, adding a medicament-containing culture medium into an experimental group for pre-incubation for 24h, then adding 400 mu M SNP for action for 24h, and determining the cell survival rate by using an MTT method.
As a result, as shown in fig. 1, the compound started to exhibit a protective effect on PC12 cells and increased the cell survival rate at an administration concentration of 1 μ M, and the compound exhibited a significant protective effect on PC12 cells at an administration concentration of 5 μ M. Wherein, the compounds 1, 5, 8, 10 and 11 can improve the cell survival rate from 60 percent to more than 90 percent. In contrast, the cell survival rate of the edaravone positive control group is only about 70%; at a concentration of 10 μ M, compounds 1, 5, 8, 10, 11 were able to increase cell viability to above 100%. Therefore, the compound has better protection effect. Among compounds 1-11, compound 5 showed the best protective effect, and was able to increase cell survival to 114% at 10 μ M; in general, compounds 1-11 can protect PC12 cells from damage caused by SNP to a certain extent, so that the cell survival rate is increased, and the cell protection effect is more obvious with the increase of the compound concentration, the drug effect is better than that of edaravone, and the drug effect of compound 5 is best.
In addition, the cell survival rate of the compounds 1, 5, 8, 10 and 11 can be improved to 90% at 5 mu M, the cell survival rate of the compounds 1, 5, 8, 10 and 11 at 10 mu M can be improved to more than 100%, while the cell survival rate of the existing 3, 5-disubstituted phenyl-1, 2, 4-triazole derivatives can only be improved to 65-75% in a nerve injury model induced by nitroprusside at 10 mu M, and the cell survival rate of part of the compounds can only be improved to about 80% in the existing 1,3, 5-trisubstituted phenyl triazole derivatives. Therefore, the disubstituted phenyl-1, 2, 4-triazole derivative provided by the invention has better neuroprotective activity (fig. 2 is a comparison of the cell survival rate of the disubstituted phenyl-1, 2, 4-triazole derivative provided by the invention with that of the existing 3, 5-disubstituted phenyl-1, 2, 4-triazole derivative and 1,3, 5-trisubstituted phenyl triazole derivative provided by the invention).
2. Effect of compound 5 against neuronal damage:
2.1 preparation of Compound 5 injections
2.1.1 castor oil injection
The formula is as follows: compound 5 (principal drug) 500mg; 20mL of polyoxyethylene castor oil polymer (cosolvent); 80mL of water for injection;
the preparation process comprises the following steps: adding 80mL of water for injection and 20mL of castor oil into a preparation container, uniformly mixing, adding 500mg of compound, heating in a water bath to 50 ℃, stirring to completely dissolve, filtering to be clear, and encapsulating.
2.1.2 Cyclodextrin injection
The formula is as follows: 500mg of compound 5 (main drug); 25mL of hydroxypropyl cyclodextrin (cosolvent); 75mL of water for injection;
the preparation process comprises the following steps: adding 75mL of water for injection and 25mL of castor oil into a preparation container, uniformly mixing, adding 500mg of compound, heating in a water bath to 50 ℃, stirring to completely dissolve, filtering to be clear, and encapsulating.
2.2 study of protective Effect of Compound 5 on ischemia-reperfusion nerve injury
2.2.1 grouping: rats were randomly divided into 6 groups, each of which was a control group (Sham) and the same procedure was performed without ischemia reperfusion; model group (Model), performing an ischemic reperfusion injury in brain; administration group: low dose (compound 5,3mg/kg), medium dose (compound 5,6mg/kg), high dose ( compound 5, 12 mg/kg), positive control (Edaravone, 5 mg/kg), vehicle 20% polyoxyethylene castor oil polymer in water; except for the sham group 10 animals, 12 were added to each group.
2.2.2 Experimental procedure: after anesthetizing the rats, the left common carotid artery, external carotid artery, and internal carotid artery were isolated by incision at the center of their necks. Tying a wire at the proximal end of an internal carotid artery, placing a hemostatic clamp at the distal end, cutting a small opening, inserting a nylon wire, slowly pushing the wire into the internal carotid artery to reach the anterior cerebral artery, blocking intracranial blood flow, and performing ischemic injury. Sterilizing the neck incision, suturing the incision, slightly pulling out the plug wire after 1.5h to recover blood supply in brain, and performing ischemia reperfusion. Intraperitoneal injections were given 1h before ischemia and 4h after reperfusion, and mice were scored neurologically 24h after surgery by the Zea Longa method (Longa E Z, weinstein P R, carlson S, et al. Reversible middle nuclear involvement with without criticism in rats [ J ]. Stroke; a J ournal of nuclear circulation,1989, 20).
2.2.3 results of the experiment
2.2.3.1 neurological scores: in the Zea longa neurological scoring method, a higher score indicates more severe neurological damage, and the neurological score of the model group is increased by 2.06 ± 0.32, indicating that the neurological function of the rat is decreased after the ischemia reperfusion injury. Neurological scoring experiments showed a corresponding decrease in neurological scores following administration of low, medium and high doses of compound 5, indicating that compound 5 can help improve the behavior of animals with cerebral ischemic injury. Compared with a sham operation group, the neurological score of animals in each group is remarkably improved (P is less than 0.0001) in the model group, and is relieved in comparison with a model control group, wherein the statistics of the high-dose group of the compound 5 are remarkably different (P is less than 0.05), so that the compound 5 has a certain protection effect on ischemia-reperfusion injury of the brain, and is suitable for preventing and treating neuron injury diseases.
2.2.3.2ttc staining: TTC staining can stain the ischemic area of the animal brain section white and the normal area red, and the results are shown in figure 3, compared with the sham operation group, the cerebral ischemic area of the model group is obviously increased to 24.59 +/-6.75%, which indicates that the brain injury is serious after the ischemic reperfusion, compared with the model group, the cerebral ischemic area of the administration group is obviously reduced, the ischemic area is reduced to 18.44 +/-6.77% when 3mg is administered, the ischemic area is reduced to 16.68 +/-4.80% when 6mg is administered, the ischemic area is reduced to 14.03 +/-6.61% when 12mg is administered, and the effect is equivalent to that of the positive drug edaravone (15.74 +/-5.04%). Compared with the sham operation group, the brain tissue of the model control group animals has obvious infarction (p is less than 0.0001); compared with a model control group, the medium and high dose groups of the test drug compound 5 and the positive control group can both significantly reduce the cerebral infarction area of model-building rats (p <0.01 or p < 0.001or p < -0.01), and the results are shown in fig. 4 and fig. 5.
2.2.3.3 Effect of Compound 5 on Oxidation related Biochemical indicators in serum
In the cerebral artery occlusion model experiment (MCAO), the abdominal cavity vein of an experimental animal is subjected to blood sampling, serum is separated, and serum indexes, namely the levels of superoxide dismutase (SOD) and Malondialdehyde (MDA), are detected by using a kit.
As shown in FIG. 6, the SOD level was decreased in the model group (1.14. + -. 0.17U/mL) as compared with that in the sham-operated group, indicating that the oxidative stress level in the animals was increased. In the administration group, the SOD level of the serum of the tested animals is increased, wherein the low dose group is 1.66 +/-0.30U/mL, the medium dose group is 1.77 +/-0.26U/mL, the high dose group is 1.92 +/-0.30U/mL, and the drug effects of the medium dose group and the high dose group are similar to that of edaravone (1.83 +/-0.27U/mL). On the other hand, the model group showed significantly higher MDA levels (30.14. + -. 6.62. Mu.M) than the sham group, and the low dose group was able to reduce the MDA levels to 22.07. + -. 4.88. Mu.M, the medium dose group to 22.26. + -. 5.14. Mu.M, and the high dose group to 20.93. + -. 4.98. Mu.M after drug administration. Therefore, the MDA level of the serum of the tested animal can be obviously reduced by the administration of the compound 5, which shows that the compound 5 can play a good antioxidation role in the animal body.
3. Lipophilicity calculation of Compounds 1-11
The structural formulae of compounds 1-11 were introduced into SwissaDME, and the lipophilicity of the compounds was calculated as the oil-water partition coefficient Log P (Daina A, michelin O, zoete V. SwissaDME: A free web tool to organic solvents, drug-lipid and media chemistry free of small molecules [ J ]. Scientific reports.2017, 42717), and compared with 3, 5-diaryl substituted oxadiazoles, as shown in Table 1.
Compounds with good blood brain barrier permeability generally have the following chemical properties: the molecular weight is less than 450, and Log P is between 2 and 5; polar surface area of molecules less than
The number of hydrogen bond donors is less than 3, the number of rotatable bonds is less than 8, the blood-brain barrier permeability of the compound is scored through software calculation, the compound usually has good blood-brain barrier permeability when the fraction is between 2 and 6, the lipophilicity of the compound is in positive correlation with the oil-water distribution coefficient Log P, the compound 1 to 11 has a larger plane aromatic ring structure and good lipophilicity, the Log P is between 2 and 5, other characteristics are integrated, the blood-brain barrier permeability is scored between 2 and 3, the chemical structure characteristics of the compound are shown to basically meet the requirement of blood brain barrier permeability, the compound structure is preliminarily judged to possibly have certain blood brain barrier crossing effect and be related to the neuroprotection effect, wherein the Log P of the compound 5 is preferably 4.26, the compound has good fat solubility, the molecular polar surface area is 68.43, the number of hydrogen bond donors is 2, the number of rotatable bonds is 5, the blood brain barrier permeability is graded to be 3.02, and the ADME parameter thereof prompts the compound to be used for treating the acute and chronic nephritisThe compounds are useful for crossing cell membranes and the blood brain barrier.
TABLE 1 calculation of ADME parameters for Compounds 1-11
4. Acute toxicity test of Compound 5
Limit test in which the test is designed according to the technical guidance principle of acute toxicity test of chemical drugs. The administration mode of each test sample was intraperitoneal injection, and administration was 1 time. The maximum concentration of each test substance was 10mg/mL, and the maximum administration volume was set to 100mL/kg, i.e., the maximum administration concentration was 1000mg/kg. The results of the limit test are shown in table 2.
TABLE 2 Limit test results for Compound 5
Note: o stands for survival and X stands for death.
As a result: determine its LD 50 >1000mg/kg. Compound 5 has lower toxicity.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. A disubstituted phenyl-1, 2, 4-triazole derivative is characterized in that the structural formula is shown as formula I:
wherein R is 1 Is CF 3 ；
R 2 Is H;
R 3 is CH (CH) 3 ) 2 、C(CH 3 ) 3 、CH(CH 2 ) 4 、(CH 2 ) 2 OH、CH 2 CF 3 、CH 2 COOH、CH 2 COOCH 2 CH 3 Pyridyl, pyrazinyl, naphthyl and benzothiazolyl.
2. The method for preparing di-substituted phenyl-1, 2, 4-triazole derivatives according to claim 1, comprising the steps of:
adding an o-hydroxybenzoic acid derivative and an o-hydroxybenzamide derivative into a solvent A, adding pyridine, adding thionyl chloride while stirring, heating and refluxing, removing the solvent and residual thionyl chloride, and recrystallizing to obtain an oxazine intermediate;
adding the oxazine intermediate and hydrazine derivatives into a solvent B, heating and refluxing, removing part of the solvent, crystallizing, and recrystallizing to obtain disubstituted phenyl-1, 2, 4-triazole derivatives;
the o-hydroxybenzoic acid derivative is 2-hydroxy-4- (trifluoromethyl) benzoic acid, and the o-hydroxybenzamide derivative is 2-hydroxybenzamide;
the hydrazine derivative is at least one of isopropyl hydrazine, tert-butyl hydrazine, cyclopentane hydrazine, hydroxyethyl hydrazine, trifluoroethyl hydrazine, ethyl hydrazino acetate, hydrazino acetic acid, hydrazino pyridine, hydrazino pyrazine, hydrazino naphthalene and hydrazino benzothiazole.
3. The method for preparing the disubstituted phenyl-1, 2, 4-triazole derivative according to claim 2, wherein the solvent a is at least one of toluene, xylene, diphenyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide; the solvent B is at least one of ethanol, propanol, isopropanol, tert-butanol, tetrahydrofuran, dioxane, butanone, acetonitrile, ethyl acetate, chloroform, 1-dichloroethane and pyridine.
4. The method for preparing disubstituted phenyl-1, 2, 4-triazole derivatives according to claim 2, wherein the ratio of the amount of the o-hydroxybenzoic acid derivative to the o-hydroxybenzamide derivative is 1: (0.9-3), wherein the material ratio of the o-hydroxybenzoic acid derivative to the thionyl chloride is 1g: (1-5) ml, wherein the mass ratio of the oxazine intermediate to the hydrazine derivative is 1: (0.9-3).
5. The use of the di-substituted phenyl-1, 2, 4-triazole derivative of claim 1or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and treatment of neuronal damage.
6. A medicament for preventing and treating neuronal injury, characterized in that the disubstituted phenyl-1, 2, 4-triazole derivative of claim 1or pharmaceutically acceptable salts thereof is used as a main active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210337251.3A CN114478410B (en) | 2022-03-31 | 2022-03-31 | Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210337251.3A CN114478410B (en) | 2022-03-31 | 2022-03-31 | Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114478410A CN114478410A (en) | 2022-05-13 |
| CN114478410B true CN114478410B (en) | 2022-11-29 |
Family
ID=81488633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210337251.3A Active CN114478410B (en) | 2022-03-31 | 2022-03-31 | Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114478410B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223579A (en) * | 1996-06-25 | 1999-07-21 | 诺瓦提斯公司 | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| WO2015079244A1 (en) * | 2013-11-28 | 2015-06-04 | The University Of Birmingham | Iron complexing agent and uses thereof in the treatment and prevention of colorectal cancer |
| CN111406217A (en) * | 2017-11-28 | 2020-07-10 | 德国西门子医学诊断产品有限公司 | Prothrombin time reagent comprising an iron chelator |
| FR3097862A1 (en) * | 2019-06-28 | 2021-01-01 | Sorbonne Universite | NEW METALLIC OR HETEROMETALLIC COMPLEXES WITH ANTI-CANCER PROPERTIES |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003053986A1 (en) * | 2001-12-21 | 2003-07-03 | Ciba Specialty Chemicals Holding Inc. | Use of metal complex compounds as oxidation catalysts |
-
2022
- 2022-03-31 CN CN202210337251.3A patent/CN114478410B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223579A (en) * | 1996-06-25 | 1999-07-21 | 诺瓦提斯公司 | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| WO2015079244A1 (en) * | 2013-11-28 | 2015-06-04 | The University Of Birmingham | Iron complexing agent and uses thereof in the treatment and prevention of colorectal cancer |
| CN111406217A (en) * | 2017-11-28 | 2020-07-10 | 德国西门子医学诊断产品有限公司 | Prothrombin time reagent comprising an iron chelator |
| FR3097862A1 (en) * | 2019-06-28 | 2021-01-01 | Sorbonne Universite | NEW METALLIC OR HETEROMETALLIC COMPLEXES WITH ANTI-CANCER PROPERTIES |
Non-Patent Citations (3)
| Title |
|---|
| A Bis-Chelating ONO/NN Ligand for the Synthesis of Heterobimetallic Platinum(II)/Rhenium(I) Complexes: Tools for the Optimization of a New Class of Platinum(II) Anticancer Agents;Benoit Bertrand等;《Chemistry—A European Journal》;20200630;第26卷;scheme 1 * |
| CAS RN 1348889-61-1;GVK BIO;《Registry》;20111205 * |
| Tridentate Complexes of Palladium(II) and Platinum(II) Bearing bis-Aryloxide Triazole Ligands: A Joint Experimental and Theoretical Investigation;Georges Dahm等;《Chemistry—An Asian Journal》;20150803;第10卷;scheme 2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114478410A (en) | 2022-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103702561B (en) | Opioid receptor ligands and methods of using and making same | |
| CN105358151A (en) | Compounds for treating spinal muscular atrophy | |
| EP3321259A1 (en) | New pyrazine derivative, and preparation method and medical application thereof | |
| CN103957710B (en) | Be used for the treatment of catarrhal compound | |
| CN101268084A (en) | Caspase inhibitor prodrugs | |
| JP2017538676A (en) | Small molecule inhibitors of mitochondrial permeability transition pore (mtPTP) | |
| KR20210097100A (en) | 2-(1-acyloxy-n-pentyl)benzoic acid and a salt formed by a basic amino acid or aminoguanidine, preparation method and use thereof | |
| KR20140129030A (en) | Compounds and methods for treating candidiasis and aspergillus infections | |
| CN113234089B (en) | Limonin compound, preparation method and application thereof as medicine for treating echinococcosis | |
| CN108440518B (en) | 3- (2-aminothiazole) -7-substituted piperazine quinolone compound and preparation method and application thereof | |
| CN114478410B (en) | Disubstituted phenyl-1, 2, 4-triazole derivative, and preparation and application thereof | |
| BR112021009921A2 (en) | pharmaceutical composition comprising histone deacetylase 6 inhibitors | |
| CN109476627B (en) | Phenolic compounds and combinations thereof with benzodiazepines fused to 1, 4-dihydropyridines for the treatment of pathologies of the central nervous system and of the vascular system | |
| CN115991698B (en) | Heterocyclic compound and preparation method and application thereof | |
| CN106928311B (en) | Limonin derivative, preparation method and medical usage | |
| CN104684894A (en) | Pyrrolidines | |
| CN114276305B (en) | Trisubstituted phenyl-1, 2, 4-triazole derivative, preparation method thereof and application thereof in treatment of neuronal injury | |
| CN109563074A (en) | Bridged piperazine derivatives | |
| CN105377264A (en) | Steroidal nitrones for treatment and prevention of cerebral stroke or ischaemia, alzheimer and parkinson disease and amyotrophic lateral sclerosis | |
| CN107011312A (en) | Jungermanniaceae D nitrogen containing derivative and preparation method thereof and the purposes in treatment tumor disease | |
| JPH04368359A (en) | Analgesic and vasodilator containing capsaicin derivative or its acid ester as effective component | |
| CN107056687B (en) | Pyridine group-containing 1, 4-pentadiene-3-ketoxime ester compound, preparation method and application | |
| JP4711961B2 (en) | 2-Methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate | |
| CN101658522A (en) | Application of tacrine short-chain dimer in preparation of medicament for treating neurodegenerative diseases | |
| CN109796405A (en) | Amber octahydro Aminacrine polymorphic and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |