A pyrazole carboxylic acid bornyl ester compound and its preparation method and application

Abstract

The present invention belongs to the technical field of drug synthesis, and particularly relates to a pyrazole carboxylic acid borneol ester compound and a preparation method and application thereof. The present invention provides a series of pyrazole carboxylic acid borneol ester compounds with novel structures, namely, compounds represented by formula (I) or pharmaceutically acceptable salts thereof. Such compounds can exert excellent neuroprotective effects in multiple ways such as scavenging free radicals and protecting neuronal cells from damage, and play an important role in the preparation of prevention or treatment of stroke, cardiovascular and cerebrovascular diseases and neurodegenerative diseases caused by excessive free radicals.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a pyrazolecarboxylic acid borneol ester compound and a preparation method and application thereof. Background Art

[0002] Cerebral ischemia reduces the ability of the antioxidant system to scavenge reactive oxygen species. When ischemic stroke occurs, the blood supply to brain tissues and cells is insufficient, leading to mitochondrial dysfunction, ATP depletion, excitotoxicity, oxidative stress, and inflammation. On the other hand, the blood-brain barrier is a unique structure within the neurovascular unit, including endothelial cells, pericytes, astrocytes, microglia, and neurons. It plays a key role in protecting neurons from neurotoxic substances. However, this protective barrier also severely hinders the delivery of therapeutic drugs to brain areas affected by ischemia, which is a major obstacle to the treatment of ischemic stroke. M1-microglia and M2-microglia are the two main phenotypes of activated microglia, which play an important role in brain injury. M2-microglia can polarize into M1-microglia shortly after ischemic stroke occurs, and a high M1 / M2 ratio is closely related to ischemic injury, because M1-microglia can secrete various proinflammatory factors, excitotoxic amino acids, matrix metalloproteinases, and chemokines, triggering inflammatory responses in the brain and destroying the tight junctions of the blood-brain barrier. Subsequently, a large number of peripheral immune cells such as neutrophils and macrophages will be recruited through the secretion of proinflammatory factors, infiltrate into the brain through the leaky blood-brain barrier, release more inflammatory factors, aggravate brain damage, further damage the brain barrier, and ultimately produce ischemia-reperfusion injury.

[0003] Free radical scavengers play a vital role in the human body's defense against free radicals and thus improve cerebral ischemic damage. The current representative drug is Edaravone, which is a brain protective agent. It is mainly used clinically to treat ischemic stroke. It mainly shows a strong antioxidant effect by eliminating hydroxyl free radicals and inhibiting lipid peroxidation, preventing cell membrane oxidative damage, and inhibiting brain edema and cerebral infarction after cerebral ischemia. In addition to its anti-stroke effect, Edaravone has also been shown to prevent oxidative damage to various extracerebral organs. However, the neuroprotective effect of Edaravone is achieved by scavenging free radicals, and the neuroprotective effect has limitations. At present, there is a lack of small molecule alternative drugs that can exert neuroprotective effects in multiple ways and have better efficacy. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a pyrazole carboxylic acid borneol ester compound and its preparation method and application. The compound can play an excellent neuroprotective role in multiple ways such as scavenging free radicals and protecting neuronal cells from damage, and is expected to be developed as an alternative drug to edaravone.

[0005] The first aspect of the present invention provides a pyrazole carboxylic acid borneol ester compound, which is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Wherein, R is a substituted or unsubstituted six-membered aromatic ring or six-membered aromatic heterocycle, and the substitution refers to substitution by 1 to 3 substituents selected from halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0008] In some embodiments, the six-membered aromatic heterocyclic ring contains 1 to 3 heteroatoms, and the heteroatom is nitrogen.

[0009] In some embodiments, the halogen is a fluorine atom or a chlorine atom.

[0010] In some embodiments, the compound represented by formula (I) is selected from any one of the following:

[0011]

[0012]

[0013] The second aspect of the present invention provides a method for preparing the above-mentioned pyrazole carboxylic acid borneol ester compound, comprising: subjecting the compound represented by formula (3) to a condensation reaction with borneol to obtain a compound represented by formula (I), and the reaction formula is as follows:

[0014]

[0015] The molar ratio of the compound represented by formula (3) to borneol is 1:1.2-1.5. The conditions of the condensation reaction include: reacting at room temperature for 8-10 hours under the protection of an inert atmosphere and in the presence of a solvent and a catalyst; preferably, the solvent includes toluene and the catalyst includes p-toluenesulfonic acid.

[0016] In some embodiments, the preparation method of the compound represented by formula (3) comprises: subjecting the compound represented by formula (2) to a hydrolysis reaction under alkaline conditions to obtain the compound represented by formula (3), and the reaction formula is as follows:

[0017]

[0018] The conditions for the hydrolysis reaction include: reflux at 30-50° C. for 4-6 hours in the presence of a solvent and a base; preferably, the solvent includes methanol or tetrahydrofuran.

[0019] In some embodiments, the preparation method of the compound represented by formula (2) comprises: subjecting the compound represented by formula (1) to a cyclization reaction with dimethyl butynedioate to obtain the compound represented by formula (2), and the reaction formula is as follows:

[0020]

[0021] The molar ratio of the compound represented by formula (1) to dimethyl butynedioate is 1:0.9-1.5. The conditions of the cyclization reaction include: in the presence of a C1-C3 lower alcohol, reacting at 0°C for 3-5 hours, adding sodium C1-C3 lower alcohol to the reaction solution, and refluxing at 70-90°C for 1-3 hours; preferably, the C1-C3 lower alcohol is methanol.

[0022] The third aspect of the present invention provides a pharmaceutical composition, which is a pharmaceutical preparation prepared from a therapeutically effective amount of the aforementioned pyrazolecarboxylic acid borneol ester compound and one or more pharmaceutically acceptable excipients.

[0023] In some embodiments, the dosage form of the pharmaceutical preparation is capsule, pill, tablet, granule or injection.

[0024] The fourth aspect of the present invention provides the use of the aforementioned pyrazolecarboxylic acid borneol ester compound or pharmaceutical composition in any of the following i) to iii): i) preparing drugs for scavenging free radicals; ii) preparing drugs for protecting neuronal cells; iii) preparing drugs for preventing, treating or assisting in the treatment of ischemia-reperfusion injury.

[0025] The beneficial effects of the present invention are:

[0026] The present invention provides a series of pyrazole carboxylic acid borneol ester compounds with novel structures. In vitro experiments have shown that the compounds can effectively scavenge free radicals, improve tert-butyl hydroperoxide (tBHP)-induced human neuroblastoma cell (SH-SY5Y cell) damage, oxygen-glucose deprivation / reoxygenation (OGD / R)-induced human neuroblastoma cell damage, and have significantly better free radical scavenging and neuroprotective effects than edaravone. In vivo experiments have shown that the compounds can protect against cerebral ischemia injury induced by middle cerebral artery occlusion (MCAO) model in mice, and significantly reduce the volume of cerebral infarction in ischemia-reperfusion mice. Therefore, the compounds play an important role in the preparation of prevention or treatment of stroke, cardiovascular and cerebrovascular diseases and neurodegenerative diseases caused by excessive free radicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The ORAC antioxidant capacity characterization diagram of the target compound, wherein A: Oxidative free radical absorption capacity characterization diagram, B: Relative fluorescence unit characterization diagram;

[0028] Figure 2 It is a characterization diagram of the chelating ability of the target compound with different metals;

[0029] Figure 3The figure is a cell morphology characterization of human neuroblastoma cell (SH-SY5Y) damage induced by oxygen glucose deprivation / reoxygenation (OGD / R);

[0030] Figure 4 This is a diagram characterizing the protective effect of the target compound on cerebral ischemia-reperfusion injury. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] The following is an exemplary description of the preparation method of the pyrazole carboxylic acid borneol ester compound of the present invention in conjunction with specific examples. The solvents used in the examples are all commercially available chemically pure or analytically pure. The structure of the compound is determined by nuclear magnetic resonance (NMR). The NMR measurement is performed using a Bruker AVANCE-600MHz nuclear magnetic resonance spectrometer, the solvent for the measurement is CDCl3 or DMSO, and the internal standard is TMS.

[0033] Example 1: Preparation of compound 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester (2a)

[0034]

[0035] Compound phenylhydrazine (1a, 6 g, 55 mmol) was dissolved in methanol (60 mL), and a methanol (40 mL) solution containing dimethyl butynedioate (7.6 mL, 62 mmol) was added dropwise under ice bath conditions. After the reaction solution was reacted at 0°C for 3 hours, sodium methoxide (4.6 g, 86 mmol) was added to the reaction solution, and refluxed at 70°C for 2 hours. After the reaction was completed, the methanol solvent was concentrated to remove it, 40 mL of water was added, and 2 mol / L HCl was added dropwise under ice bath conditions until the pH of the reaction solution was 4, and a yellow precipitate was precipitated. It was filtered by suction, and the filter cake was washed with water and dried to obtain a yellow powder 2a with a yield of 60%.

[0036] Example 2: Preparation of compound 5-hydroxy-1-phenylpyrazole-3-carboxylic acid (3a)

[0037]

[0038] 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester (2a, 1.74 g, 8 mmol) was dissolved in methanol (20 mL), and 2 mol / L NaOH (9 mL, 18 mmol) was added dropwise under ice bath, and the reaction solution was refluxed at 40°C for 5 hours. After the reaction was completed, 2 equivalents of water were added, and the reaction solution was concentrated to remove methanol. 2 mol / L HCl was added dropwise under ice bath condition until the pH of the reaction solution was 4, and a large amount of light yellow solid precipitated. It was filtered by suction, and the filter cake was washed with water and dried to obtain light yellow solid 3a with a yield of 65%.

[0039] Example 3: 1-(3,5-dichloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3b)

[0040]

[0041] Intermediate 3b is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-3,5-dichloropyridine (1b) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is a yellow solid 3b with a yield of 56.8%.

[0042] Example 4: Preparation of compound 1-(5-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3c)

[0043]

[0044] Intermediate 3c is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-5-fluoropyridine (1c) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is a yellow solid 3c with a yield of 58%. Melting point: 229.3°C-232.7°C. 1 HNMR (600MHz, DMSO-d6) δ8.56(d,J=3.0Hz,1H),7.99(td,J=8.6,3.1Hz,1H),7.80(dd,J=9.0,3.9Hz,1H),5.95(s,1H).

[0045] Example 5: Preparation of compound 5-hydroxy-1-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3d)

[0046]

[0047] Intermediate 3d is prepared by replacing phenylhydrazine (1a) with 2-hydrazinepyridine (1d) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is a yellow powder 3d with a yield of 55%. 1H NMR (300MHz, DMSO-d6) δ8.53 (ddd, J=5.0, 1.9, 0.9Hz, 1H), 8.09 (ddd, J=8.3, 7.5, 1.9 Hz,1H),7.81(dt,J=8.3,1.0Hz,1H),7.46(ddd,J=7.5,5.0,1.1Hz,1H),5.99(s,1H).

[0048] Example 6: Preparation of compound 5-hydroxy-1-(3-methylpyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3e)

[0049]

[0050] Intermediate 3e is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-3-methylpyridine (1e) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is a yellow powder 3e with a yield of 55%.

[0051] Example 7: Preparation of compound 1-(5-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3f)

[0052]

[0053] Intermediate 3f is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-5-chloropyridine (1f) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is a dark yellow solid 3f with a yield of 70%. Melting point: 216.2°C-220.5°C. 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),8.60(d,J=2.5Hz,1H),8.16(dd,J=8.7,2.6Hz,1H),7.80(d,J=8.7Hz,1H),5.98(s,1H).

[0054] Example 8: Preparation of compound 5-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3 g)

[0055]

[0056] Intermediate 3g is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-5-trifluoromethylpyridine (1g) and reacting with dimethyl butynedioate, followed by hydrolysis. The reaction process is similar to 3a, and the product is an orange-red powder of 3g with a yield of 65%. Melting point: 137.4°C-144.5°C. 1H NMR (600MHz, DMSO-d6) δ13.05(s,1H),12.31(s,1H),8.95(dt,J=2.8,1.0Hz,1H),8.44(dd,J=8.8,2.5Hz,1H),8.02(d,J=8.6Hz,1H),6.01(s,1H).

[0057] Example 9: Preparation of compound 1-(3-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3h)

[0058]

[0059] Intermediate 3h is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-3-chloropyridine (1h), reacting with dimethyl butynedioate, and then hydrolyzing. The reaction process is similar to 3a, and the product is an off-white powder 3h with a yield of 60%.

[0060] Example 10: Preparation of compound 5-hydroxy-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3i)

[0061]

[0062] Intermediate 3i is prepared by replacing phenylhydrazine (1a) with 2-hydrazine-3-trifluoromethylpyridine (1i), reacting with dimethyl butynedioate, and then hydrolyzing. The reaction process is similar to 3a, and the product is a purple powder 3i with a yield of 65%.

[0063] Example 11: Preparation of compound 5-hydroxy-1-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid (3j)

[0064]

[0065] Intermediate 3j is prepared by replacing phenylhydrazine (1a) with 2-hydrazinopyrimidine (1j), reacting with dimethyl butynedioate, and then hydrolyzing. The reaction process is similar to 3a, and the product is an orange flaky solid 3j with a yield of 63%. Melting point: 162.4℃-172.9℃. 1 HNMR (600MHz, DMSO-d6) δ12.94(s,1H),12.02(s,1H),8.95(d,J=4.9Hz,2H),7.60(t,J=4.9Hz,1H),5.98(s,1H).

[0066] Example 12: Preparation of compound 1-(4-chlorophenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3k)

[0067]

[0068] Intermediate 3k is prepared by replacing phenylhydrazine (1a) with 4-chlorophenylhydrazine (1k), reacting with dimethyl butynedioate, and then hydrolyzing. The reaction process is similar to 3a, and the product is an off-white solid 3k with a yield of 62.5%.

[0069] Example 13: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate (2-1)

[0070]

[0071] 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid (3a) (302 mg, 1.1 mmol) and borneol (220 mg, 1.43 mmol) were dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated to obtain a white powder 2-1 after silica gel column chromatography, with a yield of 13.27%. Melting point: 191.3°C-192.6°C; 13 CNMR(151MHz,DMSO-d6)δ162.35,153.78,142.70,138.53,129.47(×2),127.48,122.7 2(×2),89.48,79.63,49.09,47.89,44.73,36.73,28.05,27.20,19.94,19.06,13.87.

[0072] Example 14: (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 1-(3,5-dichloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylate (2-2)

[0073]

[0074] 1-(3,5-dichloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3b) (302 mg, 1 mmol), borneol (231.4 mg, 1.5 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-2 was obtained by silica gel column chromatography, and the yield was 20.5%. Melting point: 221.5°C-223.6°C; 1H NMR (600MHz, CDCl3) δ8.31(d,J=2.2Hz,1H),7.99(d,J=2.1Hz,1H),6.10(s,1H),5.12(dt,J =10.1,3.1Hz,1H),2.48-2.41(m,1H),2.10(ddd,J=13.3,9.4,4.4Hz,1H),1.77(ddq,J=12.0 ,8.0,3.9Hz,1H),1.72(t,J=4.6Hz,1H),1.39-1.32(m,1H),1.28(ddd,J=23.3,10.1,4.1Hz, 1H),1.14(dd,J=13.8,3.4Hz,1H),0.94(s,3H),0.90(s,3H),0.89(s,3H); HRMS(m / z):calcd for C 19 H 22 Cl2N3O3[M+H] + ,410.1033;found,410.1095.

[0075] Example 15: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 1-(5-fluoropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylate (2-3)

[0076]

[0077] 1-(5-fluoropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3c) (334.5 mg, 1.5 mmol), borneol (347 mg, 2.25 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 hours. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-3 was obtained by silica gel column chromatography, and the yield was 50%. Melting point: 109.6°C-111.0°C; 1H NMR (600MHz, CDCl3) δ11.88(s,1H),8.19(d,J=2.9Hz,1H),8.17(dd,J=9.2,4.1Hz,1H),7.70 (ddd,J=9.1,7.5,2.9Hz,1H),6.07(s,1H),5.18-5.10(m,1H),2.59-2.38(m,1H),2.10(ddd, J=13.4,9.4,4.5Hz,1H),1.79(tt,J=8.0,4.0Hz,1H),1.73(t,J=4.5Hz,1H),1.50-1.34(m,1 H),1.34-1.21(m,1H),1.14(dd,J=13.9,3.5Hz,1H),0.96(s,3H),0.91(s,3H),0.90(s,3H). 13 C NMR(151MHz,CDCl3)δ162.34,157.39(d,J C1-F =253.5Hz),156.00,150.44,144.85,133.14(d,J=27.9Hz),127.90(d,J=20.2Hz),114.90(d,J=5.1H z),90.01,80.81,49.13,47.92,44.98,36.73,28.04,27.26,19.74,18.95,13.57; HRMS(m / z):calcd for C 18 H 21 N4O3[MH] - ,358.1572;found,358.1550.

[0078] Example 16: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 5-hydroxy-1-(pyridin-2-yl)-1H-pyrazole-3-carboxylate (2-4)

[0079]

[0080] 5-Hydroxy-1-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3d) (307.755 mg, 1.5 mmol) and borneol (347.2 mg, 2.25 mmol) were dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the mixture was reacted at 120°C for 9 h. After the reaction, insoluble matter was present, which was filtered off with suction, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. A light yellow oil 2-4 was obtained by silica gel column chromatography with a yield of 6.7%. 1H NMR (600MHz, CDCl3) δ12.53(s,1H),8.32(d,J=5.1Hz,1H),8.14(d,J=8.4Hz,1H),7.94(t,J=8.0 Hz,1H),7.27(d,J=6.6Hz,1H),6.06(s,1H),5.20-5.11(m,1H),2.47(ddt,J=14.1,9.0,4.0Hz,1 H),2.11(ddd,J=13.3,9.4,4.4Hz,1H),2.01(q,J=6.7Hz,1H),1.79(ddq,J=12.4,8.2,4.2Hz,1H ),1.73(t,J=4.6Hz,1H),1.39(dt,J=16.5,10.3Hz,1H),1.25(s,1H),0.96(s,3H),0.91(s,6H). 13 C NMR (151MHz, CDCl3) δ163.08,156.96,154.81,145.34,145.10,140.44,122.09,113 .75,89.94,81.25,49.26,48.05,45.12,36.87,28.18,27.40,19.88,19.08,13.70.

[0081] Example 17: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 5-hydroxy-1-(3-methylpyridin-2-yl)-1H-pyrazole-3-carboxylate

[0082]

[0083] 5-Hydroxy-1-(3-methylpyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3e) (328.8 mg, 1.5 mmol), borneol (347 mg, 2.25 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-5 was obtained by silica gel column chromatography, and the yield was 18.75%. Melting point: 125.1°C-126.8°C; 1H NMR(600MHz, CDCl3)δ8.19(d,J=5.2Hz,1H),7.77(d,J=7.5Hz,1H),7.23-7.18(m,1H), 6.09(s,1H),5.12(d,J=10.0Hz,1H),2.83(s,1H),2.50-2.43(m,1H),2.14(ddd,J=13. 2,9.3,4.4Hz,1H),1.79(ddt,J=12.0,8.0,3.9Hz,1H),1.73(t,J=4.5Hz,1H),1.44-1. 34(m,1H),1.34-1.28(m,1H),1.15(dd,J=13.8,3.5Hz,1H),0.96(s,3H),0.91(s,6H). 13 CNMR(151MHz, CDCl3)δ162.80,157.22,151.99,143.89(×2),142.42,126.03,121.36,80.4 8,49.10,47.86,45.04,36.83,28.04,27.20,21.89,19.74,18.95,13.57; HRMS(m / z):calcd for C 20 H 24 N3O3[MH] - ,354.1823;found,354.1800.

[0084] Example 18: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 1-(5-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylate (2-6)

[0085]

[0086] 1-(5-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3f) (359.43 mg, 1.5 mmol) and borneol (347 mg, 2.25 mmol) were dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-6 was obtained by silica gel column chromatography, and the yield was 56.7%. Melting point: 186.3°C-188.6°C; 1H NMR (600MHz, CDCl3) δ11.89(s,1H),8.29(d,J=2.4Hz,1H),8.11(d,J=8.9Hz,1H),7.90(dd,J=8 .9,2.4Hz,1H),6.07(s,1H),5.17-5.11(m,1H),2.51-2.42(m,1H),2.09(ddd,J=13.3,9.4,4.4H z,1H),1.79(ddt,J=12.0,8.0,3.9Hz,1H),1.73(t,J=4.5Hz,1H),1.38(tdd,J=12.3,4.5,2.2H z,1H),1.33-1.28(m,1H),1.14(dd,J=13.9,3.5Hz,1H),0.96(s,3H),0.91(s,3H),0.90(s,3H). 13 C NMR (151MHz, CDCl3) δ162.29,156.30,152.33,145.28,144.17,140.18,129.14,114.44,90. 11,80.88,49.14,47.93,44.98,36.73,28.04,27.27,19.74,18.94,13.57; HRMS(m / z):calcd for C 19 H 21 ClN3O3[MH] - ,374.1277;found,374.1255.

[0087] Example 19: Preparation of compound (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 5-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate (2-7)

[0088]

[0089] 5-Hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3g) (409.755mg, 1.5mmol), borneol (277.704mg, 1.8mmol), dissolved in toluene (15mL), p-toluenesulfonic acid (190.21mg, 1mmol) was added under stirring, and the reaction was carried out at 120℃ for 9h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-7 was obtained by silica gel column chromatography, and the yield was 44.8%. Melting point: 144.2℃-146.3℃; 1H NMR (600MHz, CDCl3) δ11.99(s,1H),8.62(s,1H),8.27(d,J=8.7Hz,1H),8.16(d,J=11.1Hz, 1H),6.09(s,1H),5.15(ddd,J=9.9,3.4,2.1Hz,1H),2.50-2.43(m,1H),2.09(ddd,J=13.4, 9.5,4.5Hz,1H),1.80(ddq,J=12.1,7.9,4.1Hz,1H),1.74(t,J=4.5Hz,1H),1.42-1.36(m,1 H),1.35-1.28(m,1H),1.14(dd,J=13.9,3.5Hz,1H),0.96(s,3H),0.91(s,3H),0.91(s,3H). 13 C NMR (151MHz, CDCl3) δ142.36, 137.06, 136.42, 126.47, 123.55 (q, J = 4.3Hz) (×2), 117.69 (d, J = 3.3Hz), 104.91-1 02.07(m),93.70,70.54,61.31,29.38,28.18,25.21,16.97,8.28,7.50,-0.03,-0.83,-6.19; HRMS(m / z):calcd for C 20 H 21 F3N3O3[MH] - ,408.1540;found,408.1516.

[0090] Example 20: Preparation of compound (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 1-(3-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylate (2-8)

[0091]

[0092] 1-(3-chloropyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3h) (359.43 mg, 1.5 mmol), borneol (278 mg, 1.8 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 hours. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-8 was obtained by silica gel column chromatography, and the yield was 5.64%. Melting point: 230.7°C-231.6°C; 1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),8.60(dd,J=4.7,1.6Hz,1H),8.25(dd,J=8.1,1.6Hz,1H), 7.68(dd,J=8.1,4.7Hz,1H),5.90(s,1H),5.05-4.97(m,1H),2.36(ddt,J=13.9,9.9,4.1Hz,1H) ,1.99(ddd,J=13.2,9.5,4.3Hz,1H),1.77-1.70(m,1H),1.70(t,J=4.5Hz,1H),1.32(t,J=14.7H z,1H),1.29-1.21(m,1H),1.05(dd,J=13.7,3.5Hz,1H),0.92(s,3H),0.87(s,3H),0.84(s,3H). 13 C NMR(151MHz,DMSO-d6)δ162.42,154.88,148.25,147.12,143.84,140.24,129.21,127.36,87 .97,79.84,49.12,47.97,44.77,36.74,28.09,27.24,20.00,19.11,13.95; HRMS(m / z):calcd for C 19 H 21 ClN3O3[MH] - ,374.1277;found,374.1256.

[0093] Example 21: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-5-hydroxy-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate (2-9)

[0094]

[0095] 5-Hydroxy-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (3i) (327.8 mg, 1.2 mmol), borneol (240.68 mg, 1.56 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated to obtain a white powder 2-9 after silica gel column chromatography, with a yield of 28.5%. Melting point: 193.8°C-196.0°C; 1H NMR (600MHz, DMSO-d6) δ11.99(s,1H),8.92(dd,J=4.8,1.7Hz,1H),8.50(dd,J=8.0,1.7Hz,1H),7.88(dd, J=8.0,4.8Hz,1H),5.89(s,1H),5.00(ddd,J=10.0,3.4,2.0Hz,1H),2.36(ddt,J=13.8,9.9,4.2Hz,1H),1 .99(ddd,J=13.1,9.4,4.3Hz,1H),1.74(dt,J=12.1,3.9Hz,1H),1.70(t,J=4.5Hz,1H),1.36-1.28(m,1H) ,1.24(ddd,J=13.6,9.2,4.5Hz,1H),1.04(dd,J=13.7,3.5Hz,1H),0.92(s,3H),0.87(s,3H),0.83(s,3H). 13 C NMR(151MHz,DMSO-d6)δ161.88,154.82,153.04,146.45,143.31,137.74(d,J=4.7Hz),125.90,123.29-122.7 0(m),121.45,87.49,79.38,48.68,47.47,44.32,36.28,27.62,26.73,19.53,18.64,13.45; HRMS(m / z):calcd for C 20 H 21 F3N3O3[MH] - ,408.1540;found,408.1522.

[0096] Example 22: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-5-hydroxy-1-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate (2-10)

[0097]

[0098] 5-Hydroxy-1-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid (3j) (206.16 mg, 1 mmol) and borneol (185.1 mg, 1.2 mmol) were dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-10 was obtained by silica gel column chromatography, and the yield was 3%. Melting point: 184.5°C-187.2°C; 1 H NMR (600MHz, CDCl3) δ11.79 (s, 1H), 8.82 (d, J = 5.0Hz, 2H), 7.34 (t, J = 5.0Hz, 1H), 6. 11(s,1H),5.18-5.14(m,1H),2.45(ddt,J=14.0,9.7,3.9Hz,1H),2.10(ddd,J=13.2, 9.3,4.5Hz,1H),1.78(td,J=10.1,8.3,6.0Hz,1H),1.71(t,J=4.5Hz,1H),1.39-1.3 6(m,1H),1.32-1.29(m,1H),1.14(dd,J=13.9,3.4Hz,1H),0.94(s,3H),0.89(s,6H).

[0099] Example 23: Preparation of compound (1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 1-(4-chlorophenyl)-5-hydroxy-1H-pyrazole-3-carboxylate (2-11)

[0100]

[0101] 1-(4-chlorophenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (3k) (143 mg, 0.6 mmol), borneol (111 mg, 0.72 mmol), dissolved in toluene (15 mL), p-toluenesulfonic acid (190.21 mg, 1 mmol) was added under stirring, and the reaction was carried out at 120°C for 9 h. After the reaction, there were insoluble substances, which were filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated. The white powder 2-11 was obtained by silica gel column chromatography, with a yield of 25.37%. Melting point: 228.1°C-230.9°C; 1HNMR(600MHz,DMSO-d6)δ12.29(s,1H),7.80-7.77(m,2H),7.59-7.56(m,2H),5.94(s,1H), 5.02-4.98(m,1H),2.39-2.34(m,1H),2.02(ddd,J=13.2,9.4,4.4Hz,1H),1.75(ddq,J=11. 8,7.9,4.1Hz,1H),1.70(t,J=4.5Hz,1H),1.34(tdd,J=12.2,4.5,2.2Hz,1H),1.25(ddd,J= 11.9,9.4,4.4Hz,1H),1.04(dd,J=13.7,3.5Hz,1H),0.92(s,3H),0.87(s,3H),0.84(s,3H). 13 C NMR(151MHz,DMSO-d6)δ161.81,153.58,142.62,137.00,131.20,129.11(2),123.6 1(2),89.17,79.32,48.68,47.49,44.31,36.31,27.63,26.79,19.53,18.65,13.46.

[0102] Example 24: DPPH free radical scavenging experiment

[0103] Preparation of DPPH test solution: Take DPPH solid and prepare it into 50μM DPPH test solution with an absorbance of 0.45. Preparation of sample solution: The sample is dissolved in a suitable solvent to prepare a 20mM solution. Before the test, the 20mM solution of the compound to be tested is diluted with ethanol to 500μM, and edaravone is used as a positive control compound. It is then diluted with ethanol to 40μM for testing. A value measurement (test group): In a 96-well plate, use a pipette to take 40μL of the ethanol solution of the compound to be tested, and then add 160μL of DPPH solution. All the above tests were performed in three parallel operations. At room temperature for 8h, measure the A519 nm value. A0 value measurement (blank group): Use a pipette to take 40μL of ethanol solution, and then add 160μL of DPPH solution. The measured A value is A0. The experimental results (Table 1) show that compared with the positive drug edaravone, most of the target compounds showed better DPPH scavenging ability than edaravone, among which the scavenging ability of compounds 2-6 on nitrogen free radicals reached 85%.

[0104] Table 1 DPPH scavenging ability of compounds (%)

[0105]

[0106]

[0107] Example 25: ABTS free radical scavenging experiment

[0108] Preparation of ABTS working stock solution: 7.4mmol / L ABTS solution and 2.6mmol / L potassium persulfate solution were mixed in a volume ratio of 1:1, and the ABTS working stock solution was obtained by standing at room temperature in the dark for 12h; Preparation of sample solution: The sample was dissolved in DMSO to prepare a 20mM solution. Before the test, the 20mM test compound solution was diluted with ethanol to 20μM, 40μM, and 80μM in sequence. Measurement of A0 value (blank group): The ABTS working stock solution was diluted with PBS, and 40μL of ethanol solution was taken in a 96-well plate with a pipette, and then 160μL of the diluted ABTS working stock solution was added. The measured A value is A0; A value measurement (test group): In a 96-well plate, 40μL of the ethanol solution of the test compound was taken with a pipette, and then 160μL of the diluted ABTS working stock solution was added; All the above tests were performed in parallel three times. After 15 minutes of reaction at room temperature in the dark, the A value was detected at 734 nm. The experimental results (Table 2) showed that most of the target compounds showed better DPPH scavenging ability than edaravone, and the scavenging ability of compounds 2-6, 2-7, 2-8, 2-9, 2-10, and 2-11 was significantly better than that of edaravone, among which the scavenging ability of compounds 2-6, 2-7, 2-8, and 2-9 was significantly better than that of VE, and 2-6 had the strongest scavenging ability for ABTS, reaching 80.69%.

[0109] Table 2 The scavenging ability of the compounds on ABTS (%)

[0110]

[0111]

[0112] Example 26: ORAC fluorescence test antioxidant capacity

[0113] The antioxidant activity of the compounds was determined by oxygen radical absorbance capacity-fluorescein (ORAC-FL). Trolox (Tro) was used as a positive control compound. The test compound (20 μL, 2 μM) and fluorescein solution (120 μL, 117 nM) were added to a 96-well black board in sequence. The test plate was incubated at 37 ° C for 15 minutes. Subsequently, azobisisobutyramidine hydrochloride (AAPH, 60 μL, 40 mM) was added to the system with a final volume of 200 μL to start the reaction. Immediately after the addition of AAPH, fluorescence was recorded once per minute in a Tecan 96 microplate reader (lex 485nm, lem 525nm, 37 ° C) for 120 minutes. The reaction mixture was prepared in triplicate. The blank control group was measured without the use of antioxidants or in the absence of AAPH and antioxidants. The ORAC values ​​were expressed as Trolox equivalents (mean ± SD) using a standard curve calculated for each assay. Experimental results ( Figure 1 The results of Table 3 show that 2-1, 2-2 and 2-6 exhibited excellent antioxidant capacity compared to Trolox. Among them, compound 2-6 exhibited the best antioxidant capacity, with an ORAC value of 1.63, which was better than that of edaravone.

[0114] Table 3 Antioxidant test data of compounds (TE)

[0115]

[0116] Example 27: Metal Chelation Test

[0117] The metal chelating ability of the target compound was investigated by ultraviolet spectroscopy. Redox-active metals (such as iron and copper) undergo redox cycle reactions and produce reactive free radicals, such as superoxide anion radicals and nitric oxide in biological systems. The disruption of metal ion homeostasis may lead to oxidative stress, in which the formation of reactive oxygen species increases, subsequently inducing DNA damage, lipid peroxidation and other effects. This effect is involved in cardiovascular disease, atherosclerosis, neurological diseases, chronic inflammation and other diseases. The mechanism of metal-induced free radical formation is affected by cellular antioxidants. Many low molecular weight antioxidants (vitamin C, vitamin E, glutathione, etc.) can chelate metal ions, thereby reducing the generation of reactive oxygen species. Similarly, compounds that can chelate with metal ions may improve their free radical scavenging ability.

[0118] The metal salts used in the test are AlCl3, MgSO4, K2CO3, CuI, CuCl2, FeSO4, FeCl3 and ZnCl2. The methanol solution of the test compound 2-6 (1.0 mL, 100 μM) was added to the methanol solution containing the metal ion (1.0 mL, 100 μM), incubated on a shaker at 37°C for 2 hours, and then the solution was transferred to a quartz cell to measure the absorbance of the solution at 200-550 nm. For selected experimental results, see Figure 2 Compared with 2-6, after adding CuCl2, FeCl3, FeSO4, ZnCl2 and CuI, 2-6 has a maximum absorption peak at 250nm. In addition, with the addition of CuCl2, an additional absorption peak appeared in the absorption spectrum at 205nm, and the minimum absorption peak moved to 220nm. It is worth noting that after adding CuCl2, the maximum absorption peak at 205nm moved to 340nm, which indicates that compound 2-6 and Cu 2+ , Fe 3+ It has a significant chelating effect.

[0119] Example 28: Evaluation of the protective effect of t-butyl hydroperoxide (tBHP)-induced damage in human neuroblastoma cells (SH-SY5Y cells)

[0120] SH-SY5Y cells were prepared at a concentration of 8×10 4 100 μL of cell suspension (8×10 cells / mL) was added to each well of a 96-well cell culture plate. 3 cells), and the plate was placed in a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, the compound was prepared with a 400μM tBHP DMEM solution. Then, the tBHP DMEM solution containing different concentrations of the compound was added to a 96-well plate and cultured in a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, 15μL of MTT solution (5mg / mL) was added to each well and incubated in a 37°C shaker for 4 hours, the supernatant of each well was discarded, and 100μL of DMSO was added to each well, and the cell was shaken on a cell shaker for 10 minutes. Finally, the OD value was read at a wavelength of 492nm with a multifunctional microplate reader to calculate the cell growth inhibition rate. The experimental results (Table 4) show that 2-1, 2-7, 2-8, 2-9, 2-10, and 2-11 exhibited better neuroprotective effects than edaravone. Among them, compound 2-10 exhibited the best neuroprotective ability, with a cell survival rate of 85.46%.

[0121] Table 4 Effects of compounds on tBHP-induced SH-SY5Y cells

[0122]

[0123]

[0124] Example 29: Evaluation of the protective effect of oxygen glucose deprivation / reoxygenation (OGD / R)-induced damage in human neuroblastoma cells

[0125] The human neuroblastoma cells selected were SH-SY5Y cells. The experimental method was as follows: a bottle of cells in the logarithmic growth phase was taken, and trypsin cell digestion solution was added to digest the cells to make the adherent cells fall off, and the concentration was prepared to 6×10 4 100 μL of cell suspension (6×10 cells / mL) was added to each well of a 96-well cell culture plate. 3 cells), and the plate was placed in a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, DMEM was replaced with EBSS. The cells were placed in a tri-gas incubator and cultured for 4 hours. Thereafter, DMEM containing different concentrations of compounds was cultured in a 37°C, 5% CO2 incubator for 24 hours. Finally, 15 μL MTT solution (5 mg / mL) was added to each well and incubated in a 37°C shaker for 4 hours, the supernatant of each well was discarded, and 100 μL DMSO was added to each well and shaken on a cell shaker for 10 minutes. Finally, the OD value was read at a wavelength of 492 nm using a multifunctional microplate reader to calculate the cell growth inhibition rate. The experimental results are shown in Tables 5 and Figure 3 Table 5 shows that 2-2 and 2-6 exhibited excellent neuroprotective effects compared to edaravone. Among them, compound 2-6 exhibited the best neuroprotective ability, with a cell survival rate of 83.41%; Figure 3 It can be seen that compared with the injury group, edaravone and compounds 2-6 can improve cell damage and shrinkage caused by hypoxia and glucose deprivation.

[0126] Table 5 OGD / R induced SH-SY5Y cells

[0127]

[0128] Example 30: Evaluation of the protective effect on cerebral ischemia induced by middle cerebral artery occlusion (MCAO) model in mice

[0129] Drug preparation: accurately weigh 10 mg of the compound 2-6 of the present invention or butylphthalide, add 0.5 mL of PEG, then add 9.5 mL of PBS, dissolve by ultrasonication, and prepare a 1 mg / mL solution;

[0130] Administration and dosage: The administration method is intraperitoneal injection, and the dosage is 10 mg / kg;

[0131] The middle cerebral artery occlusion (MCAO) model was used to induce cerebral ischemia injury. After ICR mice were anesthetized with 2% chloral hydrate (0.2 mL / 10 g), the animals were fixed on the operating table in a supine position. The skin was cut along the midline of the neck, the neck muscle tissue was bluntly separated, the right common carotid artery (CCA) was exposed and carefully freed, the accompanying vagus nerve was gently peeled off, the external carotid artery branch (ECA) running inward and superficial was ligated and cut, and the pterygopalatine artery, which was a branch artery running outward near the base of the skull, was separated and ligated. The proximal end of the CCA was ligated with a surgical thread, and a small opening was cut at the distal end of the ligature with ophthalmic scissors. The nylon thread (diameter 0.22 mm) was inserted along the small opening, and the thread was stopped when a slight resistance was felt after about 9±1 mm. The insertion depth of the thread plug was determined according to the mark, and the extravascular part of the thread plug was ligated and fixed to prevent the thread plug from slipping. After 2 hours of right cerebral ischemia, about 10 mm of the fishing line in the lumen of the internal carotid artery was carefully withdrawn to allow blood flow in the internal carotid artery to be reperfused. The skin was sutured and the mice were returned to the cage for careful feeding. The same surgical procedure was performed on sham-operated mice, but the middle cerebral artery was not blocked. The body temperature of the animals was kept constant at 37±0.5℃ during the operation. The drug was administered immediately after cerebral ischemia and reperfusion, and the infarct volume was measured by TTC staining 72 hours after administration. The experimental results of some compounds are shown in the figure. Figure 4 As shown: Figure 4 The figures are TTC staining images of coronal sections of the brains of four groups of mice, namely, the negative control group (sham operation group), the model group, the compound 2-6 group of the present invention, and the positive control group (butylphthalide group). The red tissue in the figure is the normal brain tissue, and the white tissue is the infarcted brain tissue. It can be seen that compared with the MCAO group, compound 2-6 can significantly reduce the volume of cerebral infarction in ischemia-reperfusion mice.

[0132] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A pyrazolecarboxylic acid bornyl ester compound, characterized in that: It is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Wherein, R is a substituted or unsubstituted six-membered aromatic ring or six-membered aromatic heterocycle, and the substitution is substitution with 1 to 3 substituents selected from halogen, C1-C6 alkyl or C1-C6 haloalkyl.

2. The pyrazolecarboxylic acid borneol ester compound according to claim 1, characterized in that: The six-membered aromatic heterocyclic ring contains 1 to 3 heteroatoms, and the heteroatoms are nitrogen.

3. The pyrazolecarboxylic acid borneol ester compound according to claim 1, characterized in that: The halogen is a fluorine atom or a chlorine atom.

4. The pyrazolecarboxylic acid borneol ester compound according to claim 1, characterized in that: The compound represented by formula (I) is selected from any one of the following compounds 2-1 to 2-11:

5. A method for preparing the pyrazolecarboxylic acid bornyl ester compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises: subjecting the compound represented by formula (3) to a condensation reaction with borneol to obtain the compound represented by formula (I), and the reaction formula is as follows: The molar ratio of the compound represented by formula (3) to borneol is 1:1.2-1.5; The conditions of the condensation reaction include: reacting at room temperature for 8 to 10 hours under the protection of an inert atmosphere and in the presence of a solvent and a catalyst.

6. The preparation method according to claim 5, characterized in that: The preparation method of the compound represented by formula (3) comprises: subjecting the compound represented by formula (2) to a hydrolysis reaction under alkaline conditions to obtain the compound represented by formula (3), and the reaction formula is as follows: The conditions of the hydrolysis reaction include: reflux at 30-50° C. for 4-6 hours in the presence of a solvent and a base.

7. The preparation method according to claim 6, characterized in that: The preparation method of the compound represented by formula (2) comprises: subjecting the compound represented by formula (1) to a cyclization reaction with dimethyl butynedioate to obtain the compound represented by formula (2), and the reaction formula is as follows: The molar ratio of the compound represented by formula (1) to dimethyl butynedioate is 1:0.9-1.5; The conditions of the cyclization reaction include: in the presence of C1-C3 lower alcohol, reacting at 0° C. for 3 to 5 hours, adding sodium C1-C3 lower alcohol to the reaction solution, and refluxing at 70 to 90° C. for 1 to 3 hours.

8. A pharmaceutical composition, characterized in that The invention is a pharmaceutical preparation prepared from a therapeutically effective amount of the pyrazolecarboxylic acid borneol ester compound according to any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, characterized in that The dosage form of the pharmaceutical preparation is capsule, pill, tablet, granule or injection.

10. Use of the pyrazolecarboxylic acid borneol ester compound according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 8 to 9 in any one of the following i) to iii): i) preparing drugs for scavenging free radicals; ii) preparing drugs for protecting neuronal cells; iii) preparing drugs for preventing, treating or assisting in treating cerebral ischemia-reperfusion injury.

Images