CN109180712B - 2-arrowhead alcohol arylboronic acid ester derivatives and application thereof - Google Patents
2-arrowhead alcohol arylboronic acid ester derivatives and application thereof Download PDFInfo
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- CN109180712B CN109180712B CN201810897164.7A CN201810897164A CN109180712B CN 109180712 B CN109180712 B CN 109180712B CN 201810897164 A CN201810897164 A CN 201810897164A CN 109180712 B CN109180712 B CN 109180712B
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- acid ester
- arrowhead
- arylboronic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
2-arrowhead alcohol aryl boric acid ester derivatives and application thereof, wherein the structure of the derivatives accords with the general formula (I):
wherein: r1、R2Is alkyl, R1、R2May be linked to form a ring structure. The compound is sensitive to free radicals caused by ischemia, can release 2-arrowol at an ischemic part, and has a good protective effect on ischemic injury. Can be used for preparing medicine for treating diseases caused by ischemia injury.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to 2-arrowol arylboronic acid ester derivatives and application thereof.
Background
Cerebral infarction (ischemic stroke) has the characteristics of high mortality, high disability rate, high recurrence rate and the like, and seriously harms human health. Because the brain tissue structure is delicate and complex, and is particularly sensitive and fragile to ischemia and hypoxia injury, the clinical application of the treatment drug with definite curative effect is rare so far. 2-sagittiol (Borneolum Syntheticum) has bidirectional regulating and protecting effects on central nervous system. One is the bi-directional regulation of the center. Borneol has two-way regulation effect on central nerve excitability, and has the functions of tranquilizing and allaying excitement and restoring consciousness. The second is the protection effect on the central nervous system. The borneol has protective effect on the brain, is beneficial to the recovery of encephaledema, protects the subsequent injury caused by cerebral ischemia and improves the damaged and awakening capability. Borneol also has the function of promoting the division of glial cells. In addition, 2-sagittanol (borneol) is beneficial to preventing and treating coronary spasm and can relieve myocardial injury caused by ischemia. The side effect of 2-arrowhead alcohol is mainly anaphylactic reaction, the large dose of borneol can stimulate the gastrointestinal tract, the conditions of nausea, vomiting, abdominal pain and diarrhea can be caused, the central nerve can be excited too much, convulsion, consciousness loss and spasm can be caused finally, and serious patients can cause respiratory failure and death. The applicant found that: the 2-arrowhead alcohol aryl borate derivative has better stability, and can release 2-arrowhead alcohol under the action of free radicals. Because a large number of free radicals exist in the ischemic part, the derivatives are suggested to release 2-sagittol in the ischemic part to generate a protective effect. And meanwhile, the side effect can be reduced.
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides an arylboronic acid ester derivative of 2-arrowhead alcohol, which can specifically release the 2-arrowhead alcohol under the action of free radicals. Because a large number of free radicals exist in the ischemic part, the derivatives are suggested to release 2-sagittol in the ischemic part to generate a protective effect.
The technical scheme is as follows: an arylboronic acid ester derivative of 2-arrowhead alcohol, the structure of which conforms to the general formula (I):
wherein: r1、R2Is alkyl, or R1、R2The connection forms a ring structure.
The preferable structure of the arylboronic acid ester derivatives of 2-arrowhead alcohol is as follows:
the 2-arrowhead aryl boric acid ester derivative or the pharmaceutically acceptable salt thereof is applied to the preparation of the medicine for treating ischemic injury such as cerebral apoplexy.
A medicine for treating ischemic injury contains arylboronic acid ester derivative of the 2-arrowol as effective component.
Has the advantages that: the medicine can release 2-arrowol at an ischemic part to generate a protective effect. And meanwhile, the side effect can be reduced.
Detailed Description
The following examples are given to enable a person skilled in the art to fully understand the invention, but do not limit it in any way.
Example 1: synthesis of target compound:
1.1 Synthesis of target Compound 1:
the synthetic route is as follows:
the operation is as follows: triphosgene (1.78g, 6mmol) was dissolved in 40mL of toluene at 0 deg.C, then pyridine (0.47g, 6mmol) was added slowly and dissolved in 10mL of toluene over 30min, and (+) 2-sagitol (0.62g, 4mmol) was added slowly and dissolved in 40mL of toluene over 30min, then stirred at room temperature for 24 h. After completion of the reaction, toluene was distilled off under reduced pressure to obtain white crystals, which were dissolved in 30mL of dichloromethane, methyl 4-hydroxymethylphenylboronate (0.72g, 4mmol) was dissolved in 10mL of dichloromethane and 2mL of LDMSO at 0 ℃, which was added dropwise to the above solution, and triethylamine (0.4g, 4mmol) was added dropwise to the above reaction solution, followed by stirring at room temperature for 24 hours. After completion of the reaction, the white solid was removed by filtration, and column chromatography was performed on the filtrate to obtain a white solid (0.38 g).1H NMR(400MHz,CDCl3):0.83(s,3H)，0.87(s,3H)，0.90(s,3H)，1.20～1.34(m,2H)，1.66～1.68(t,2H)，1.72～1.79(m，2H)，1.90～2.40(m,1H),3.40(s,6H),4.86～4.90(m，1H)5.42(s,2H),7.43(d,2H),7.85(d,2H)。
1.2 Synthesis of target Compound 2:
the synthetic route is as follows:
the operation is as follows: reference compound 1 was synthesized according to the synthetic procedure.1H NMR(400MHz,CDCl3):0.84(s,3H)，0.88(s,3H)，0.91(s,3H)，1.10(s,6H),1.22～1.34(m,2H)，1.66～1.69(t,2H)，1.70～1.79(m，2H)，1.90～2.42(m,1H),3.90(t,4H),4.86～4.93(m，1H)，5.44(s,2H),7.,4(d,2H),7.86(d,2H)。
1.3 Synthesis of target Compound 3:
the synthetic route is as follows:
the operation is as follows: synthetic procedure reference compound 1 synthetic procedure. Reference compound 1 was synthesized according to the synthetic procedure.1HNMR(400MHz,CDCl3):0.83(s,3H)，0.87(s,3H)，0.90(s,3H)，1.10(s,6H),1.20～1.34(m,2H)，1.66～1.68(t,2H)，1.70～1.79(m，2H)，1.90～2.40(m,1H),3.80-3.84(m,2H),4.86～4.90(m，1H)5.42(s,2H),7.43(d,2H),7.85(d,2H)。
1.4 Synthesis of target Compound 4:
the synthetic route is as follows:
the operation is as follows: reference compound 1, wherein: the 2-arrowhead alcohol is synthesized into the 2-arrowhead alcohol.1H NMR(400MHz,CDCl3):0.84(s,3H)，0.87(s,3H)，0.91(s,3H)，0.96(t,6H),1.21～1.34(m,2H)，1.40～1.60(m,8H),1.66～1.69(t,2H)，1.71～1.79(m，2H)，1.91～2.42(m,1H),3.84(t,4H),4.87～4.92(m，1H)，5.43(s,2H),7.,4(d,2H),7.86(d,2H)。
1.5 Synthesis of target Compound 5:
the synthetic route is as follows:
the operation is as follows: reference compound 1 was synthesized according to the synthetic procedure.1H NMR(400MHz,CDCl3):0.82(s,3H)，0.86(s,3H)，0.89(s,3H)，1.20～1.32(m,2H)，1.34(s,12H),1.65～1.68(t，2H)，1.70～1.78(m，2H)，1.90～2.40(m,1H),4.84～4.89(m，1H)，5.42(s,2H),7.42(d,2H),7.83(d,2H)。
Example 2: determination of the sensitivity of a target Compound to free radicals
Taking a proper amount of a target compound, and preparing a solution with the concentration of 0.1mmol/L by using 95% ethanol. Taking 1mL of the mixture and adding 2mmol/LH2O2Then the mixture was mixed with 1mL of ethanol solution, and the mixture was left at 25 ℃ for 1 hour to measure the concentration of 2-sagittol. And adding 1mL of distilled water into 1mL of the solution, mixing the solution evenly, standing the mixture for 1 hour at 25 ℃, and measuring the concentration of the 2-arrowhead alcohol in the solution.
Compounds referred to in the examples of Table 1 are in H2O2Concentration of released 2-sagittol in the Presence (mmol/L)
| Compound (I) | Aqueous solution (H free)2O2) | 1mmol/L of H2O2 |
| 1 | 0.01 | 0.09 |
| 2 | 0.01 | 0.08 |
| 3 | 0.01 | 0.08 |
| 4 | 0.01 | 0.08 |
| 5 | 0.01 | 0.08 |
The results show that: the target compound has better stability, and the target compound quickly releases 2-arrowol under the action of free radicals. The experimental results show that the target compound can rapidly release 2-arrowhead alcohol at the ischemic part due to the existence of a large amount of free radicals at the ischemic part.
Example 3: protective effect of target compound on focal cerebral ischemia reperfusion
3.1 preparation of focal cerebral ischemia reperfusion model
After mice were anesthetized with 2% chloral hydrate (0.2mL/10g, i.p.), the animals were supine fixed on the operating table, the skin was incised along the middle of the neck, neck muscle tissue was bluntly isolated, and the right Common Carotid Artery (CCA) was exposed and carefully freed; gently dissect the vagus nerve with the accompanying, ligate and cut the internal and superficial external carotid artery branches (ECA); the Internal Carotid Artery (ICA) was advanced and the lateral branch, the pterygopalatine artery, was located near the base of the skull and was isolated and ligated. The proximal end of the CCA is ligated with a surgical thread; the distal end of the ligature is cut open with an eye scissors, a section of surgical nylon thread (8/0 size for mouse) is heated into a ball shape and is inserted along the small opening respectively until slight resistance is felt by the insertion of about 16-17mm (mouse), which indicates that the front end of the suture plug reaches the anterior cerebral artery. To this end, the blood supply to the Middle Cerebral Artery (MCA), including the carotid artery and the anterior junctional collateral branch of the cerebral Webster, has been blocked. And judging the depth of the inserted wire bolt according to the mark. The external part of the blood vessel of the thread bolt is tied and fixed, so as to prevent the thread bolt from slipping. After the right side brain is ischemic for 1h, the thread plug is carefully pulled out, and the broken end is ligated to realize reperfusion after ischemia. The skin was sutured and carefully fed back into cages. The body temperature of the animals was kept constant at 37. + -. 0.5 ℃ during the surgery.
3.2 protective Effect of target Compounds on focal cerebral ischemia reperfusion
The middle cerebral artery occlusion model causes the infarction of the ischemic lateral cortex, striatum and other parts, after TTC staining, the normal tissue is red, and the infarcted area is white. The target compounds 5(1.0mg/kg) and (+) -2-sagittol (1.0mg/kg) were administered into the tail vein 1 time immediately after cerebral ischemia reperfusion, neurological deficit symptoms were evaluated 48 hours after cerebral ischemia, animals were sacrificed, brains were collected, TTC stained, and infarct areas of stained brain discs (8 per group) were observed.
TABLE 2 Effect of object Compound 5 on cerebral ischemic neurological deficit symptom and infarct size
| Neurological deficit symptom scoring | Infarct size | |
| Model set | 2.3±0.7 | 64.3±19.8 |
| Artificial operation group | 0.5±0.5 | 2.0±2.2 |
| Solvent set | 2.0±0.6 | 60.6±20.4 |
| (+) -2-sagittol | 1.5±0.6 | 46.5±14.6 |
| Compound 5 | 1.1±0.4 | 42.3±16.2 |
Compared with a model control group, the target compound 5 can improve the neurological deficit score and obviously reduce the cerebral infarction area, and the drug effect is superior to that of (+) -2-sagittol. Considering that the molecular weight of the compound 5 is 414, and the molecular weight of the (+) -2-arrowhead is 154, the compound 5 obtains better drug effect at smaller molar concentration, and the neuroprotective effect of the compound 5 is better than that of the (+) -2-arrowhead.
Claims (3)
1. A2-arrowhead aryl boric acid ester derivative is characterized in that the structure is as follows:
2. use of an arylboronic acid ester derivative of 2-sagittol as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of an ischemic injury.
3. A medicament for treating ischemic injury, which comprises an arylboronic acid ester derivative of 2-sagittol according to claim 1 as an active ingredient.
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| CN201810897164.7A CN109180712B (en) | 2018-08-08 | 2018-08-08 | 2-arrowhead alcohol arylboronic acid ester derivatives and application thereof |
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| CN201810897164.7A CN109180712B (en) | 2018-08-08 | 2018-08-08 | 2-arrowhead alcohol arylboronic acid ester derivatives and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046179A (en) * | 2008-04-09 | 2011-05-04 | 英菲尼提制药公司 | Inhibitors of fatty acid amide hydrolase |
| CN102516107A (en) * | 2011-11-03 | 2012-06-27 | 南京医科大学 | N-benzylaniline derivatives and application thereof |
| WO2017183734A1 (en) * | 2016-04-18 | 2017-10-26 | Taisho Pharmaceutical Co., Ltd. | Prodrug of amino acid derivative |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046179A (en) * | 2008-04-09 | 2011-05-04 | 英菲尼提制药公司 | Inhibitors of fatty acid amide hydrolase |
| CN102516107A (en) * | 2011-11-03 | 2012-06-27 | 南京医科大学 | N-benzylaniline derivatives and application thereof |
| WO2017183734A1 (en) * | 2016-04-18 | 2017-10-26 | Taisho Pharmaceutical Co., Ltd. | Prodrug of amino acid derivative |
Non-Patent Citations (1)
| Title |
|---|
| 4-异丙基苯硼酸的合成与表征;张永强 等;《化工时刊》;20060909;第20卷(第9期);第40-41页 * |
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