CN113845424B - Right-embedding alcohol ester compound and its pharmaceutical use - Google Patents

Right-embedding alcohol ester compound and its pharmaceutical use Download PDF

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CN113845424B
CN113845424B CN202111199113.5A CN202111199113A CN113845424B CN 113845424 B CN113845424 B CN 113845424B CN 202111199113 A CN202111199113 A CN 202111199113A CN 113845424 B CN113845424 B CN 113845424B
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alcohol ester
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李飞
陈天乐
王涛
丁朱姝
张般若
顾嘉颖
周鑫
陈冬寅
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Nanjing Medical University
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Abstract

Right embedded alcohol ester compound and its pharmaceutical use, and its structure accords with general formula (I)Wherein: r is R 1 、R 2 ＝‑H、‑NH 2 Or are connected with each other to form a ring structure, R 3 ＝‑COOR 4 Or CH (CH) 2 OH，R 4 ＝‑H，‑CH 2 CH 2 N(CH 3 ) 2 Or an alkyl group of 1 to 3 carbon atoms. The medicine has good effect of reducing cerebral apoplexy injury, and can be used for preparing medicine for treating cerebral apoplexy injury.

Description

Right-embedding alcohol ester compound and its pharmaceutical use
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a dextrol ester compound and a pharmaceutical application thereof.
Background
Cerebral apoplexy is a serious hazard to human health. Right-hand Borneol (Borneol) has a clear anti-cerebral ischemia effect (Journal of Biomedical Research,2017, 31:306-314). Right-hand methanol selectively agonizes the alpha 2 GABAA receptor with less likelihood of sleepiness side effects and with good safety compared to non-selective GABAA receptors. However, the dexterol has low oral bioavailability and is difficult to dissolve in water, and a large amount of organic solvent is needed to be added when the dexterol is prepared into injection, so that the difficulty of the pharmaceutical preparation is increased, and the risk of clinical administration is increased. Literature Theranostics,2021, 11 (12): 5970-5985 reports that ZL006-05 and its analogues ZL006-05B have the effect of selectively agonizing the α2GABAA receptor, but that ZL006-05 and its analogues ZL006-05B are both poorly water soluble and have low oral bioavailability.
The invention 2021103905049 discloses a medicinal application of dextromethorphan aminosalicylate, and the structure of the medicinal application accords with the following general formula:
the medicines also have the effect of selectively exciting the alpha 2 GABAA receptor, but the water solubility is still poor, and the oral bioavailability is about 20 percent.
Chinese invention CN 2021103911232 discloses a class of α2gabaa receptor agonists, the structure of which corresponds to the following general formula:wherein: />-NHCH 3 、N(CH 3 ) 2 Or->R 1 = -H or-CH 3 ，/>or-NH 2 ，R 3 -H or alkyl of 1-4 carbon atoms.
It should be noted that: the compounds of the invention are capable of up-regulating the effect of the GABAA receptor consisting of the α2 subunit in an in vitro cell model, whereas the control compounds 1,2,3 have no similar effect. Prompting: the presence of a hydroxyl structure at the beta position of the carboxyl group plays an important role in maintaining its agonism.
Control Compound 3
Disclosure of Invention
The technical problems to be solved are as follows: the invention provides a dextrol ester compound, pharmaceutically acceptable salts thereof and pharmaceutical application thereof. The medicine has good water solubility or good oral bioavailability and good effect of reducing the damage of stroke. Can be used for preparing medicines for treating cerebral apoplexy injury.
The technical scheme is as follows: right embedded alcohol ester compounds with the structure of general formula (I):
wherein: r is R 1 、R 2 ＝-H、-NH 2 Or are connected with each other to form a ring structure, R 3 ＝-COOR 4 Or CH (CH) 2 OH，R 4 ＝-H，-CH 2 CH 2 N(CH 3 ) 2 Or an alkyl group of 1 to 3 carbon atoms.
Preferred structures are shown in any one of the following structures 1-9:
application of the dextrates compounds or pharmaceutically acceptable salts thereof in preparing medicaments for treating cerebral apoplexy injury.
The effective component of the medicine for treating cerebral apoplexy is the dextrates ester compound and pharmaceutically acceptable salt thereof.
The beneficial effects are that: the medicine can selectively excite alpha 2 GABAA receptor, has the effect of reducing stroke injury, and can be used for preparing medicine for treating cerebral stroke injury.
Drawings
FIG. 1 effects of target compound 1, control compound 2, control compound 3 on neurological deficit symptoms;
FIG. 2 effects of Compound 3, compound 5, compound 6, compound 9 on neurological deficit symptoms;
FIG. 3 effect of target compound 1, control compound 2, control compound 3 on cerebral infarction area (%);
FIG. 4 influence of target compound 3, target compound 5, target compound 6, target compound 9 on cerebral infarction area (%).
Detailed Description
The following examples are intended to enable those skilled in the art to fully understand the invention and are not intended to limit the invention in any way.
EXAMPLE 1 Synthesis of target Compound
1.1 Synthesis of target Compounds 1,2
1) Synthesis of Mono-dextro-camphene malonate (target Compound 1)
The synthetic route is as follows:
borneol (5.00 mmol) was dissolved in 10mL of toluene, and cyclopropylester malonate (5.00 mmol) was added thereto for reflux reaction for 5 hours. After the completion of the reaction, toluene was dried by spin-drying, 50mL of ethyl acetate was added, the mixture was washed with saturated brine, and the organic layer was separated and then dried over anhydrous sodium sulfate and allowed to stand. Sand production, EA: pe=2:1 column passing, yields the product. 1 H NMR(400MHz，Chloroform-d)δ4.96(d，1H)，3.44(s，2H)，2.40-2.31(m，1H)，1.87(d，1H)，1.79-1.66(m，2H)，1.34-1.18(m，2H)，1.02(d，1H)，0.89(s，3H)，0.86(s，3H)，0.83(s，3H).
2) Synthesis of 3-methyl malonate dexbornyl alcohol ester (target compound 2)
The synthetic route is as follows:
monobornyl malonate (target compound 1,2.40g,10.0 mmol) was taken and dissolved in 40mL of methanol, and 1.0mL of thionyl chloride was reacted under reflux for 5h. After the reaction, spin-drying. Sand production, EA: pe=2:1 column passing, yields the product. 1 H NMR(400MHz，Chloroform-d)δ4.97(d，1H)，3.68(s，3H)，3.46(s，2H)，2.42-2.31(m，1H)，1.88(d，1H)，1.79-1.65(m，2H)，1.34-1.16(m，2H)，1.03(d，1H)，0.89(s，3H)，0.86(s，3H)，0.83(s，3H).
3) Synthesis of 3-ethyl malonate dexcamphene ester (target Compound 3)
The same method as the reference target compound 2 is used for synthesizing white powder by taking single-right camphol malonate and ethanol as raw materials. 1 H NMR(400MHz，Chloroform-d)δ4.97(d，1H)，4.13(t，2H)，3.46(s，2H)，2.43-2.31(m，1H)，1.89(d，1H)，1.79-1.64(m，2H)，1.35-1.16(m，5H)，1.03(d，1H)，0.89(s，3H)，0.86(s，3H)，0.83(s，3H).
4) Synthesis of 3-isopropyl malonate dexbornyl alcohol ester (target compound 4)
The same method as the reference target compound 2 is used for synthesizing white powder by taking single-right camphol malonate and isopropanol as raw materials. 1 H NMR(400MHz,Chloroform-d)δ4.96-4.92(m,2H),3.44(s,2H),2.41–2.31(m,1H),1.87(d,1H),1.80–1.66(m,2H),1.36–1.18(m,8H)，1.02(d,1H),0.89(s,3H),0.86(s,3H),0.83(s,3H).
5) Synthesis of 3- (2-N, N-dimethylethyl) malonate dexbornyl alcohol ester (target compound 5)
The same method as the reference target compound 2 is used for synthesizing white powder by taking mono-right-borneol malonate and N, N-dimethylethanolamine as raw materials. 1 H NMR(400MHz,Chloroform-d)1H NMR(400MHz,Chloroform-d)δ4.97(d,1H),4.46(t,2H),4.35(s,3H),3.52-3.43(m,4H),2.82(s,6H),2.42–2.31(m,1H),1.88(d,1H),1.79–1.65(m,2H),1.34–1.16(m,2H),1.03(d,1H),0.89(s,3H),0.86(s,3H),0.83(s,3H).
6) Synthesis of 1, 1-Dicarboxylic acid mono-right-camphene ester cyclopropane (target Compound 6)
The same procedure was followed for the synthesis of the target compound 1, starting from 6, 6-dimethyl-5, 7-dioxaspiro 2.5 octane-4, 8-dione and dextroamphenol as white powders. 1 H NMR(400MHz,DMSO-d6)δ4.78(d,1H),2.26–2.16(m,1H),1.85(dd,1H),1.65(d,2H),1.31–1.10(m,6H),0.91(d,1H),0.81(d,6H),0.75(s,3H).
7) Synthesis of methyl 1, 1-diformate, dexcamphol ester cyclopropane (target compound 7)
The same procedure as for the reference compound 2 was repeated except that 1, 1-dicarboxylic acid mono-right camphene ester cyclopropane and methanol were used as raw materials to synthesize a white powder. 1 H NMR(400MHz,DMSO-d6)δ4.78(d,1H),3.66(s,3H),2.26–2.15(m,1H),1.85(dd,1H),1.65(d,2H),1.31–1.10(m,6H),0.91(d,1H),0.81(d,6H),0.75(s,3H).
8) Synthesis of methyl 1, 1-diformate, dexcamphol ester cyclopropane (target compound 8)
The same procedure as for the reference compound 2 was repeated except that 1, 1-dicarboxylic acid mono-right camphene ester cyclopropane and methanol were used as raw materials to synthesize a white powder. 1 H NMR(400MHz,DMSO-d6)δ4.78(d,1H),4.13(t,2H),2.26–2.15(m,1H),1.85(dd,1H),1.65(d,2H),1.31–1.10(m,8H),0.91(d,1H),0.81(d,6H),0.75(s,3H).
9) Synthesis of serine dexbornyl ester (target Compound 9)
The synthetic route is as follows:
taking outN-Boc-O-benzyl-L-serine(6.00 mmol), borneol (6.60 mmol), DMAP (3.00 mmol), DCC (9.00 mmol) are dissolved in 15mL of dichloromethane, reacted for 12h at 40 ℃, filtered by suction, dried by spinning, and made into sand, PE: EA=10:1 is passed through a column to obtain transparent oily substance (9-1). The oily substance (9-1) was taken and added to a solution of dichloromethane/trifluoroacetic acid=2:1, and reacted for 3 hours, dried by spin, and the trifluoroacetic acid was removed by spin evaporation of the tape with dichloromethane to give a yellow oily substance (9-2). Taking yellow oily matter (9-2), dissolving in dichloromethane, reducing with hydrogen palladium on carbon, reacting for 12h at 40 ℃, after the reaction is completed, carrying out suction filtration, spin-drying the obtained product, namely, dissolving in EA (ethylene oxide) after spin-drying the obtained product, introducing HCl gas, generating precipitate, and carrying out suction filtration to obtain the final product (9). 1 H NMR(400MHz,DMSO-d 6 )δ5.56(q,1H),4.93–4.81(m,1H),4.08(t,1H),3.80(p,2H),2.30–2.18(m,1H),1.89-1.82(m,1H),1.65(d,2H),1.24-1.18(m,2H),1.00(d,1H),0.84(d,3H),0.81(s,3H),0.77(d,3H).
EXAMPLE 2 Effect of target Compounds on GABAA receptors containing different alpha subunits
GABA currents were recorded by electrophysiological whole cells in HEK293 cells recombinantly expressing both α1/β2/γ2 and α2/β3/γ2 GABAARs, selected from 0.01, 0.1, 1, 10, 100, 1000nM concentrations for detection. The results are shown in Table 1, in which GABA currents on GABAARs of the α2/β3/γ2 subtype are significantly increased and α1/β2/γ2 is shown to have good dose dependency and selectivity after administration of the target compounds, and GABAARs of the α1/β2/γ2 subtypeNo change in GABA current was observed. According to the dose-response curve fitted by the computer, emax and EC of GABA of alpha 2/beta 3/gamma 2 type GABAAR are calculated 50 。
As can be seen from table 1: the compound 1 of the invention has good selectivity to GABAA receptor composed of alpha 2 subunit, which suggests good safety. The agonism of the GABAA receptor consisting of the alpha 2 subunit by other compounds of interest was determined in the same way.
TABLE 1 GABA currents Emax and EC for target compounds for the α2/β3/γ2 GABAA receptors 50 (nM)
Emax EC 50 Emax EC 50
Target compound 1 108.6±21.8 1.46±0.003 Target compound 7 / /
Target compound 2 / / Target compound 8 / /
Target compound 3 / / Target Compound 9 107.5±20.7 1.39±0.003
Target compound 4 / / Control Compound 1 / /
Target compound 5 / / Control Compound 2 / /
Target compound 6 106.6±22.3 1.44±0.003 Control Compound 3 / /
As can be seen from table 1: the target compounds 1, 6 and 9 have good agonism on GABAA receptor formed by alpha 2 subunit. The control compound showed no significant agonism. The target compounds 2,3, 4 and 5 are ester derivatives of the target compound 1, and can be metabolized into the target compound 1 in vivo. The target compounds 7 and 8 are ester derivatives of the target compound 6, and can be metabolized into the target compound 6 in vivo.
EXAMPLE 3 protective Effect of target Compounds in rat focal cerebral ischemia reperfusion model
A rat middle cerebral artery occlusion (Middle cerebral artery occlusion, MCAO) cerebral ischemia reperfusion model was prepared using a middle cerebral artery thrombosis method. Pharmacodynamics study: there were 5 groups in total, namely, a model group, an edaravone group (6.0 mg/kg), a compound 1 group (10 mg/kg), a compound 2 group (10 mg/kg), and a compound 3 group (10 mg/kg). The animals of each group were subjected to 1 hour of cerebral ischemia reperfusion and then to 1 hour of tail vein injection administration, and the neurological deficit symptoms were observed 24 hours after cerebral ischemia reperfusion to determine the cerebral infarction area.
3.1 preparation of cerebral ischemia model
A middle cerebral artery occlusion (Middle cerebral artery occlusion, MCAO) cerebral ischemia reperfusion model was prepared using a middle cerebral artery thrombosis method. The animals were anesthetized with gas (isoflurane) by first placing the rats in the induction box of the MSS-3 small animal anesthesia machine for anesthesia, then fixing the supine position of the rats on a rat plate connected with a respiratory mask, sterilizing the skin, cutting the middle of the neck, separating the right common carotid artery, external carotid artery, internal carotid artery, gently dissecting the vagus nerve, ligating and cutting the external carotid artery. The proximal end of the common carotid artery was clamped, an incision was made from the distal end of the ligature of the external carotid artery, an inserted 2438-A5 wire plug (hemispherical on top, 5-6mm coated on the front) was bifurcated through the common carotid artery into the internal carotid artery, and then gently inserted until there was slight resistance (about 20mm from the bifurcation), blocking blood supply to the middle cerebral artery, suturing the neck skin, sterilizing, and placing back in the cage. After 90min of ischemia, the rats were again anesthetized by induction, fixed on the rat plates, the neck skin was cut off, the plugs were found out and gently pulled out, blood was restored for reperfusion, neck skin was sutured, disinfected, and returned to the cages for feeding.
3.2 evaluation of neurological deficit symptoms
The neurological deficit symptoms were evaluated using the modified Bederson 5 assay.
0: when the tail is lifted and suspended, the two forelimbs of the animal extend to the direction of the floor, and no other behavior defects exist
1: when the tail is lifted and suspended, the operation of the animal is manifested as elbow buckling, shoulder internal rotation, elbow abduction and close to the chest wall on the (left) side forelimb
2: placing the animal on a smooth plate, pushing the shoulder of the operation to reduce resistance when moving to the opposite side
3: when the animal freely walks, the animal circulates or turns to the opposite side of the operation
4: flaccid limb paralysis and no spontaneous movement of limbs
3.3 cerebral infarction area determination
The method is carried out by adopting a method reported in literature. Animals were anesthetized with 10% chloral hydrate, the brains were removed by head breaking, the olfactory bulb, cerebellum and low brain stem were removed, the brain surface blood trace was rinsed with normal saline, the surface residual water trace was sucked off, left at-80 ℃ for 7min, immediately after removal, the coronal section was made vertically downward at the line-of-sight intersection plane, and cut into pieces every 2mm backward, the brain pieces were placed in TTC (20 g/L) dye solution freshly prepared with normal saline for incubation at 37 ℃ for 90min, normal brain tissue was stained dark red, ischemic brain tissue was pale, after rinsing with normal saline, the brain pieces were rapidly arranged in order from front to back, the surface residual water trace was sucked dry, and photographed. The photographs were counted using Image analysis software (Image Tool), the right ischemic area (white area) and the right area were delineated, and the percentage of cerebral infarction area was calculated using the following formula.
3.4 statistical analysis
Quantitative data are expressed as mean ± standard error. The cerebral infarction area and the neurological deficit symptom score are measured by single factor analysis of variance, the Scheff's test is used for measuring the difference significance between the two groups, the death rate and the body weight are measured by ANOVA test, stata statistical software is used for analysis, and the difference P <0.05 is defined as the difference significance.
3.5 Effect of the test agent on the symptoms of neurological deficit
The effects of target compound 1, target compound 5, target compound 6, target compound 9, control compound 1 and dexterol on the neurological deficit symptoms are shown in fig. 1, and the effects of target compound 1 (10.0 mg/kg), target compound 5 (10.0 mg/kg), target compound 6 (10.0 mg/kg), target compound 9 (10.0 mg/kg) and dexterol group (1.5 mg/kg) on the neurological deficit symptoms are significantly improved compared with the model group. Control compound 3 (10.0 mg/kg) had no significant improvement.
3.6 Effect of the test substance on cerebral infarction area (%)
The effect of target compound 1, target compound 5, target compound 6, target compound 9, control compound 1, and dexterol on cerebral infarction area (%) is shown in fig. 2, and the effect of target compound 1 (10.0 mg/kg), target compound 5 (10.0 mg/kg), target compound 6 (10.0 mg/kg), target compound 9 (10.0 mg/kg), and dexterol group (1.5 mg/kg) on cerebral infarction area was significantly improved as compared with the model group. Control compound 3 (10.0 mg/kg) had no significant improvement.

Claims (4)

1. The right embedded alcohol ester compound is characterized by comprising the following specific structures:
。
2. the pharmaceutically acceptable salts of dexterol esters of claim 1.
3. Use of the right-embedding alcohol ester compound as claimed in claim 1 or the right-embedding alcohol ester compound as claimed in claim 2 in the preparation of a medicament for treating cerebral stroke injury.
4. A medicament, characterized in that the active ingredient is the dextroisolaricireside compound of claim 1 or the pharmaceutically acceptable salt of the dextroisolaricireside compound of claim 2.
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Application publication date: 20211228

Assignee: Suzhou Nanyi University Innovation Center

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Denomination of invention: Right Kan alcohol ester compounds and their medicinal applications

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Record date: 20240429