CN113845424A - Right camphol ester compound and pharmaceutical application thereof - Google Patents

Right camphol ester compound and pharmaceutical application thereof Download PDF

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CN113845424A
CN113845424A CN202111199113.5A CN202111199113A CN113845424A CN 113845424 A CN113845424 A CN 113845424A CN 202111199113 A CN202111199113 A CN 202111199113A CN 113845424 A CN113845424 A CN 113845424A
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target compound
compound
ester compound
camphanol
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CN113845424B (en
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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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    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract

The right embedding alcohol ester compound and the medical application thereof have the structure conforming to the general formula (I)
Figure DDA0003304277770000011
Wherein: r1、R2＝‑H、‑NH2Or are linked to each other to form a cyclic structure, R3＝‑COOR4Or CH2OH，R4＝‑H，‑CH2CH2N(CH3)2Or an alkyl group of 1 to 3 carbon atoms. The medicine has good effect of reducing the stroke damage, and can be used for preparing the medicine for treating the stroke damage.

Description

Right camphol ester compound and pharmaceutical application thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to right camphol ester compounds and pharmaceutical application thereof.
Background
Stroke seriously harms human health. Right camphol (Borneol) has a clear effect on anti-cerebral ischemia (Journal of biological Research, 2017, 31: 306-. The dexamphenicol selectively agonizes the alpha 2 GABAA receptor and has less possibility of causing a lethargy side effect compared with a non-selective GABAA receptor, and has good safety. However, the dextral has low oral bioavailability and is difficult to dissolve in water, and when the dextral is prepared into injection, a large amount of organic solvent is required to be added, so that the difficulty of drug delivery preparation is increased, and the risk of clinical medication is increased. The document Theranostics, 2021, 11 (12): 5970-.
Figure BDA0003304277750000011
The invention 2021103905049 in China discloses the medicinal use of a kind of amino salicylic acid right camphanol ester, the structure of which conforms to the following general formula:
Figure BDA0003304277750000012
the medicine also has the function of selectively exciting alpha 2 GABAA receptors, but the water solubility is still poor, and the oral bioavailability is about 20 percent.
The invention CN 2021103911232 discloses an alpha 2 GABAA receptor agonist, the structure of which conforms to the following general formula:
Figure BDA0003304277750000021
wherein:
Figure BDA0003304277750000022
-NHCH3、N(CH3)2or
Figure BDA0003304277750000023
R1is-H or-CH3，
Figure BDA0003304277750000024
or-NH2，R3-H or alkyl of 1 to 4 carbon atoms.
It should be noted that: the compounds of the invention are capable of up-regulating the effects of the GABAA receptor constituted by the α 2 subunit in an in vitro cell model, whereas the control compounds 1, 2, 3 have no similar effect. And (4) prompting: the presence of a hydroxyl structure beta to the carboxyl group plays an important role in maintaining its agonistic action.
Figure BDA0003304277750000025
Control Compound 3
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides a right camphanolide ester compound, pharmaceutically acceptable salts thereof and pharmaceutical application thereof. The medicine has good water solubility or good oral bioavailability, and has good effect of reducing stroke injury. Can be used for preparing medicine for treating cerebral apoplexy injury.
The technical scheme is as follows: a right camphanol ester compound has a structure in accordance with a general formula (I):
Figure BDA0003304277750000026
wherein: r1、R2＝-H、-NH2Or are linked to each other to form a cyclic structure, R3＝-COOR4Or CH2OH，R4＝-H，-CH2CH2N(CH3)2Or an alkyl group of 1 to 3 carbon atoms.
The preferred structure is as shown in any one of structures 1-9 below:
Figure BDA0003304277750000031
the application of the right camphol ester compounds or pharmaceutically acceptable salts thereof in preparing medicines for treating cerebral apoplexy injury.
The medicine for treating cerebral apoplexy injury contains the right campylol ester compound and its pharmaceutically acceptable salt as effective component.
Has the advantages that: the medicine can selectively excite alpha 2 GABAA receptor, has the effect of reducing stroke injury, and can be used for preparing medicines for treating stroke injury.
Drawings
FIG. 1 Effect of target Compound 1, control Compound 2, control Compound 3 on the symptoms of neurological deficit;
FIG. 2 Effect of Compound of interest 3, Compound of interest 5, Compound of interest 6, Compound of interest 9 on neurological deficit symptoms;
FIG. 3 Effect of the object Compound 1, the control Compound 2, and the control Compound 3 on the cerebral infarction area (%);
fig. 4 shows the effect of target compound 3, target compound 5, target compound 6, and target compound 9 on the cerebral infarction area (%).
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 the object Compound
1.1 Synthesis of target Compounds 1, 2
1) Synthesis of Mono-Right camphanol malonate (target compound 1)
The synthetic route is as follows:
Figure BDA0003304277750000041
borneol (5.00mmol) is taken and dissolved in 10mL toluene, and then the cyclopropyl malonate (5.00mmol) is added for reflux reaction for 5 h. After the reaction, toluene was spin-dried, 50mL of ethyl acetate was added, the mixture was washed with saturated brine, and the organic layer was separated, added with anhydrous sodium sulfate and allowed to stand. Preparing sand, and passing through a column by EA: PE (2: 1) to obtain the product.1H 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 ester of malonic acid, right camphanol ester (target compound 2)
The synthetic route is as follows:
Figure BDA0003304277750000042
taking the ester of mono-right camphanol malonate (target compound 1, 2.40g, 1)0.0mmol), dissolved in 40mL of methanol, 1.0mL of thionyl chloride, and reacted under reflux for 5 h. After the reaction is finished, spin-drying. Preparing sand, and passing through a column by EA: PE (2: 1) to obtain the product.1H 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 and right camphanol ester (target compound 3)
Referring to the target compound 2, the compound is synthesized into white powder by taking the glycerol malonate and the ethanol as raw materials.1H 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 ester-camphanol malonate (target compound 4)
Referring to the target compound 2, the compound is synthesized into white powder by taking the raw materials of the mono-right camphanol malonate and the isopropanol.1H 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-ester-camphanol ester (target compound 5)
Referring to the target compound 2, the material is synthesized into white powder by the same method with the raw materials of the malonicacid monotrophanol ester and the N, N-dimethylethanolamine.1H 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-dimethanol-camphanol cyclopropane (target compound 6)
According to the same method as that of the target compound 1, 6-dimethyl-5, 7-dioxaspiro 2.5 octane-4, 8-dione and dexborneol are used as raw materials to synthesize white powder.1H 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 1, 1-dimethyl-phthalate-right-camphanol cyclopropane (target compound 7)
Referring to the target compound 2, the compound is synthesized into white powder by using 1, 1-mono-right camphanol diformate cyclopropane and methanol as raw materials.1H 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 1, 1-dimethyl formate-dexamphanol cyclopropane (target compound 8)
Referring to the target compound 2, the compound is synthesized into white powder by using 1, 1-mono-right camphanol diformate cyclopropane and methanol as raw materials.1H 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 Right camphanol serine (target compound 9)
The synthetic route is as follows:
Figure BDA0003304277750000051
getN-Boc-O-benzyl-L-serine(6.00mmol), borneol (6.60mmol), DMAP (3.00mmol), DCC (9.00mmol), dissolved in 15mL dichloromethane, reacted at 40 ℃ for 12h, filtered by suction, dried by spinning, made into sand, and passed through a column with PE: EA of 10:1 to obtain a transparent oily substance (9-1). Taking the oily substance (9-1), adding dichloromethane-trifluoroacetic acid solution (2: 1), reacting for 3h, spin-drying, and spin-evaporating with dichloromethane to remove trifluoroacetic acid to obtain a yellow oily substance (9-2). Dissolving the yellow oily substance (9-2) in dichloromethane, reducing with hydrogen and palladium on carbon, reacting at 40 ℃ for 12h, performing suction filtration after the reaction is finished, performing spin-drying on the column (dichloro: methanol is 30: 1), dissolving the obtained product in EA, introducing HCl gas to generate a precipitate, and performing suction filtration to obtain the final product (9).1H NMR(400MHz,DMSO-d6)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 the object Compounds on the GABAA receptor containing different alpha subunits
The GABA current is recorded by using electrophysiological whole cells through HEK293 cells of two GABAARs of alpha 1/beta 2/gamma 2 and beta 02/beta 13/gamma 2 which are expressed in a recombination mode, and the concentration of the GABAAR is selected from 0.01, 0.1, 1, 10, 100 and 1000nM for detection. As shown in Table 1, after administration of the objective compound, GABA current was significantly increased on GABAAR of α 2/β 3/γ 2 subtype, α 1/β 2/γ 2 and exhibited good dose-dependence and selectivity, and GABA current was not changed on GABAAR of α 1/β 2/γ 2 subtype. Calculating Emax and EC of GABA of alpha 2/beta 3/gamma 2 type GABAAR according to dose-effect curve fitted by computer50。
As can be seen from table 1: the compound 1 has good selectivity on GABAA receptors formed by alpha 2 subunits, and the good safety is suggested. The agonism of other target compounds on the GABAA receptor composed of α 2 subunit was determined in the same manner.
TABLE 1 GABA currents Emax and EC for the compounds of interest at the α 2/β 3/γ 2 GABAA receptor50(nM)
Emax EC50 Emax EC50
Object 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 compound 1, the target compound 6 and the target compound 9 have good agonistic action on a GABAA receptor formed by alpha 2 subunits. The control compound showed no significant agonism. The target compound 2, the target compound 3, the target compound 4, and the target compound 5 are ester derivatives of the target compound 1, and can be metabolized in vivo to the target compound 1. The target compound 7 and the target compound 8 are ester derivatives of the target compound 6, and can be metabolized in vivo to the target compound 6.
Example 3 protective Effect of the object Compound on the model of rat focal cerebral ischemia reperfusion
A Middle Cerebral Artery Occlusion (MCAO) cerebral ischemia reperfusion model of rats is prepared by a Middle cerebral artery embolization method. Pharmacodynamic study: in total, 5 groups were set, namely a model group, an edaravone group (6.0mg/kg), a compound 1 group (10mg/kg), a compound 2 group (10mg/kg), and a compound 3 group (10 mg/kg). The animals of each group were administered 1 time of cerebral ischemia-reperfusion by tail vein injection 1 hour after cerebral ischemia-reperfusion, and then the neurological deficit symptoms were observed 24 hours after cerebral ischemia-reperfusion, and the cerebral infarction area was measured.
3.1 preparation of cerebral ischemia model
A Middle Cerebral Artery Occlusion (MCAO) cerebral ischemia reperfusion model is prepared by a Middle cerebral artery thrombosis method. Animal is anesthetized with gas (isoflurane), and the method comprises the steps of firstly placing a rat into an induction box of an MSS-3 small animal anesthesia machine for anesthesia, then fixing the rat in a supine position on a rat board connected with a breathing mask, disinfecting skin, incising the center of the neck, separating the right common carotid artery, the external carotid artery and the internal carotid artery, slightly stripping vagus nerve, ligating and cutting the external carotid artery. Clamping the proximal end of the common carotid artery, making an incision from the distal end of the ligature of the external carotid artery, inserting a 2438-A5 thread plug (the top end is hemispherical, the front end is 5-6mm coated with silica gel), entering the internal carotid artery through the bifurcation of the common carotid artery, then slowly inserting until slight resistance exists (about 20mm from the bifurcation), blocking the blood supply of the middle cerebral artery, suturing the skin of the neck, sterilizing, and putting back into a cage. After 90min of ischemia, the rats are induced to be anesthetized again, fixed on a rat board, the skin of the neck is cut open, the cord plug is found to be pulled out slightly, the blood supply is recovered for reperfusion, the skin of the neck is sutured, the rat is disinfected and placed back into a cage for feeding.
3.2 symptom evaluation of neurological deficit
The symptom of neurological deficit was assessed using a modified Bederson 5-score.
0: when the tail is lifted and suspended, the two forelimbs of the animal extend to the direction of the floor without other behavior defects
1: when the tail is lifted and suspended, the operation of the animal shows that the elbow of the left forelimb is flexed, the shoulder is rotated inwards, the elbow is expanded outwards and is tightly attached to the chest wall
2: the animal is placed on a smooth plate, and resistance is reduced when the side shoulder of the pushing operation moves to the opposite side
3: when the animal walks freely, the animal circulates or rotates towards the opposite side of the operation
4: flaccid limbs and trunk without spontaneous movement
3.3 cerebral infarction area measurement
The method is carried out by adopting a method reported in the literature. The animals are anesthetized by 10% chloral hydrate, the head is broken and the brain is taken, the olfactory bulb, cerebellum and lower brainstem are removed, the blood stain on the surface of the brain is washed by normal saline, the residual water stain on the surface is sucked off, the animals are placed at minus 80 ℃ for 7min, the animals are taken out and then are vertically downwards made into coronal section on the cross plane of the sight line immediately, and are cut into slices at intervals of 2mm backwards, the brain slices are placed in TTC (20g/L) dye solution freshly prepared by normal saline for incubation for 90min at 37 ℃, normal brain tissues are dyed into deep red, ischemic brain tissues are pale, the brain slices are quickly arranged from front to back in sequence after being washed by the normal saline, the residual water stain on the surface is sucked off, and the pictures are taken. The photographs were counted by using Image analysis software (Image Tool), and the right ischemic area (white area) and the right area were delineated, and the percentage of the cerebral infarct size was calculated by the following formula.
Figure BDA0003304277750000081
3.4 statistical analysis
Quantitative data are expressed as mean ± sem. The cerebral infarction area and the symptom score of the neurological deficit are measured by adopting one-factor variance analysis and Scheffe's test to determine the difference significance between the two groups, the mortality and the body weight are tested by adopting ANOVA, Stata statistical software is used for analyzing, and the difference P <0.05 is defined as the difference significance.
3.5 Effect of test substances on symptoms of neurological deficit
The effect of the target compound 1, the target compound 5, the target compound 6, the target compound 9, the control compound 1 and the right camphanol on the symptoms of the neurological deficit is shown in figure 1, and the target compound 1(10.0mg/kg), the target compound 5(10.0mg/kg), the target compound 6(10.0mg/kg), the target compound 9(10.0mg/kg) and the right camphanol (1.5mg/kg) have a remarkable improvement effect on the symptoms of the neurological deficit compared with the model group. The control compound 3 group (10.0mg/kg) had no significant improvement.
3.6 Effect of test substance on cerebral infarct size%
The effect of target compound 1, target compound 5, target compound 6, target compound 9, control compound 1 and dexanethol on cerebral infarction area (%) is shown in fig. 2, and target compound 1(10.0mg/kg), target compound 5(10.0mg/kg), target compound 6(10.0mg/kg), target compound 9(10.0mg/kg) and dexanethol (1.5mg/kg) have a significant effect of improving cerebral infarction area compared with the model group. The control compound 3 group (10.0mg/kg) had no significant improvement.

Claims (5)

1. A right camphanol ester compound is characterized in that the structure of the right camphanol ester compound conforms to the general formula (I):
Figure FDA0003304277740000011
wherein: r1、R2＝-H、-NH2Or are linked to each other to form a cyclic structure, R3＝-COOR4Or CH2OH，R4＝-H，-CH2CH2N(CH3)2Or an alkyl group of 1 to 3 carbon atoms.
2. The right campholate compounds of claim 1, wherein the compounds have the specific structure:
Figure FDA0003304277740000012
3. a pharmaceutically acceptable salt of a retinoid as claimed in claim 2.
4. The use of the compounds of the right campholesterone class of any of claims 1 to 3 and the pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of stroke injuries.
5. A medicament for treating stroke injury, characterized in that the effective component is the embelia alcohol ester compound as claimed in any one of claims 1 to 3 and pharmaceutically acceptable salts thereof.
CN202111199113.5A 2021-10-14 2021-10-14 Right-embedding alcohol ester compound and its pharmaceutical use Active CN113845424B (en)

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CN116407529A (en) * 2023-03-24 2023-07-11 南京医科大学 Pharmaceutical use of esters of 3-nitro-2, 6-dihydroxybenzoic acid right-hand or fenchyl alcohol
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CN116407529A (en) * 2023-03-24 2023-07-11 南京医科大学 Pharmaceutical use of esters of 3-nitro-2, 6-dihydroxybenzoic acid right-hand or fenchyl alcohol
CN116407529B (en) * 2023-03-24 2024-05-10 南京医科大学 Pharmaceutical use of esters of 3-nitro-2, 6-dihydroxybenzoic acid right-hand or fenchyl alcohol

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