CN114181087A - 2, 6-dihydroxy benzoic acid right camphol ester compound and pharmaceutical application thereof - Google Patents

2, 6-dihydroxy benzoic acid right camphol ester compound and pharmaceutical application thereof Download PDF

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CN114181087A
CN114181087A CN202111331218.1A CN202111331218A CN114181087A CN 114181087 A CN114181087 A CN 114181087A CN 202111331218 A CN202111331218 A CN 202111331218A CN 114181087 A CN114181087 A CN 114181087A
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李飞
李伦家
徐楠
陈倩
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Nanjing Yuanju Pharmaceutical Technology Co ltd
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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Abstract

2, 6-dihydroxy benzoic acid right damnacanthol ester compounds, the structure accords with the general formula (I)
Figure DDA0003348934400000011
Wherein: r is-H, -OH, -NR1R2，
Figure DDA0003348934400000012
or-CONR3R4。R1，R2-H, alkyl of 1 to 6 carbon atoms,
Figure DDA0003348934400000013
or-COR5；R3，R4，R5-H, alkyl of 1 to 3 carbon atoms. The medicine has good effects of reducing stroke injury and relieving pain, and can be used for preparing medicines for treating cerebral stroke injury and neuropathic pain.

Description

2, 6-dihydroxy benzoic acid right camphol ester compound and pharmaceutical application thereof
Technical Field
The invention belongs to the field of pharmacy, and provides 2, 6-dihydroxy-benzoic acid right chamaenol ester compounds, pharmaceutically acceptable salts thereof and pharmaceutical application thereof.
Background
Stroke seriously harms human health. (+) -2-Borneol (Borneol) has a clear anti-cerebral-ischemic effect (Journal of biological Research,2017,31: 306-314). (+) 2-anethol selectively agonizes the α 2 GABAA receptor, and has less potential for the development of drowsiness side effects than non-selective GABAA receptors, and is safer. However, (+) 2-anethol has low oral bioavailability and is difficult to dissolve in water, and when the injection is prepared, a large amount of organic solvent is required to be added, so that the difficulty of the drug preparation is increased, and the risk of clinical medication is increased. Thus, there is a clinical need for α 2 GABAA receptor agonists that are more water soluble.
Figure BDA0003348934380000011
Neuropathic Pain (NP) is pain caused by damage or disease to the somatosensory system. Clinical manifestations include touch-induced pain, hyperalgesia and spontaneous pain. NP is one of the most common clinical chronic pains, and most neuropathic pain patients can have pain lasting for months or even years, and are often accompanied by negative emotions such as anxiety, depression and the like, so that the life quality of the patients is seriously influenced. Pregabalin (pregabalin) is a clinically common therapeutic agent for neuropathic pain, but long-term administration can lead to analgesic tolerance. (+) 2-anethol has good analgesic effect, and neuropathic pain needs to be taken for a long time, so that the oral route is more reasonable, but (+) 2-anethol has low oral bioavailability, so that the clinical application of (+) anethol is limited. Thus, there is a clinical need for orally effective α 2 GABAA receptor agonists.
Therefore, the alpha 2 GABAA receptor stimulant with better water solubility or effective oral administration is obtained, and the clinical application value is good.
The literature Theranosics, 2021, 11(12):5970-5985 reports that ZL006-05 and its analogue ZL006-05B have the effect of selectively exciting alpha 2 GABAA receptors, but ZL006-05 and its analogue ZL006-05B have poor water solubility and low oral bioavailability.
Figure BDA0003348934380000021
The invention of China 2021103905049 discloses the pharmaceutical use of a class of aminosalicylic acid (+) -2-borneol esters, the structure of which conforms to the following general formula:
Figure BDA0003348934380000022
the water solubility of the medicine is still poor, and the oral bioavailability is about 20%.
The invention 2021103911232 discloses an alpha 2 GABAA receptor agonist, the structure of which conforms to the following general formula:
Figure BDA0003348934380000023
wherein:
Figure BDA0003348934380000024
-NHCH3、N(CH3)2or
Figure BDA0003348934380000025
R1is-H or-CH3，
Figure BDA0003348934380000026
or-NH2，R3-H or alkyl of 1 to 4 carbon atoms.
The medicine has good water solubility and oral bioavailability of about 20%.
Figure BDA0003348934380000031
Disclosure of Invention
The technical problem to be solved is as follows: provides 2, 6-dihydroxy-benzoic acid right chamaenol ester compounds, pharmaceutically acceptable salts thereof and medicinal application thereof. The medicine has good protection effect on the damage of primary cortical neurons cultured in vitro, and has good effects of reducing stroke damage and easing pain. Can be used for preparing medicine for treating cerebral apoplexy injury and neuropathic pain.
The technical scheme is as follows: a2, 6-dihydroxy benzoic acid right chamaenol ester compound has a structure which accords with a general formula (I):
Figure BDA0003348934380000032
wherein: r is-H, -OH, -NR1R2，
Figure BDA0003348934380000033
or-CONR3R4。R1，R2-H, alkyl of 1 to 6 carbon atoms,
Figure BDA0003348934380000034
or-COR5；R3，R4，R5-H, alkyl of 1 to 3 carbon atoms.
The preferred structure is as shown in any one of structures 1-24 below:
Figure BDA0003348934380000035
Figure BDA0003348934380000041
Figure BDA0003348934380000051
the 2, 6-dihydroxybenzoic acid right champignon ester compounds or pharmaceutically acceptable salts thereof are applied to the preparation of medicines for treating cerebral apoplexy injuries or neuropathic pains.
Has the advantages that: the compound has good protection effect on primary cortical neuron injury cultured in vitro, and has the effects of reducing stroke injury and easing pain. Can be used for preparing medicine for treating cerebral apoplexy injury and neuropathic pain. Meanwhile, it is pointed out that: in an in vitro cell model, the compound provided by the invention has a protective effect strength on primary cortical neuron injury cultured in vitro, which is obviously superior to that of a compound (a control compound 1) disclosed by 2021103905049 in an embodiment of Chinese invention, a compound (a control compound 2) disclosed by 2021103911232 in Chinese invention or an analogue (a control compound 3) with a 2, 4-dihydroxy structure. The experimental results (table 1) suggest that: the 2, 6-dihydroxy structure plays an important role in improving the cytoprotective effect of the compound. In animal models, the efficacy of the compound of the present invention in resisting cerebral stroke injury and neuropathic pain is also significantly better than that of the compound of the embodiment of chinese invention 2021103905049 (control compound 1), the compound disclosed in chinese invention 2021103911232 (control compound 2) or the analog having 2, 4-dihydroxy structure (control compound 3), suggesting that: the 2, 6-dihydroxy structure has an important effect on improving the drug effect. The 2, 6-dihydroxy substitution in the compounds has structural specificity for obtaining better drug effect.
Drawings
FIG. 1 shows the effect of compound 1, compound 3 and edaravone on neurological deficit symptoms;
FIG. 2 shows the effect of target compound 1, control compound 3 and edaravone linalool on cerebral infarction area (%);
FIG. 3 Effect of Compound 2 object, Compound 13 object, Compound 14 object, Compound 16 object on neurological deficit symptoms.
Fig. 4 influence of cerebral infarct size (%) for target compound 2, target compound 13, target compound 14, and target compound 16.
Fig. 5 shows analgesic effects of oral administration of target compound 13(10mg/kg, i.g.), target compound 16(10mg/kg, i.g.), and control compound 3(10mg/kg, i.g.) on neuralgia in rats.
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 2, 6-dihydroxy-benzoic acid right camphanol ester (target compound 1)
The synthetic route is as follows:
Figure BDA0003348934380000061
7.8g (5mmol) of 2, 6-dihydroxybenzoic acid and right camphol (4mmol) were dissolved in 10mL of dichloromethane, DCC (7.5mmol) and DMAP (1mmol) were added, and reacted at 55 ℃ for 6 hours. After the reaction is finished, filtering the filtrate by suction, adding Ethyl Acetate (EA) for dissolving after spin-drying, washing the solution for three times by using 100mL of saturated saline solution, collecting an organic layer, drying the organic layer, and preparing sand by using petroleum ether (PE, 60-90 ℃): passing through a column under the condition that Ethyl Acetate (EA) is 30:1, spinning and pulping the product to obtain white powder.1H NMR(400MHz,DMSO-d6)(ppm):δ7.03(t,1H),6.28(d,2H),5.01-4.07(m,1H),2.34-2.26(m,1H),2.04-1.98(m,1H),1.71-1.63(m,2H),1.22–1.13(m,2H),1.06-1.04(m,1H),0.88(s,3H),0.82(s,6H).
2) Synthesis of 2,4, 6-trihydroxy benzoic acid right camphanol ester (target compound 2)
The same method is used for synthesizing the reference target compound 1 by taking 2,4, 6-trihydroxybenzoic acid and dexamphanol as raw materialsWhite powder.1HNMR(400MHz,DMSO-d6)δ(ppm):5.78(s,2H),4.94(d,1H),2.34-2.28(m,1H),2.09(s,1H),1.68-1.63(m,2H),1.27(d,2H),1.16(t,1H),0.85(s,3H),0.82(s,3H),0.80(s,3H).
1.2 Synthesis of target Compound 3
The synthetic route is as follows:
Figure BDA0003348934380000071
synthesis of 2, 6-dihydroxy-3-nitrobenzoic acid right camphanol ester (3-1)
10mL of acetic anhydride and 2.90g (10.0mmol) of 2, 6-dihydroxy-benzoic acid right camphanol ester (target compound 1) are added into a dry eggplant-shaped bottle, 5mL of mixed solution of acetic anhydride and 0.63g of fuming nitric acid is dropwise added at 0-4 ℃, the reaction is continued for 1 hour after the addition is finished, the mixture is poured into a mixture of 50mL of water and 50g of crushed ice, the mixture is stirred for 1 hour and filtered, and 2.5g of yellow solid (2, 6-dihydroxy-3-nitrobenzoic acid right camphanol ester) is obtained.1H NMR(400MHz,DMSO-d6)δ(ppm):8.00(d,1H),6.54(d,1H),5.04(d,1H),2.33-2.29(m,1H),1.86-1.82(m,1H),1.71–1.60(m,2H),1.25-1.13(m,2H),1.07-1.03(m,1H),0.88(s,3H),0.83(s,6H).
Synthesis of 2, 6-dihydroxy-3-aminobenzoic acid right camphanol ester (3)
1.68g of 2, 6-dihydroxy-3-nitrobenzoic acid (camphanol) (5.0mmol) was added to a dry eggplant-shaped bottle, 50mL of methanol was added to dissolve the mixture, 0.7g of 10% palladium carbon was added to the solution, and the mixture was subjected to hydrogenation reduction and reacted overnight at room temperature. After the thin-layer plate monitoring reaction is completed, a Buchner funnel is used for filtering palladium carbon, the filtrate is concentrated to 10mL, deionized water is slowly dripped until white solid is separated out, and the white solid which is 2, 6-dihydroxy-3-aminobenzoic acid right camphanol ester is obtained by suction filtration.1H NMR(400MHz,DMSO-d6)δ(ppm):6.66(d,1H),6.17(d,1H),5.02(d,1H),2.37-2.29(m,1H),2.07-2.01(m,1H),1.74–1.60(m,2H),1.31-1.02(m,3H),0.88(s,3H),0.83(s,6H).
1.3 Synthesis of target Compounds 4-10
1)2, 6-dihydroxy-3-methylaminobenzoic acid dexamphanol ester (target compound 4)
The synthetic route is as follows:
Figure BDA0003348934380000072
in a dry eggplant-shaped bottle, 1g of 4-aminosalicylic acid bornyl ester (3.46mmol) and 0.62g of paraformaldehyde (6.92mmol) were added, 10mL of methanol was added to completely dissolve the mixture, 0.19g of palladium on carbon (0.346mmol) was added thereto, and the mixture was subjected to hydrogenation reduction and reacted at 25 ℃ for 12 hours. After the thin-layer plate completely reacts, a Buchner funnel filters out palladium carbon, filtrate is dried by spinning, and the obtained product is subjected to sand column chromatography to obtain 0.81g of white solid which is the p-methylamino salicylic acid borneol ester (the target compound 6).1H NMR(400MHz,DMSO-d6)δ(ppm):6.64(d,1H),6.08(d,1H),5.03(d,1H),2.85(s,3H),2.36-2.28(m,1H),2.06-2.00(m,1H),1.73–1.60(m,2H),1.30-1.01(m,3H),0.89(s,3H),0.83(s,6H).
2)2, 6-dihydroxy-3-dimethylaminobenzoic acid Right camphanol ester (target compound 5)
Referring to the synthesis method of the target compound 4, the temperature of the hydrogenation reduction reaction was changed to 60 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.02(d,1H),3.01(s,6H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,2H),1.31-1.01(m,3H),0.89(s,3H),0.83(s,6H).
3)2, 6-dihydroxy-3-ethylaminobenzoic acid Right camphanol ester (target compound 6)
Referring to the synthesis method of a target compound 4, 4-amino salicylic acid borneol ester and acetaldehyde are taken as raw materials for synthesis.1H NMR(400MHz,DMSO-d6)δ(ppm):6.70(d,1H),6.19(d,1H),5.03(d,1H),3.50-3.42(m,2H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,2H),1.31-1.01(m,6H),0.89(s,3H),0.83(s,6H).
4)2, 6-dihydroxy-3-isopropylaminobenzoic acid Right camphanol ester (target compound 7)
Referring to the synthesis method of the target compound 4, the synthesis method takes 4-amino salicylic acid borneol ester and acetone as raw materials.1H NMR(400MHz,DMSO-d6)δ(ppm):6.68(d,1H),6.17(d,1H),5.02(d,1H),3.99-3.92(m,1H),2.36-2.28(m,1H),2.08-2.00(m,1H),1.75–1.60(m,2H),1.31-1.01(m,9H),0.89(m,3H),0.83(m,6H).
5)2, 6-dihydroxy-3-isobutylaminobenzoic acid right camphanol ester (target compound 8)
Referring to the synthesis method of a target compound 4, 4-amino salicylic acid borneol ester and butanone are taken as raw materials for synthesis.1H NMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.03(d,1H),2.82-2.77(m,1H),2.37-2.29(m,1H),2.08-2.01(m,1H),1.75–1.55(m,4H),1.31-1.01(m,6H),0.91-0.89(m,6H),0.83(s,6H).
6)2, 6-dihydroxy-3-cyclopentylaminobenzoic acid Right camphanol ester (target compound 9)
Referring to the synthesis method of the target compound 4, the synthesis method takes 4-amino salicylic acid borneol ester and cyclopentanone as raw materials.1H NMR(400MHz,DMSO-d6)δ(ppm):6.68(d,1H),6.17(d,1H),5.02(d,1H),2.65-2.61(m,1H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.87–1.53(m,8H),1.49-1.41(m,2H),1.31-1.01(m,3H),0.89(s,3H),0.83(s,6H).
7)2, 6-dihydroxy-3-cyclohexylaminobenzoic acid Right camphanol ester (target compound 10)
Referring to the synthesis method of the target compound 4, 4-amino-salicylic acid borneol ester and cyclohexanone are used as raw materials for synthesis.1H NMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.02(d,1H),2.59-2.56(m,1H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,4H),1.51–1.45(m,4H),1.31-1.01(m,7H),0.89(s,3H),0.83(s,6H).
1.4 Synthesis of target Compound 11
Synthetic route of target compound 11:
Figure BDA0003348934380000091
20mL of acetic anhydride, 5.32g (20.0mmol) of 3, 5-di-tert-butyl-2, 6-dihydroxybenzoic acid (11-1, refer to the chemical world, 1987(08):10-12 synthesis) were added to a dry eggplant-shaped bottle, 5mL of a mixed solution of acetic anhydride and 1.26g of fuming nitric acid was added dropwise at 0-4 ℃, the reaction was continued for 1 hour after the addition, 100mL of a mixture of water and 50g of crushed ice was poured, stirring was carried out for 1 hour, and filtration was carried out to obtain 5.50g of 4-nitro-3, 5-di-tert-butyl-2, 6-dihydroxybenzoic acid (11-2).
To a dried eggplant-shaped bottle was added 3.11g of 4-nitro-3, 5-di-tert-butyl-2, 6-dihydroxybenzoic acid (11-2), 25mL of toluene and 3.25g of nitromethane, and 7.5g of aluminum trichloride was added in portions at 10 to 20 ℃ with stirring, and after the addition, stirring was continued at 25 ℃ for 5 hours, and then 100mL of water was added. 30mL of concentrated hydrochloric acid was added to the aqueous phase, and 100mL of methylisobutylketone was used to remove the solvent by evaporation to obtain 2.0g of crude 4-nitro-2, 6-dihydroxybenzoic acid.
1.0g (5mmol) of 4-nitro-2, 6-dihydroxybenzoic acid and 4mmol of dexbornyl alcohol were dissolved in 10mL of dichloromethane, and DCC (7.5mmol) and DMAP (1mmol) were added to react at 55 ℃ for 6 hours. After the reaction is finished, filtering the filtrate by suction, adding Ethyl Acetate (EA) for dissolving after spin-drying, washing the solution for three times by using 100mL of saturated saline solution, collecting an organic layer, drying the organic layer, and preparing sand by using petroleum ether (PE, 60-90 ℃): ethyl Acetate (EA) ═ 30:1, passing through a column, spin-drying a product, and pulping to obtain white powder. Is 4-nitro-2, 6-dihydroxybenzoic acid camphanol ester (1.0g, 11-4).
0.8g of 4-nitro-2, 6-dihydroxybenzoic acid right camphanol (11-4) is added into a dry eggplant-shaped bottle, 50mL of methanol is added for dissolving, 0.2g of 10% palladium carbon is added, hydrogenation reduction is carried out, and the reaction is carried out at room temperature overnight. After the thin-layer plate monitoring reaction is completed, a Buchner funnel is used for filtering out palladium carbon, the filtrate is concentrated to 10mL, deionized water is slowly dripped until white solid is separated out, and 0.6g of white solid which is 4-amino-2, 6-dihydroxy benzoic acid right camphanol ester (target compound 11) is obtained by suction filtration.1H NMR(400MHz,DMSO-d6)δ(ppm):6.98(t,1H),6.23(d,2H),5.02-4.07(m,1H),2.34-2.25(m,1H),2.04-1.96(m,1H),1.71-1.62(m,2H),1.23–1.13(m,2H),1.07-1.04(m,1H),0.88(s,3H),0.83(s,6H).
1.5 Synthesis of target Compounds 12-13
1) Synthesis of 2, 6-dihydroxy-4-dimethylaminobenzoic acid Right camphanol ester (target compound 12): referring to the synthesis method of the target compound 5, the synthesis method takes 2, 6-dihydroxy-4-aminobenzoic acid right camphanol ester (the target compound 11) and paraformaldehyde as raw materials.1H NMR(400MHz,DMSO-d6)δ7.04(ppm):(t,1H),6.28(d,2H),5.00-4.07(m,1H),3.01(s,6H),2.33-2.25(m,1H),2.05-1.96(m,1H),1.70-1.62(m,2H),1.22–1.13(m,2H),1.06-1.04(m,1H),0.88(s,3H),0.83(s,6H).
2) Synthesizing 2, 6-dihydroxy-4- (2-hydroxy-3, 5-dichloro) benzyl aminobenzoic acid (target compound 13):
the synthetic route is as follows:
Figure BDA0003348934380000101
mixing 3.0g (10mmol) of 4-amino-2, 6-dihydroxy-benzoic acid right camphanol ester with 10mL of ethanol solution of 3, 5-dichlorosalicylaldehyde with 1.9g (10mmol) of 10mL of ethanol solution, stirring at room temperature for 2 hours, filtering to obtain imine (13-1), suspending the imine in 20mL of methanol solution, adding sodium borohydride in batches at 0-4 ℃ until the solution fades, adding 10mL of water, adjusting to neutral with hydrochloric acid, and continuously adding 20mL of water. Filtering to obtain white powder. Is 2, 6-dihydroxy-4- (2-hydroxy-3, 5-dichloro) benzyl aminobenzoic acid, camphanol ester (target compound 13).1H NMR(400MHz,DMSO-d6)7.38(s,1H),7.14(s,1H),5.94(d,1H),5.78(s,2H),4.98(d,1H),4.31(s,2H),0.85-2.05(m,16H)。
1.6 Synthesis of target Compound 14:
Figure BDA0003348934380000102
cooling 6.2mL of 16 wt.% (mass concentration) hydrochloric acid solution to 0-5 ℃ by using an ice water bath, then adding 2.9g of 2, 6-dihydroxy-4-aminobenzoic acid right camphanol ester (target compound 11) while keeping stirring, dropwise adding a solution prepared from 0.7g of sodium nitrite and 1.2mL of water after the addition is finished, keeping the temperature at 8-10 ℃, and keeping the temperature and stirring for 30min after the dropwise addition is finished to obtain a diazotization product; and (3) dropwise adding the diazotization product into 5.0mL of 8M sodium bisulfite solution at the temperature of 80-85 ℃, and after dropwise adding, keeping the temperature and stirring for 30 min. Then, 25mL of 30 wt.% hydrochloric acid solution was added dropwise to obtain intermediate 14-1 hydrochloride; and (3) cooling the reaction liquid to room temperature, adjusting the pH value to 6 by using ammonia water, dropwise adding 1.3g of ethyl acetoacetate while keeping stirring, heating to 95 ℃ after dropwise adding, carrying out reflux stirring reaction for 3 hours, stopping heating, cooling, and carrying out suction filtration to obtain the target compound 3.1H NMR(400MHz,Chloroform-d)δ6.93(s,2H),5.92(s,1H),4.80(dt,1H),2.34-30(m,1H),2.28(s,3H),1.86-1.80(m,1H),1.75-1.70(m,1H),1.68-1.66(m,1H),1.32–1.17(m,2H),1.01(dd,1H),0.85(s,3H),0.81(s,6H).
1.7 Synthesis of target Compounds 15-20
Synthetic route to target compound 15:
Figure BDA0003348934380000111
synthesis of target Compound 16 referring to the method for synthesizing the target Compound 15, a white solid was synthesized from 2, 6-dihydroxy-3-aminobenzoic acid, Right camphanol ester (target Compound 3) and acetyl chloride.1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05(dd,2H),0.88(s,3H),0.83(s,6H).
Synthesis of target Compound 17 referring to the method for synthesizing target Compound 15, 2, 6-dihydroxy-3-aminobenzoic acid Right camphanol ester (target Compound 3) and propionyl chloride are used as raw materials to synthesize a white solid.1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.45-2.42(m,2H),2.33-2.30(m,1H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05-1.01(m,5H),0.88(s,3H),0.83(s,6H).
Synthesis of target Compound 18 referring to the method for synthesizing target Compound 15, a white solid was synthesized from 2, 6-dihydroxy-3-aminobenzoic acid, Right camphanol ester (target Compound 3) and butyryl chloride.1H NMR(400MHz,DMSO-d6)δ(ppm):7.10(d,1H),6.31(d,1H),5.00(d,1H),2.41-2.38(m,2H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.79–1.75(m,1H),1.65(q,2H),1.26–1.09(m,2H),1.05(dd,2H),0.90-0.88(m,6H),0.83(s,6H).
Synthesis of target Compound 19 referring to the method for synthesizing target Compound 15, 2, 6-dihydroxy-3-methylaminobenzoic acid Right camphanol ester (target Compound 4) and acetyl chloride are used as raw materials to synthesize white solid.1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05(dd,2H),0.88(s,3H),0.83(s,6H).
Synthesis of target Compound 20 referring to the method for synthesizing target Compound 15, a white solid was synthesized from 2, 6-dihydroxy-4-aminobenzoic acid, Right camphanol ester (target Compound 11) and acetyl chloride.1H NMR(400MHz,DMSO-d6)δ(ppm):6.97(t,1H),6.22(d,2H),5.02-4.08(m,1H),2.34-2.24(m,1H),2.04-1.96(m,4H),1.71-1.62(m,2H),1.23–1.13(m,2H),1.07-1.04(m,1H),0.88(s,3H),0.83(s,6H).
1.8 Synthesis of target Compounds 21-24
Synthesis of target compound 21:
the synthetic route is as follows:
Figure BDA0003348934380000121
10.6g (50mmol, prepared by reference to 2014: 627. sub. 631 university of Zhejiang industries) of 2, 6-dihydroxy-4-methyl benzoic acid and 6.6g (40mmol) of dexborneol are dissolved in 30mL of dichloromethane, DCC (75mmol), DMAP (10mmol) are added, and the mixture reacts at 55 ℃ for 6 hours. After the reaction is finished, filtering the filtrate by suction, adding 30mL of Ethyl Acetate (EA) for dissolving after spin-drying, washing the filtrate three times by using 100mL of saturated saline solution, mixing an organic layer with 100mL of ammonia water solution, stirring for 24 hours, extracting the mixture in 30mL of dichloromethane three times, drying the organic layer, preparing sand, and adding petroleum ether (PE, 60-90 ℃, and the like): passing through a column under the condition that Ethyl Acetate (EA) is 30:1, spinning and pulping the product to obtain white powder. Is 2, 6-dihydroxy-4-formamidobenzoic acid, right camphanol ester (target compound 21).1H NMR(400MHz,DMSO-d6)δ(ppm):7.15(s,2H),4.95(d,1H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.64(m,2H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
Synthesis of target Compound 22 referring to the method for synthesizing the target Compound 21, 2, 6-dihydroxy-4-methyl benzoic acid and dimethylamine are used as raw materials to synthesize a white solid.1H NMR(400MHz,DMSO-d6)δ(ppm):7.16(s,2H),4.95(d,1H),2.93(s,6H),2.36-2.28(m,1H),2.11(s,1H),1.68-1.64(m,2H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
Synthesis of target Compound 22 reference target Compound 21 Synthesis methodThe compound is synthesized by taking 2, 6-dihydroxy-4-methyl benzoic acid and diethylamine as raw materials, and is a white solid.1H NMR(400MHz,DMSO-d6)δ(ppm):7.14(s,2H),4.94(d,1H),3.99(t,4H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.63(m,2H),1.35(q,4H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
Synthesis of target Compound 22 referring to the method for synthesizing target Compound 21, 2, 6-dihydroxy-4-methyl benzoic acid and isopropylamine are used as raw materials to synthesize a white solid.1H NMR(400MHz,DMSO-d6)δ(ppm):7.13(s,2H),4.93(d,1H),4.17-4.15(m,1H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.64(m,2H),1.28-1.24(d,8H),1.15(t,1H),0.88(s,3H),0.83(s,6H).
EXAMPLE 2 protective Effect of target Compounds on Primary cortical neuronal damage cultured in vitro
2.1 Primary neuronal culture
And (3) killing pregnant mice with gestational age of 16d by dislocation of cervical vertebrae, taking the pregnant mice, placing the pregnant mice on an ice box, sequentially sterilizing the whole body by using a benzalkonium bromide solution and a 75% ethanol solution, and then sterilizing the head skin by using iodophor. Carefully taking out bilateral cortex, placing in pre-cooled D-Hank's solution (10mL), washing, peeling off meninges, washing twice with D-Hank's solution, sucking to dry D-Hank's, shearing cortex tissues, transferring to preheated 0.125% pancreatin digestive juice (4mL) at 37 ℃, digesting for 8min at 37 ℃, taking out, adding 5mL of DMEM/F12+ 10% FBS to stop digestion, and gently blowing and beating dispersed tissues. Centrifuging at 2500rpm for 3 min, discarding supernatant, adding Neralbasal culture medium containing 2% B27, mixing, filtering with 400 mesh sieve, counting cells, and counting cells by 1 × 105Per cm2Inoculating in PORN-coated 24-well plate, placing at 37 deg.C, 95% air + 5% CO2The mixed humid gas of (1) is cultured in an incubator. Half of the medium was changed on days 1 and 4 of cell culture.
2.2 glutamic acid moulding
Glu and Gly modeling was performed on the 8 th day of in vitro neuron culture to test the protective effect of the drug on the injury. The tested drugs are set to have three concentrations of 0.1 mu mol/L, 1 mu mol/L and 10 mu mol/L (1000 Xmother solution prepared by DMSO and diluted by culture medium), and are pre-incubated for 30 min; normal and model controls were supplemented with equal concentrations of DMSO (0.1%) were incubated. After the incubation is finished, the culture medium containing Glu (final concentration of 10 mu mol/L) and Gly (final concentration of 50 mu mol/L) is replaced for incubation for 30min for the model control group and the tested drug group, and the model is made by simulating the ischemia injury; the normal control was incubated with medium changed without Glu and Gly. After the molding is finished, the culture medium in the 24-well plate is discarded, 300 mu L of new culture medium is added into each well, and leaked LDH is collected. After 6 hours, 300. mu.L of medium (i.e., extracellular fluid) was recovered, and 300. mu.L of ddH was added to each well2O, placing in a refrigerator with the temperature of-80 ℃, repeatedly freezing and thawing for 3 times, and recovering 300 mu L ddH2O (i.e. intracellular fluid). The collected intracellular and extracellular fluids are stored at-80 ℃ and are to be detected.
2.3 LDH assay
The cells were frozen and thawed on ice, and absorbance was measured using an LDH kit (Nanjing Panthenium A020-2-2) according to the instructions. The OD values of the intracellular and extracellular fluids were measured as OD values — control OD values, and the LDH leakage rate was extracellular fluid OD value/(extracellular fluid OD value + intracellular fluid OD value).
The cell protection rate is (model group LDH leakage rate-sample group LDH leakage rate)/(model group LDH leakage rate-normal group LDH leakage rate): 100%
TABLE 1 neuronal cell protection against glutamate injury by the target Compounds
Figure BDA0003348934380000131
Figure BDA0003348934380000141
As can be seen from table 1: the target compound has good protection effect on glutamic acid-damaged neuron cells, has better dose-effect relationship, has the drug effect remarkably superior to that of a control compound, has better neuroprotective effect at lower concentration but has higher concentration (10)-6mol/L、10-5mol/L), its neuroprotective effect is weakened.
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 BDA0003348934380000151
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 influence of the target compound 1, the control compound 3 and the edaravone dexanediol on the symptoms of the neurological deficit is shown in figure 1, and compared with the model group, the edaravone dexanediol (6.0mg/kg +1.5mg/kg), the target compound 1 group (10.0mg/kg) and the control compound 3 group (10.0mg/kg) have a remarkable improvement effect on the symptoms of the neurological deficit. The target compound 1 group is obviously better than the control compound 3 group, and is equivalent to edaravone right mosaic alcohol.
3.6 Effect of test substance on cerebral infarct size%
The influence of the target compound 1, the control compound 3 and the edaravone right chamaenol on the cerebral infarction area (%) is shown in fig. 2, namely the edaravone right chamaenol (6.0mg/kg +1.5mg/kg), the target compound 1 group (10.0mg/kg) and the control compound 3 group (10.0mg/kg) have obvious improvement effect on the cerebral infarction area compared with the model group. The target compound 1 group is obviously better than the control compound 3 group, and is equivalent to edaravone right mosaic alcohol.
The protective effects of Compound 2 of interest (10.0mg/kg), Compound 13 of interest (10.0mg/kg), Compound 14 of interest (10.0mg/kg) and Compound 16 of interest (10.0mg/kg) in ischemia-reperfusion were determined in the same manner using the MCAO model for 2 hours. The effect on the symptoms of neurological deficit is shown in fig. 3, and the effect on the cerebral infarct size (%) is shown in fig. 4.
EXAMPLE 4 oral analgesic Effect of the object Compound
4.1 method for preparing model of neuropathic pain
A neuropathic pain model was prepared using the Spinal Nerve Ligation (SNL). 2% chloral hydrate (0.2mL/10g) was injected intraperitoneally to anaesthetize the mice, and after the righting reflex disappeared, the mice were fixed in the prone position. A Kim and Chung method is adopted to make a model: blunt dissection of a median skin incision approximately 3-5cm long from the L4-S2 level in the back of the rat, dissection of the paravertebral muscles to the sixth lumbar spinous process, exposure and resection of the exposed and excised right L5/L6 articular processes, partial biting of the L6 transverse process, thereby enabling exposure of the right L4-L6 spinal nerve, gentle dissection of the L5 nerve, and tight ligation of L5 with 5-0 silk. Then the incision is sutured layer by layer, the skin is sterilized at V, and the breeding is continued. The postoperative animal has abnormal gait, and the postoperative hind limb has no other malformation changes except mild eversion and toe tightening. A similar method was used to prepare the rat SNL model.
4.2 behavioural assays
Rats were assessed for mechanical Paw Withdrawal Thresholds (PWT) using von frey filaments to assess mechanical nociception in mice, respectively. All groups of mice had basal pain thresholds determined two days prior to surgery. The administration groups were tested for PWT and PWL before and 1, 2,4,6, 8, 10, 12, and 24h after administration, respectively. The basal pain threshold in rats was determined by a similar method.
4.3 method for measuring the mechanical paw reaction threshold (PWT)
The 50% withdrawal threshold was calculated using von frey filaments. The 50% of the foot-contracting threshold is measured by the method of up-and-down, the contact stimulation is used in the experiment to measure the 50% of the foot-contracting threshold of the mouse hind foot, wherein the mechanical strength can cause 50% of the foot-contracting reaction by multiple times of mechanical stimulation. Hind limb plantar midsection was stimulated with 0.02, 0/04, 0.07,0.16,0.4,0.6,1.0,1.4, and 2.0g of force in sequence. An organic glass box (45cm by 5cm by 11cm) is placed on a metal screen, after the mouse adapts to the organic glass box for 30 minutes, the middle part of the plantar of the hind limb of the rat is vertically stimulated by von frey cellosilk for a duration of less than 4s, and the mouse is regarded as positive reaction when the foot is lifted or licked, otherwise, the mouse is regarded as negative reaction. Starting to use the force of 0.4 for stimulation, and selecting a force of 0.6 on the hind toe for stimulation if the hind toe does not respond to the foot contraction; if the foot contraction reaction exists, selecting the next force with the force of 0.16 for stimulation, and repeating the stimulation for 4 times in sequence when a reaction different from the previous reaction (from the foot contraction reaction to the foot non-contraction reaction or from the foot non-contraction reaction to the foot contraction reaction) occurs, and finishing the determination of the 50% foot contraction threshold value for 6 times in total. If the force required to be applied exceeds 2.0 or is below 0.02, the side threshold is directly noted as 2.0 or 0.02, with 30s per stimulation interval.
In the experiment, the consistent measurement methods such as force direction, force application speed and fiber yarn bending degree, force maintaining stability, force removing speed and the like are kept as much as possible. In addition, the criteria for determining the response to mice were as consistent as possible.
The 50% foot reduction threshold is calculated using the formula: the 50% withdrawal threshold is 10log (X) + k delta (X is the force used by the last stimulus; k is the coefficient for the different stimulus modalities, looked up in a coefficient table; delta is the average of the adjacent spacing of the stimulus forces, where delta is 0.224)
4.4 analgesic Effect of the target Compounds on neuropathic pain in rats
The analgesic effect of target compound 13(10mg/kg, i.g.), target compound 16(10mg/kg, i.g.), control compound 3(10mg/kg, i.g.) on rat neuralgia is shown in fig. 5. The target compound has obvious analgesic effect on neuropathic pain, and the drug effect of the target compound is obviously superior to that of a control compound 3.

Claims (5)

1.2, 6-dihydroxy benzoic acid right down methanol ester compound, the structure conforms to the general formula (I)
Figure FDA0003348934370000011
Wherein: r is-H, -OH, -NR1R2，
Figure FDA0003348934370000012
or-CONR3R4；R1，R2-H or alkyl of 1 to 6 carbon atoms,
Figure FDA0003348934370000013
or-COR5；R3，R4，R5-H or alkyl of 1 to 3 carbon atoms.
2. The compounds of the 2, 6-dihydroxybenzoic acid right damascenol class of claim 1, characterized in that said structure is any of the following:
Figure FDA0003348934370000014
Figure FDA0003348934370000021
3. a pharmaceutically acceptable salt of a compound of the 2, 6-dihydroxybenzoic acid right chamaenol class of claim 1 or 2.
4. The use of the compounds of the right daminolide 2, 6-dihydroxybenzoate class of any of claims 1-3 and their pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of stroke damage or neuropathic pain.
5. A medicament for the treatment of stroke damage or neuropathic pain, characterized in that the active principle comprises a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN117045773A (en) * 2023-09-11 2023-11-14 江苏毫末医药生物科技有限公司 Use of pharmaceutical compositions for the treatment of pain
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

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN117045773A (en) * 2023-09-11 2023-11-14 江苏毫末医药生物科技有限公司 Use of pharmaceutical compositions for the treatment of pain

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