Water-soluble bornyl ester compound and application thereof

Abstract

The invention discloses a water-soluble bornyl ester compound and application thereof, the structure of the water-soluble bornyl ester compound is as shown in general formula I, R is acetic acid 2-oxoethyl ester of organic heterocyclic ring, amino acid 2-oxoethyl ester, glycolate of amino acid, acetal of monodisperse polyethylene glycol chain, carbonate, ester or glycosyl; the compound is good in water solubility, the problems that borneol is difficult to dissolve in water and difficult to prepare can be well solved, and in an inflammatory depression animal model, the bornyl ester compound shows good anti-inflammatory, anti-depression and cerebral apoplexy treatment effects and has great application prospects.

Description

Technical Field

[0001] The present invention relates to a water-soluble borneol ester compound and also relates to application of the compound in preparing drugs for inflammatory depression and stroke. Background Art

[0002] Borneol, also known as borneol, 2-borneol, and borneol, has a wide range of pharmacological effects and potential therapeutic value in many diseases. Inflammatory depression is a subtype of depression, and its pathogenesis is closely related to chronic low-grade inflammation. Studies have shown that proinflammatory cytokines (such as IL-6, TNF-α, and IL-1β) can induce depressive-like behaviors by affecting neurotransmitter metabolism, neuroplasticity, and hypothalamic-pituitary-adrenal (HPA) axis function. Borneol can inhibit LPS- or stress-induced microglial hyperactivation, inhibit the production of NLRP3 inflammasomes and the activation of the NF-κB signaling pathway (Int Immunopharmacol, 2022, 113, 109315), reduce the release of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and promote the expression of anti-inflammatory cytokines (IL-10).

[0003] In recent years, studies have found that borneol can improve depressive symptoms by regulating neuroinflammation, protecting the blood-brain barrier (BBB), and regulating neurotransmitters, making it a potential antidepressant drug (Oxid. Med. Cell. Longevity, 2022, 2022: 9354555). Borneol has potential molecular targets in the brain, including GABA. A , TRPM8, TRPA1 and TRPV3 receptors, which generally have analgesic, antibacterial and protective effects against cerebral ischemia, fear or depression (Acta Pharmacol Sin, 2023, 44: 1600–1611; Biochem. Biophys. Res. Commun, 2018, 495(2): 1588–1593). In the ischemia-reperfusion model, borneol has a neuroprotective effect, can reduce infarct size, and significantly improve the neurobehavioral scores of rats (J Pharm Pharmacol, 2021, 73, 272-280; Front Pharmacol, 2021, 12: 606682; J Pharm Pharmacol, 2022, 74(2): 236-249; Int J Nanomedicine, 2020, 15: 5977-5989).

[0004] In July 2020, Xiansheng Pharmaceutical's concentrated solution of idarucizumab and dexamethasone for injection, "Xinbixin," was approved for marketing, confirming the application of borneol in the treatment of stroke (Stroke, 2021; 52:772–780). Borneol itself has a neuroprotective effect in stroke models, and combined with idarucizumab, it has a synergistic neuroprotective effect (J Biomed Res, 2017, 31(4):306-314; Eur J Pharmacol, 2014, 740:522–531). Based on the neuroprotective anti-stroke effect of borneol alone, borneol injection SPT-07A has completed a phase I clinical trial (Eur J Clin Pharmacol, 2020, 76:785–793). Borneol is easily soluble in ethanol, chloroform, gasoline, or ether, but almost insoluble in water. Therefore, the application of borneol in medicine faces formulation difficulties. Simcere's "Xianbixin" injection is a concentrated solution of edaravone and borneol. It requires the addition of multiple excipients, resulting in poor patient compliance during injection. Borneol's water insolubility presents significant challenges in its formulation. Increasing the use of cosolvents can increase side effects, necessitating the development of more water-soluble borneol derivatives to improve its clinical application. Summary of the Invention

[0005] Purpose of the invention: The purpose of the present invention is to provide a water-soluble borneol ester compound, and also provide a preparation method of the above-mentioned compound and its application in the preparation of inflammatory depression and stroke drugs.

[0006] Technical solution: The water-soluble borneol ester compound of the present invention has a structure as shown in general formula I:

[0007]

[0008] Wherein, R is 2-oxoethyl acetate, 2-oxoethyl aminoacetate, glycolate of an amino acid, acetal of a monodisperse polyethylene glycol chain, carbonate, ester or sugar group of an organic heterocyclic ring.

[0009] The organic heterocycle is morpholine, furan, thiophene, pyrrole, imidazole, thiazole, pyrazole, pyridine, pyrimidine, pyrazine, indole or quinoline; preferably morpholine, piperazine, piperidine, pyrrole or pyridine.

[0010] The amino group is N-methylethylamine, ethylamine, 2-propylamine, propylamine, N-methylpropylamine, trimethylamine, butylamine, N-methylbutylamine or 3-butylamine; preferably N-methylethylamine, trimethylamine, 2-propylamine or ethylamine.

[0011] The amino acid is glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid or glutamic acid; preferably glycine or alanine.

[0012] The monodisperse polyethylene glycol chain is polyethylene glycol methyl ether M-PEG with 2-10 ethylene glycol units, preferably M-PEG with 7 ethylene glycol units, in the form of acetal, carbonate or ester.

[0013] The saccharide group is glucose, mannose, galactose, allose, altrose, gulose, idose, talose, ribose, xylose, arabinose or lyxose; preferably glucose.

[0014] Specifically, R is

[0015] R1 is

[0016] R2 is

[0017] R3 is

[0018] The structure of the above compound is as follows:

[0019]

[0020] The compound includes pharmaceutically acceptable salts thereof, including hydrochloride, trifluoroacetate, and sodium salt.

[0021] The water-soluble borneol ester compounds can also be used in the preparation of drugs for treating inflammatory depression and stroke.

[0022] Among them, the applications include drugs for asthma, hypertension, myocardial hypertrophy, myocardial infarction, heart failure, antiplatelet, atherosclerosis or analgesia caused by inflammatory depression and stroke.

[0023] Principle of the Invention: The water-soluble borneol ester compounds of the present invention can be hydrolyzed by esterases present in the body to rapidly release the active ingredient and exert its pharmacological effects. The good solubility of water-soluble borneol in water eliminates the need for large amounts of cosolvents in the formulation, thereby addressing the side effects caused by cosolvents and poor compliance during injection.

[0024] Specifically, due to the influence of electron defects, the hydroxyl group at the α position of the carboxyl group is theoretically easily attacked by hydrolases and hydrolyzed after forming an ester, and compounds containing glycolate esters hydrolyze faster. The water-soluble borneol compound developed by the present invention utilizes the glycolate prodrug principle. It is catalyzed by potassium carbonate and sodium iodide to connect water-soluble organic heterocyclic groups such as morpholine and piperidine at room temperature to form a carboxylate modification. After the borneol core is connected to glycolic acid, water-soluble amino acid groups alanine and glycine are introduced at the hydroxyl end under the nucleophilic catalysis of 4-dimethylaminopyridine and salted to improve its water solubility.

[0025] Highly efficient monodisperse polyethylene glycol methyl ether (M-PEG) was linked to borneol, and modified with M-PEG having 2-10 ethylene glycol units to form acetal, carbonate, and ester compounds with the hydroxyl groups of borneol, respectively, to obtain a highly water-soluble borneol compound. The prodrug's water solubility was maximized when M-PEG with 7 ethylene glycol units was linked, increasing it by 50-200 times, respectively. Furthermore, the biocleavable bond provided excellent release.

[0026] Glutaric anhydride was used as a carrier to synthesize borneol glutaric acid conjugates. Under alkaline conditions, the hydroxyl group acts as a nucleophilic group to attack the carbonyl carbon, resulting in the anhydride ring opening to form a borneol glutaric acid monoester product to enhance solubility. The water solubility is increased by about 100 times.

[0027] Glucose modification is used to effectively improve water solubility. As a common group that enhances water solubility, 2,3,4,6-O-acetyl-D-pyranose undergoes glycosylation reaction with the hydroxyl group of borneol under the catalysis of trichloroacetonitrile and DBU to synthesize borneol glycosylated prodrug and improve its water solubility.

[0028] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the water-soluble borneol ester compound of the present invention has good water solubility, the compound does not use any cosolvent, and dissolves rapidly in normal saline at room temperature, and the water solubility is increased by about tens to one hundred times, while reducing the use of cosolvents and improving compliance; in addition, the hydrolysis action of esterases present in the body can be utilized to quickly release the original drug to exert pharmacological effects; when applied to the treatment of inflammatory depression and stroke, it can effectively alleviate the depressive-like behavior of mice, inhibit the activation of microglia, reduce neurological dysfunction, etc., and achieve a highly effective therapeutic effect on inflammatory depression and stroke. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is the general structural formula of water-soluble borneol ester compounds;

[0030] Figure 2 is the conversion rate of borneol released from each water-soluble borneol ester compound in SD rat plasma;

[0031] Figure 3 Water-soluble borneol ester compounds alleviate depressive-like behavior in mice. (A) Schematic diagram of the experimental design, (B) Body weight of mice before and after the experiment, (CE) After injection of drugs and LPS, the depressive-like behavior of mice was assessed using the tail suspension test (C), forced swim test (D), and sucrose preference test (E).

[0032] Figure 4 Water-soluble borneol esters inhibit microglial activation in the LPS-induced depression model in mice. (A) Co-staining of microglia with iba-1 (green, microglial marker) and DAPI (blue, nucleus marker) in hippocampal tissues of mice from different groups. Scale bar, 200 μm; (B) Analysis of microglial density; (C-D) Immunofluorescence staining of microglia in the dentate gyrus (DG) (C) and excluding the dentate gyrus (Exclude DG) (D) regions of the hippocampus under different treatment conditions; (E) Analysis of microglial morphology; (FI) Analysis of the number of branch endpoints (F), cell body area (G), total branch length (H), and number of branches (I) of microglia.

[0033] Figure 5 Water-soluble borneol ester compounds reduce the cerebral infarction volume in mice in the MCAO stroke model, including (A) representative images of TTC staining of the mouse brain after MCAO modeling; (B) statistical diagram of the cerebral infarction area in mice; (CD) Longa neurological function score (C) and mNSS score (D) in mice; (E) changes in body weight of mice before and after ischemia. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below with reference to the examples. The test materials used in the examples can all be purchased through conventional channels.

[0035] Example 1

[0036] Synthesis of Borneol Acetyl Chloride (BP-1)

[0037] Natural borneol ((+)-borneol) (10 g, 64.8 mmol) and chloroacetyl chloride (7.32 g, 64.8 mmol) were dissolved in dry DCM. Pyridine (21.4 mL, 162 mmol) was slowly added dropwise at -10°C. The reaction solution was slowly warmed to room temperature and stirred overnight. The pH was adjusted to 2 with 3N HCl, extracted with DCM (50 mL), and the organic layer was washed with saturated brine (50 mL x 3). The organic layer was collected and concentrated under reduced pressure. The product was then chromatographed on a silica gel column using PE as the developing solvent to obtain 12.4 g of BP-1, a colorless, viscous liquid, in an 83% yield. 1H NMR(400MHz, CDCl3)δ:4.95(1H,m),4.05(2H,s),2.44-2.31(1H,m),1.97-1.87(1H,m),1.81-1.71 (1H,m),1.69(1H,dd),1.28(2H,m),1.00(1H,dd),0.89(3H,s),0.86(3H,s),0.83(3H,s).MS(M+H) + :231.1

[0038] Example 2

[0039] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 2-morpholin-4-yl acetate (3a)

[0040] 1-Piperidineacetic acid (2 g, 8.7 mmol), K2CO3 (1.2 g, 8.67 mmol), and NaI (1.29 g, 8.67 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 40 min. BP-1 (2 g, 8.67 mmol) was added and stirred at 70°C for 4 h. EA was used for extraction (100 mL), and H2O (50 mL x 3) was added to remove DMF. The product was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was then purified by silica gel column chromatography (PE:EA = 4:1, R f =0.3) to give 1.4 g of light yellow viscous liquid, yield: 45.9%. 1 H NMR (400MHz, CDCl3) δ4.97-4.89(m,1H),4.63(s,2H),3.27(s,2H),2.60-2.46(m,4H),1.91-1.79(m,1H),1.72(m,1H),1.66 (m,1H),1.64-1.51(m,4H),1.47-1.36(m,2H),1.28-1.11(m,4H),1.03-0.94(m,1H),0.86(s,3H),0.83(s,3H),0.79(s,3H). 13 C NMR (101MHz, CDCl3) δ170.10,167.99,81.36,60.92,60.07,54.30,48.95,47 .94,44.85,36.52,27.99,27.07,25.82,23.86,19.73,18.85,13.49.MS(M+H) + :340.2

[0041] Example 3

[0042] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 2-(4-methylpiperazin-1-yl)acetate (3b)

[0043] 4-Methyl-1-piperazineacetic acid (1.25 g, 8.67 mmol) was used as the starting material. The remaining steps were the same as those for compound 3a. The product was a yellow solid with a yield of 57.61%. 1 H NMR (400MHz, CDCl3) δ5.24 (s, 0H), 4.95 (s, 2H), 4.61 (s, 1H), 3.98 (s, 2H), 3.59 (d, J = 37.5Hz, 2H), 3.08 (d, J = 14.7Hz, 1H), 2.8 9(s,8H),2.80(s,8H),2.27(s,1H),1.81(s,2H),1.19(d,J=33.9Hz,2H),0.90(s,1H),0.82(s,3H),0.80(s,3H),0.76(s,3H). 13 C NMR(101MHz, CDCl3)δ167.16,164.15,82.17,63.87,62.07,55.24,51.60,48.98,47.99,44.76,36.49,27.97,27.03,19.70,18.81,13.54.MS(M+H) + :353.2

[0044] Example 4

[0045] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 2-(piperidin-2-yl)acetate (3c)

[0046] (S)-1-(tert-Butyloxycarbonyl)piperidine-2-carboxylic acid (1.98 g, 8.67 mmol) was used as the starting material. The remaining steps were the same as those for compound 3a. The tert-Butyloxycarbonyl group was removed by stirring in HCl / EA solution to give 1.77 g of a white solid with a yield of 83%. 1H NMR (400MHz, CDCl3) δ4.94(d,J=11.2Hz,1H),4.87(d,J=15.8Hz,1H),4.63(d,J=15.8Hz,1H),4.14(s,1H),3.55(d,J=10.3Hz,1H),3.16(d,J=12.9 Hz,1H),2.32(d,J=10.0Hz,2H),2.18(s,1H),1.96-1.59(m,7H),1.31-1. 16(m,2H),0.99(d,J=13.9Hz,1H),0.86(s,3H),0.83(s,3H),0.79(s,3H). 13 C NMR (101MHz, CDCl3) δ167.90,167.21,81.89,61.88,55.59,48.98,48.00,44 .81,36.52,28.00,27.05,25.55,21.72,20.93,19.74,18.84,13.58.MS(M+H) + :338.2

[0047] Example 5

[0048] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 2-(pyrrolidin-1-yl)acetate (3d)

[0049] 2-(1-pyrrolidinyl)acetic acid (1.68 g, 13 mmol) was used as the starting material. The remaining steps were the same as those for compound 3a. 1 g of a light yellow viscous liquid was obtained. The yield was 22%. 1 H NMR (400MHz, CDCl3) δ4.97-4.91(1H,m),4.65(2H,s),3.44(2H,s),2.66(4H,dd),1.90-1.84(1H,m ),1.84-1.78(4H,m),1.76-1.61(2H,m),1.33-1.13(4H,m),0.86(3H,s),0.84(3H,s),0.80(3H,s). 13 CNMR (101MHz, CDCl3) δ156.23,154.40,85.13,68.79,65.34,63.23,59.17,58.36,55.89,49.22,42.40,41.67,39.09,35.79,35.08,30.80. 13C NMR(101MHz, CDCl3)δ156.23,154.40,85.13,68.79,65.34,63.23,59.17,58.36,55.89,49.22,42.40,41.67,39.09,35.79,35.08,30.80.MS(M+H) + :323.2

[0050] Example 6

[0051] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 2-(piperidin-1-yl)acetate (3e)

[0052] 1-Piperidineacetic acid (2 g, 8.7 mmol) was used as the starting material. The remaining steps were similar to those for compound 3a. 1.4 g of a light yellow viscous liquid was obtained with a yield of 45.9%. 1 H NMR (400MHz, CDCl3) δ4.97-4.89(m,1H),4.63(s,2H),3.27(s,2H),2.60-2.46(m,4H),1.91-1.79(m,1H),1.72(m,1H),1.66( dt,1H),1.64-1.51(m,4H),1.47-1.36(m,2H),1.28-1.11(m,4H),1.03-0.94(m,1H),0.86(s,3H),0.83(s,3H),0.79(s,3H). 13 C NMR (101MHz, CDCl3) δ170.10,167.99,81.36,60.92,60.07,54.30,48.95,47 .94,44.85,36.52,27.99,27.07,25.82,23.86,19.73,18.85,13.49.MS(M+H) + :338.2

[0053] Example 7

[0054] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)ethyl 3-aminobutyrate (3f)

[0055] 3-(Boc-amino)butyric acid (0.881 g, 4.33 mmol) was used as the starting material. The remaining steps were similar to those for compound 3c, resulting in a white solid with a yield of 89.39%. 1H NMR (400MHz, CDCl3) δ4.92(d,J=9.6Hz,1H),4.77–4.56(m,2H),4.11–3.82(m,2H),2.94(d,J=51.2Hz,2H),2.30(s,1H),2.02(d,J=10.2Hz,3 H),1.80(s,1H),1.68(d,J=21.8Hz,2H),1.51(s,3H),1.22(d,J=7.7Hz,3H),0.96(d,J=13.8Hz,1H),0.85(s,3H),0.83(s,3H),0.78(s,3H). 13 CNMR(101MHz,CDCl3)δ171.31,169.60,168.15,81.78,61.44,60.50,48.97,47.96,4 4.82,38.24,36.50,27.99,27.05,21.14,19.73,18.85,18.53,14.26,13.55.MS(M+H) + :298.2

[0056] Example 8

[0057] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)ethyl 3-(methylamino)propanoate (3g)

[0058] N-Boc-3-(methylamino)propionic acid (1.76 g, 8.67 mmol) was used as the starting material, and the remaining steps were the same as those for compound 3c. The product was a white solid (3.39 g) with a yield of 98.38%. 1 H NMR (400MHz, CDCl3) δ4.92(d,J=9.9Hz,1H),4.66(s,2H),3.30(t,J=7.0Hz,2H),3.08(t,J=7.0Hz,2H),2.72(s,3H),2.36 –2.25(m,1H),1.84–1.62(m,3H),1.23(d,J=32.2Hz,2H),0.97(d,J=17.3Hz,1H),0.86(s,3H),0.83(s,3H),0.79(s,3H). 13 C NMR (101MHz, CDCl3) δ169.48,167.89,81.65,61.56,48.96,47.95,44.80,36.50,33.27,30.51,27.99,27.03,19.72,18.85,13.54.MS(M+H) + :298.2

[0059] Example 9

[0060] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)ethyl 3-aminopropanoate (3h)

[0061] Boc-β-alanine (1.64 g, 8.67 mmol) was used as the starting material, and the remaining steps were similar to those for compound 3c. The product was a pale yellow liquid (1.54 g) with a yield of 80.3%. 1 H NMR (400MHz, CDCl3) δ4.95(d,J=9.9Hz,1H),4.62(s,2H),3.42(d,J=5.8Hz,2H),2.60(t,J=5.9Hz,2H),2.39–2.25(m,1H ),1.80(s,1H),1.66(d,J=4.5Hz,2H),1.29–1.15(m,3H),0.99(d,J=13.9Hz,1H),0.87(s,3H),0.84(s,3H),0.80(s,3H). 13 CNMR(101MHz, CDCl3)δ168.14,81.54,61.07,48.99,47.96,44.87,36.52,28.44,28.01,27.07,19.72,18.85,13.50.MS(M+H) + :284.1

[0062] Example 10

[0063] 2-Oxo-2-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)ethyl N,N-dimethylglycinate (3i)

[0064] N,N-dimethylglycine (0.9 g, 8.67 mmol) was used as the starting material. The remaining steps were similar to those for compound 3c. 0.8 g of a light yellow viscous liquid was obtained. The yield was 30%. 1 H NMR (400MHz, CDCl3) δ4.97-4.93(1H,m),4.65(2H,s),3.27(2H,s),2.37(4H,s),2.35-2.30(2H,m),1.84 (1H,ddd),1.77-1.62(2H,m),1.24(3H,ddt),1.03-0.95(1H,m),0.87(3H,s),0.84(3H,s),0.80(3H,s). 13C NMR (101MHz, CDCl3)155.81,152.80,86.67,70.07,65.45,58.82,58.01,55.59,55.05,48.58,45.75,41.88,41.25,35.13,34.40,30.18.MS(M+H) + :298.2

[0065] Example 11

[0066] 4-Oxo-4-(((1S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)butanoic acid (BP-4)

[0067] To a solution of borneol (10 g, 64.83 mmol) in triethylamine (43 mL) was added succinic anhydride (8.11 g, 81.1 mmol) and a catalytic amount of 4-dimethylaminopyridine (29 mg, 236.9 μmol). The mixture was stirred at room temperature overnight under Ar. Ethyl acetate was added, and the organic phase was rinsed with 3 M / L HCl solution until the triethylamine was completely removed. The organic phase was then removed by distillation under reduced pressure. The product was purified by silica gel column chromatography (PE:EA = 2:1, Rf = 0.15) to afford 16.32 g of BP-4, a light yellow, viscous liquid, in a 99% yield. 1 H NMR (400MHz, CDCl3) δ4.97-4.81(1H,m),2.74-2.55(4H,m),2.45-2.25(1H,m),1.96-1.84(1H,m),1.8 0-1.69(1H,m),1.69(1H,s),1.32-1.14(3H,m),0.95(1H,dd),0.88(3H,s),0.85(3H,s),0.80(3H,s). 13 C NMR (101MHz, CDCl3) δ178.54,172.44,80.59,48.85,47.87,44.92,36.68,29.35,28.06,27.14,19.76,18.89,13.49.

[0068] Example 12

[0069] (1S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl 4-hydroxybutyrate (BP-5)

[0070] Sodium borohydride (2.79 g, 73.7 mmol) was added to anhydrous THF (75 mL). BP-4 (18.01 g, 70.81 mmol) was slowly added dropwise under ice-bath conditions. The mixture was stirred for 2 h while maintaining the temperature until no bubbles appeared. I2 (9 g, 35.41 mmol) in THF (64 mL) was added dropwise. Stirred in an ice-bath for 1 h. THF was removed by distillation under reduced pressure, and ethyl acetate (100 mL) was added to produce a precipitate. The precipitate was filtered and washed once with saturated NaHCO3 solution (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and filtered to obtain BP-5 (8.51 g, 35.41 mmol, 50.0%) as a colorless viscous liquid. 1 H NMR (400MHz, CDCl3) δ4.86-4.79(1H,m),3.60(2H,q),2.65(1H,s),2.44-2.35(2H,m),2.33-2.23(1H,m),1.93-1.77 (3H,m),1.68(1H,ddt),1.63-1.57(1H,m),1.31-1.11(2H,m),0.90(1H,dd),0.84(3H,s),0.81(3H,s),0.77(3H,s). 13 C NMR (101MHz, CDCl3) δ174.43,80.11,61.92,48.79,47.83,44.90,36.81,31.44,28.07,27.14,19.74,18.88,13.57.

[0071] Example 13

[0072] (1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-(alanyloxy)butyrate (3j)

[0073] Boc-L-Ala (1.57 g, 8.32 mmol) was dissolved in DCM (20 mL), and BP-5 (2 g, 8.32 mmol) and a catalytic amount of DMAP were added. N,N'-dicyclohexylcarbodiimide (DCC) (1.72 g, 8.32 mmol) in DCM (30 mL) was slowly added dropwise to the reaction solution and stirred overnight. The filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 2 g of a yellow viscous liquid in a 77% yield. 1H-NMR (400MHz, CDCl3) δ4.25-4.02(m,2H),4.28-4.08(m,2H),3.89-3.66(m,1H),3.97-3 .70(m,1H),2.52-2.40(m,2H),2.50-2.24(m,3H),2.38-2.26(m,1H),2.03-1.89(m,3H), 2.05-1.68(m,5H),1.87-1.68(m,2H),1.63(dt,1H),1.45-1.36(m,4H),1.60-1.16(m,7H ),1.35-1.14(m,3H),0.96(dt,1H),0.96(dt,2H),0.91(s,3H),0.88(s,3H),0.82(s,3H). 13 C NMR(101MHz, CDCl3)δ173.51,174.25,80.03,64.39,48.99,47.55,44.91,36.48,30.42,27.62,26.81,23.86,18.84,17.94,17.46,12.67.MS(M+H) + :312.2

[0074] Example 14

[0075] (1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl 4-(glycyloxy)butyrate (3k)

[0076] Using Boc-L-Gly (1.46 g, 8.32 mmol) as starting material, the synthesis method was the same as 3j, and 2.07 g of yellow viscous liquid was obtained with a yield of 80%. 1 H-NMR (400MHz, CDCl3) δ8.76(s,2H),4.87(d,1H),4.26(s,2H),4.15-4.09(m,2H),2.65(s,1H),2.53-2.38(m,2H),2.35-2.28(m,1H ),1.95-1.85(m,2H),1.78-1.70(m,1H),1.67(d,1H),1.29-1.19(m,2H),0.98-0.91(m,1H),0.89(s,3H),0.86(s,3H),0.81(s,3H). 13C NMR(101MHz, CDCl3)δ175.31,173.20,80.24,64.31,63.72,53.76,48.83,47.89,44.92,36.88,28.11,27.19,24.22,19.78,18.91,13.63.MS(M+H) + :298.1

[0077] Example 15

[0078] Sodium 5-oxo-5-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)pentanoate (3l)

[0079] Borneol (1.47 g, 4 mmol) and triethylamine (1.26 mL, 9 mmol) were dissolved in dichloromethane. Glutaric anhydride (1.03 g, 9 mmol) was then gradually added to the dichloromethane under a nitrogen atmosphere at 40°C. The reaction mixture was refluxed under nitrogen for 2 h. After completion of the reaction under TLC monitoring, triethylamine hydrochloride and excess hydrochloric acid were removed with 0.1 N HCl and water, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography. An equivalent amount of 1 M / L NaOH solution was added to form the sodium salt. The acetone was slowly evaporated until a solid precipitated, resulting in 9.38 g of a white solid with a yield of 67.4%. 1 H NMR (400MHz, CDCl3) δ4.86(d,J=9.9Hz,1H),2.42(d,J=7.4Hz,2H),2.38(d,J=7.5Hz,2H),2.32(s,1H),1.98-1.91( m,2H),1.88(s,1H),1.68(d,J=26.5Hz,2H),1.25-1.20(m,2H),0.91(s,1H),0.87(s,3H),0.84(s,3H),0.79(s,3H). 13 C NMR (101MHz, CDCl3) δ179.02,173.32,80.13,60.54,48.81,44.92,36.88,33.62,28.09,20.04,18.89,13.58.MS(M+H) + :298.0

[0080] Example 16

[0081] 2,5,8,11,14,17,20-Heptaoxadocosan-22-ol

[0082] Under N2 atmosphere, a suspension of NaH (1.0 g, 25.0 mmol) was added to THF (60 mL) at 0°C, followed by a solution of m-PEG3 (2.0 g, 16.6 mmol) in THF (20 mL). After addition, the stirred mixture was warmed to room temperature and stirred for 30 min, followed by the addition of a solution of macrocyclic sulfate (5.1 g, 20.0 mmol) in THF (20 mL). The resulting mixture was stirred at room temperature for 12 hours and then concentrated under vacuum. The resulting residue was dissolved in water (50 ml) and washed with DCM. The aqueous layer was concentrated and then dissolved in THF (100 mL). Water (0.6 mL, 33.3 mmol) and H2SO4 (0.4 mL, 8.4 mmol) were then added to the reaction mixture and refluxed for 3 h. The reaction was neutralized with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give m-peg7 as a clear oil (4.3 g, yield 88%). 1 H NMR (400MHz, CDCl3) δ3.66 (s, 2H), 3.59 (d, J = 3.0Hz, 22H), 3.56–3.53 (m, 2H), 3.50–3.47 (m, 2H), 3.32 (s, 3H). 13 C NMR (101MHz, CDCl3) δ72.60,71.96,70.65,70.64,70.60,70.55,70.37,61.73,59.09.

[0083] Example 17

[0084] 1-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)-2,3,6,9,12,15,18,21-octaoxatetracosane (3m)

[0085] Under a nitrogen atmosphere, a suspension of NaH (645 mg, 60% dispersion in mineral oil, 16.2 mmol) in THF (30 mL) was slowly added to a solution of M-PEG7 (1 g, 4.93 mmol) in THF (20 mL) at 0°C. After addition, the stirred mixture was warmed to room temperature and stirred for 30 minutes. A solution of bornyl chloride (1.68 g, 4.93 mmol) in THF (20 mL) was then added. The resulting mixture was stirred at room temperature for 12 hours, concentrated in vacuo, and the residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 50 / 1) to yield 1.36 g of a yellow oil in a 54.41% yield. 1H NMR (400MHz, CDCl3) δ4.66(d,J=18.8Hz,2H),3.64(s,2H),3.59(d,J=4.2Hz,22H),3.49(d,J=9.1Hz,2H),3.32(s,1H),2.13 (d,J=34.4Hz,1H),1.88(s,1H),1.60(d,J=27.5Hz,3H),1.17(d,J=8.5Hz,3H),0.98–0.86(m,1H),0.80(s,3H),0.78(s,9H). 13 CNMR (101MHz, CDCl3) δ94.91,82.11,71.97,70.65,66.68,59.11,49.06,47. 65,45.01,39.04,36.41,28.33,26.71,25.95,19.83,18.92,13.81.MS(M+Na) + :529.2

[0086] Example 18

[0087] (1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 2,5,8,11,14,17,20,23-octaoxapentacosane-25-oate (3n)

[0088] Trifluoroacetic acid (14.3 mL, 192.5 mmol) was added to a solution of the tert-butyl ester wzj-bp-2n (0.8 g, 1.76 mmol) and anisole (1.0 mL, 8.8 mmol) in CHCl (20 mL) and stirred at room temperature for 5 h. The reaction mixture was evaporated to dryness under vacuum to yield the acid as a red oil, which was used directly in the next step without further purification. Then, under a nitrogen atmosphere, natural borneol (0.27 g, 1.76 mmol) was added to a solution of the acid (0.8 g, 1.76 mmol), DMAP (473 mg, 3.8 mmol), and DCC (1.9 g, 9.2 mmol) in CHCl (50 mL). After stirring at room temperature for 16 h, the resulting mixture was filtered, and the filtrate was diluted with ethyl acetate (150 mL) and washed with hydrochloric acid (1N aq, 2 x 150 mL) and then with NaHCO (1N aq, 2 x 150 mL). The organic layer was collected and concentrated in vacuo to obtain a light red oil, which was purified by silica gel column chromatography (CH2Cl2 / MeOH=20 / 1) to obtain a yellow viscous liquid with a yield of 46%. 1H NMR (400MHz, CDCl3) δ4.12(s,0H),3.62(s,28H),3.34(s,3H),1.85(s,2H),1.63(d ,J=31.0Hz,4H),1.24(d,J=34.3Hz,4H),0.96(d,J=54.8Hz,3H),0.83–0.79(m,6H). 13 C NMR (101MHz, CDCl3) δ72.69,71.97,70.65,70.31,61.74,59.13,45.10,39.04,34.03,28.34,25.96,25.69,20.27,18.76,17.62,13.43.MS(M+Na) + :557.1

[0089] Example 19

[0090] 2,5,8,11,14,17,20-Heptaoxadocosan-22-yl 1H-imidazole-1-carboxylate (2o)

[0091] 1,1′-Carbonyldiimidazole (CDI, 1.9 g, 11.76 mmol) was used as the starting material. A solution of M-PEG 7 (2.0 g, 5.88 mmol) in CH2Cl2 (10 mL) was added to a CH2Cl2 solution (40 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 20 / 1) to afford a clear oil (1.8 g, 70.51% yield). 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.40(s,1H),7.02(s,1H),4.51(s,2H),3.79(s,2H),3.60(s,24H),3.33(s,3H). 13 C NMR (101MHz, CDCl3) δ137.22,130.63,117.25,71.93,70.73,70.61,68.63,67.19,61.62,59.05,53.56.

[0092] Example 20

[0093] ((1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl)2,5,8,11,14,17,20-heptaoxadocosan-22-yl carbonate (3o)

[0094] BP-2O (1.8 g, 4.14 mmol), DMAP (142 mg, 1.1 mmol), and natural borneol (1.28 g, 8.28 mmol) were added to a DMF (30 mL) solution. The reaction mixture was maintained at 60°C for 48 hours, cooled to room temperature, concentrated in vacuo, and then purified by silica gel (CH2Cl2 / MeOH = 20 / 1) column chromatography. The product was 2.02 g, with a yield of 93.65%. 1 H NMR(400MHz, CDCl3)δ7.95(s,1H),5.25(s,1H),4.21(s,1H),3.92(s,1H), 3.79–3.46(m,15H),3.31(s,1H),2.86(d,J=31.8Hz,10H),2.29–2.11(m,1H ),1.85(d,J=24.9Hz,2H),1.65(s,1H),1.55(d,J=9.1Hz,1H),1.18(d,J=1 0.8Hz,2H),0.88(d,J=16.8Hz,2H),0.80(s,3H),0.79(s,3H),0.78(s,3H). 13 C NMR (101MHz, CDCl3) δ94.91,82.11,71.97,70.65,66.68,59.11,49.06,47.6 5,45.01,39.04,36.41,28.33,26.71,25.95,19.83,18.92,13.81.MS(M+Na) + :543.1

[0095] Example 21

[0096] (2S,3R,4R,5S,6S)-2-(Hydroxymethyl)-6-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol (3p)

[0097] Under Ar at 0°C, trichloroacetonitrile (0.864 mL, 8.61 mmol) and DBU (0.13 mL, 0.86 mmol) were added dropwise to a solution of 2,3,4,6-O-acetyl-D-pyranose (1 g, 2.87 mmol) in DCM (9 mL) and stirred overnight. After completion, the reaction mixture was concentrated under reduced pressure and filtered through a column. The product was stirred overnight under Ar at 0°C with BF3·OEt2 (128.60 μL, 1.01 mmol) and (+)-borneol (469.63 mg, 3.04 mmol) in dry DCM. The product was washed with saturated NaHCO3, dried over anhydrous MgSO4, concentrated under reduced pressure, and filtered through a column. The product was then added dropwise to a solution of MeONa (0.5 M / MeOH, 0.8 mL, 0.4 mmol) in MeOH (1 mL) and stirred overnight for deacetylation. The pH was adjusted to neutral with 3N HCl / MeOH, and the mixture was concentrated under reduced pressure to give a white solid (88 mg) in a yield of 34%. 1 H-NMR(400MHz, CDCl3)δ8.66(1H,d),6.53(1H,t),5.52(1H,dt),5.27(1H,d),5.23-5.04(2H, m),4.32-4.14(2H,m),4.14-4.00(1H,m),2.06(3H,s),2.03(3H,s),2.02(3H,s),2.00(3H,s). 13 C-NMR (101MHz, CDCl3) δ170.63,170.00,169.57,160.84,92.95,70.06,69.92,69.77,67.83,61.43,20.75,20.66,20.52.MS(M+H) + :317.1

[0098] Example 22

[0099] The solubility of the water-soluble borneol ester compound of the present invention in normal saline at room temperature;

[0100] The experimental results are shown in Table 1:

[0101] Table 1. Solubility of various water-soluble borneol ester compounds in room temperature physiological saline

[0102]

[0103] Except for compound wzj-bp-3n, the water solubility of the synthesized borneol ester compounds is increased by about 30 to hundreds of times compared with the borneol original drug, indicating that the water solubility of the synthesized water-soluble borneol ester compounds has been significantly improved, which has significant benefits compared with the existing original drugs.

[0104] Example 23

[0105] The conversion rate of the water-soluble borneol ester compound of the present invention in the blank plasma of SD rats is:

[0106] The experimental results are as follows Figure 2 As shown:

[0107] The compound wzj-bp-3o takes the shortest time to be converted into borneol and has the highest conversion rate, and complete conversion can be achieved in about 20 minutes. It is planned to use the compound wzj-bp-3o in mouse model experiments.

[0108] Example 24

[0109] The water-soluble borneol ester compounds of the present invention alleviate the depressive-like behavior of mice:

[0110] Drug preparation: Use 0.9% saline solution to prepare a 5 mg / ml water-soluble borneol ester drug solution and a 0.2 mg / ml LPS solution, respectively. Store both in a refrigerator at 4°C and use them immediately after preparation.

[0111] Depression Mouse Model: C57 male mice were randomly divided into three groups after being housed freely for 7 days: control group, model group, and water-soluble borneol ester group (50 mg / kg). Water-soluble borneol esters (50 mg / kg) were intraperitoneally injected at 9:00 am daily for the first two days of the experiment. On the third day, water-soluble borneol esters (50 mg / kg) were intraperitoneally injected at 9:00 am. Two hours later, LPS (2 mg / kg) was intraperitoneally injected. A sucrose preference test was performed on the third day, a tail suspension test on the fourth day, and a forced swim test on the fifth day. Drugs were administered as scheduled on the day of behavioral testing.

[0112] Tail suspension test: This test can record the desperate immobility of mice. Apply tape approximately 1 cm from the tip of the mouse's tail and hang the mouse upside down on a horizontal bar 30 cm above the ground. Place a cylindrical plastic tube at the base of the tail to prevent the tail from climbing. Hang for 6 minutes and measure the immobility time for the last 4 minutes. After recording the duration, carefully remove the experimental animal, remove the tape, and return it to the original cage for record keeping. After each mouse test is completed, clean the feces and urine in the instrument in a timely manner to avoid affecting the results of the next test. When the mouse stops struggling and its body remains in a vertical upside-down position, it is considered immobile.

[0113] Forced swim test: This test is conducted in a transparent cylindrical container 45 cm high and 19 cm in diameter, filled with 23 cm of water (25 ± 1°C). Mice are placed in the container. The test lasts 6 minutes. The first 2 minutes are the acclimation period, and the final 4 minutes of immobility are recorded.

[0114] Sucrose Preference Assay: Anhedonic responses were assessed using a standard sucrose preference test. Mice underwent a two-day acclimation period and were deprived of food and water for 10 hours before the experiment. All tubes were weighed before testing. During the test, mice were housed individually and had free access to either plain water or a 1% sucrose solution from two separate 50 ml conical tubes for 24 hours. The tubes were then reweighed. At the end of the 24-hour testing period, sucrose preference was calculated by dividing the total amount of sucrose consumed by the total amount of liquid consumed.

[0115] The experimental results are as follows Figure 3 and Figure 4 As shown:

[0116] Figure 3 Results showed that compared with the control group, the model group mice showed no significant weight changes, but their depressive-like behaviors worsened. Water-soluble borneol esters rapidly dissolved and converted to borneol, increasing their absorption in the body and alleviating the depressive-like behaviors of the mice. This was demonstrated by a statistically significant decrease in immobility time in the tail suspension test and forced swim test by approximately 50% and an increase in sugar water consumption by approximately 30%. Values ​​shown are mean ± SEM, n = 6. *p < 0.05 and **p < 0.01, model group compared with control group; #p < 0.05 and ##p < 0.01, drug group compared with model group.

[0117] Figure 4Water-soluble borneol esters inhibit microglial activation in a LPS-induced mouse model of depression. (A) Co-staining of microglia with iba-1 (green, a microglial marker) and DAPI (blue, a nucleus marker) in hippocampal tissue from different mouse groups. Scale bar, 200 μm. (B) Analysis of microglial density (number of cells per square millimeter) in the dentate gyrus (DG) and excluding the DG hippocampus (excluding the DG) is shown. The results showed that water-soluble borneol esters inhibited LPS-induced microglial proliferation. Values ​​shown are mean ± SEM, n = 7. ***p < 0.001, model group compared with control group; ##p < 0.01 and ###p < 0.001, drug group compared with model group. (CD) Immunofluorescence staining of microglia in the dentate gyrus (DG) (C) and excluding the dentate gyrus (Exclude DG) (D) regions of the hippocampus under different treatment conditions. Colocalization of iba-1 (green) and DAPI (blue) is shown. Scale bar, 200 μm. (E) Analysis of microglial morphology. Figures show morphological, binarized, and skeletonized images of microglia under different treatment conditions. Scale bar, 20 μm. (FI) Analysis of branch endpoint number (F), cell body area (G), total branch length (H), and branch number (I) of microglia. The results showed that the water-soluble borneol acetate prodrug inhibited LPS-induced microglial cell body enlargement, branch shortening, and reduction. Values ​​shown are mean ± SEM, n = 10. *p<0.05, **p<0.01 and ***p<0.001, comparison between model group and control group; #p<0.05, ##p<0.01 and ###p<0.001, comparison between drug group and model group.

[0118] Example 25

[0119] Protective effect of the water-soluble borneol ester compound of the present invention in the mouse MCAO model:

[0120] Drug preparation: Use 0.9% normal saline solution to prepare water-soluble borneol acetate prodrug solutions with concentrations of 0.7 mg / ml and 0.2 mg / ml respectively, and use them immediately after preparation.

[0121] Transient middle cerebral artery occlusion (tMCAO) model: C57 male mice were housed ad libitum for 7 days and then randomly divided into three groups: sham surgery, model group, low-dose (2 mg / kg), and high-dose (7 mg / kg) water-soluble borneol acetate prodrug groups. Mice underwent tMCAO surgery. Mice were anesthetized, and the common, external, and internal carotid arteries were isolated. The proximal ends of the external and common carotid arteries were ligated, and a suture was inserted from the external carotid artery to the origin of the anterior cerebral artery, thereby occluding the middle cerebral artery blood supply. After 1.5 hours, the suture was removed and blood flow was restored. At 0 hours of reperfusion, mice in the prodrug group were injected with water-soluble borneol acetate prodrug via the tail vein.

[0122] like Figure 5 (A) is a representative image of TTC staining of the brain after MCAO modeling in mice, and (B) is a statistical diagram of the cerebral infarction area in mice. The results show that compared with the sham-operated group, the infarct volume in the model group was significantly increased due to the ischemia-reperfusion surgery. However, after intervention with a high-dose water-soluble borneol ester compound, the compound rapidly dissolved and converted into borneol, significantly improving the permeability of the blood-brain barrier in the infarcted area, while also having anti-inflammatory and inhibiting cell apoptosis, reducing the infarct volume in the mouse model. Furthermore, with increasing the concentration of borneol compound administered, the cerebral infarction area of ​​mice was significantly reduced. Values ​​shown are mean ± SEM, n ≥ 7.

[0123] Mice were assessed using the Longa neurological function score and mNSS. The results showed that high-dose borneol esters reduced neurological deficits. Values ​​are mean ± SEM, n = 6-10. *p < 0.05 compared to the model group.

Claims

1. A water-soluble borneol ester compound, characterized in that: The structure of the compound is shown in general formula I: Wherein, R is 2-oxoethyl acetate, 2-oxoethyl aminoacetate, glycolate of an amino acid, acetal of a monodisperse polyethylene glycol chain, carbonate, ester or sugar group of an organic heterocyclic ring.

2. The water-soluble borneol ester compound according to claim 1, characterized in that The organic heterocycle is morpholine, furan, thiophene, pyrrole, imidazole, thiazole, pyrazole, pyridine, pyrimidine, pyrazine, indole or quinoline.

3. The water-soluble borneol ester compound according to claim 1, characterized in that: The amino group is N-methylethylamine, ethylamine, 2-propylamine, propylamine, N-methylpropylamine, trimethylamine, butylamine, N-methylbutylamine or 3-butylamine.

4. The water-soluble borneol ester compound according to claim 1, characterized in that The amino acid is glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid or glutamic acid.

5. The water-soluble borneol ester compound according to claim 1, characterized in that: The monodisperse polyethylene glycol chain is polyethylene glycol methyl ether M-PEG with a length of 2-10 ethylene glycol units.

6. The water-soluble borneol ester compound according to claim 1, characterized in that: The saccharide group is glucose, mannose, galactose, allose, altrose, gulose, idose, talose, ribose, xylose, arabinose or lyxose.

7. The water-soluble borneol ester compound according to claim 1, characterized in that: The structure of the compound is as follows:

8. The water-soluble borneol ester compound according to claim 1, characterized in that: The compounds include pharmaceutically acceptable salts thereof.

9. Use of the water-soluble borneol ester compound according to claim 1 in the preparation of a drug for treating inflammatory depression and stroke.

10. The use according to claim 9, characterized in that The applications include drugs for asthma, hypertension, myocardial hypertrophy, myocardial infarction, heart failure, antiplatelet, atherosclerosis or analgesia caused by inflammatory depression and stroke.

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