Norbornane derivative and pharmaceutical use thereof

Abstract

The present disclosure relates to a norbornene derivative and a pharmaceutical use thereof. Specifically, the present disclosure relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for treating cardiovascular and cerebrovascular diseases.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a norbornane derivative and the pharmaceutical use thereof. Background Art

[0002] A stroke is a disease characterized by sudden interruption or severe reduction of cerebral blood supply; it can be classified into two major types, namely ischemic stroke and hemorrhagic stroke. The common types of the former include embolic cerebral infarction and cerebral thrombosis, which are mainly caused by occlusion of arteries supplying blood to the brain, resulting in ischemia and hypoxia of brain tissue. The common types of the latter are cerebral hemorrhage and subarachnoid hemorrhage, which are primarily induced by rupture of cerebral blood vessels leading to intracerebral bleeding.

[0003] (+)-Borneol is a norbornane derivative, which is capable of selectively agonizing the a2 GABAA receptor, and has a clear anti-cerebral ischemia effect and a good brain protection effect for cerebral ischemic reperfusion models (Journal of Biomedical Research, 2017, 31(4): 306-314). In addition, it also exhibits pharmacological effects including anti-inflammatory and analgesic activity, anticoagulant activity, anti-myocardial ischemia activity, reversing tumor drug resistance, as well as improving wakefulness and cognitive function in rats subjected to long-term continuous operation.

[0004] As a lipophilic agent, (+)-borneol has a clear effect of promoting drug absorption and penetration across the blood-brain barrier and promoting drug distribution in the brain, but it also suffers from the drawbacks of poor water solubility and low oral bioavailability. Summary of the Invention

[0005] The disclosure provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,

[0006] In some embodiments, the compound or the pharmaceutically acceptable salt thereof is

[0007] In another aspect, the disclosure further provides a compound or a pharmaceutically acceptable salt thereof,          OH.

[0008] In some embodiments, the compound or the pharmaceutically acceptable salt thereof is

[0009] The disclosure further provides an isotopically substituted compound of the aforementioned compound or the pharmaceutically acceptable salt thereof. In some embodiments, the isotopically substituted compound is a deuterated compound.

[0010] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0011] In certain embodiments, the pharmaceutical composition comprises 0.01%-99.99% of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the isotopically substituted compound thereof, on the basis of the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1%-99.9% of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the isotopically substituted compound thereof. In certain embodiments, the pharmaceutical composition comprises 0.5%-99.5% of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the isotopically substituted compound thereof. In certain embodiments, the pharmaceutical composition comprises 1%-99% of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the isotopically substituted compound thereof. In certain embodiments, the pharmaceutical composition comprises 2%-98% of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the isotopically substituted compound thereof.

[0012] In certain embodiments, the pharmaceutical composition comprises 0.01%-99.99% of a pharmaceutically acceptable excipient, on the basis of the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2%-98% of a pharmaceutically acceptable excipient.

[0013] The disclosure further provides a method for treating cardiovascular and cerebrovascular diseases, comprising administering to a patient a therapeutically effective amount of the aforementioned compound or the pharmaceutically acceptable salt thereof or the isotopically substituted compound thereof, or the aforementioned pharmaceutical composition.

[0014] The disclosure further provides the use of the aforementioned compound or the pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the manufacture of a medicament for treating cardiovascular and cerebrovascular diseases.

[0015] The cardiovascular and cerebrovascular diseases of the disclosure include, but are not limited to, ischemic cerebrovascular disease, cerebral infarction (stroke or cerebral stroke), myocardial infarction, and coronary heart disease.

[0016] The pharmaceutically acceptable salts of the compounds of the disclosure may be selected from the group consisting of inorganic salts or organic salts. The inorganic salts are selected from the group consisting of hydrochloride, hydrobromide, phosphate, or sulfate; and the organic salts are selected from the group consisting of acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, citrate, maleate, tartrate, fumarate, or lactate.

[0017] The compounds of the disclosure may exist in specific geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, and all such mixtures fall within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and mixtures thereof are encompassed within the scope of the disclosure. The compounds comprising asymmetric carbon atoms of the disclosure may be isolated in optically active pure or racemic forms. The optically active pure forms may be resolved from the racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0018] Optically active (R)- and (S)-isomers and D and L isomers may be prepared using chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, where the molecule comprises a basic functional group (such as amino) or an acidic functional group (such as carboxy), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers using conventional methods well known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is generally accomplished by using chromatography, which uses chiral stationary phases, optionally in combination with chemical derivatization methods (e.g., formation of carbamates from amines).

[0019] In the chemical structures of the compounds of the disclosure, the bond "  / " represents an unspecified configuration; that is, if the chemical structure exists as stereoisomers, the bond "  / " can be "   " or "   ", or both the configurations of "   " and "   " are involved.

[0020] In the chemical structures of the compounds of the disclosure, the bond "   " represents an unspecified configuration, that is, it may be the Z or E configuration, or contain both configurations.

[0021] The compounds and intermediates of the disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton transfer. For example, the compound of the disclosure includes the tautomeric change between A and B as shown below.

[0022] All tautomeric forms are included within the scope of the disclosure. The nomenclatures of the compounds do not exclude any tautomers.

[0023] The disclosure further includes isotopically labeled compounds of the disclosure that are identical to those recited herein, but have one or more atoms replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, respectively.

[0024] Unless otherwise specified, when a position is specifically designated as deuterium (D), it should be understood that the position has a deuterium abundance at least 1000 times the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The expression "having deuterium at an abundance greater than the natural abundance of deuterium" in the compounds in the examples may mean having deuterium at an abundance at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or having deuterium at a higher abundance. The disclosure further includes various deuterated forms of the compound of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art may synthesize deuterated forms of the compound of formula (I) by referring to relevant literature. The deuterated forms of the compound of formula (I) can be prepared using commercially available deuterated starting materials, or can be synthesized using deuterated reagents via conventional techniques. The deuterated reagents include, but are not limited to, deuterated borane, borane-d3 in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0025] "Optionally" or "optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "C1-6 alkyl optionally substituted with halogen or cyano" means that halogen or cyano may but need not be present. The description includes the instance where the alkyl is substituted with halogen or cyano and the instance where the alkyl is not substituted with halogen or cyano. Explanation of terms:

[0026] The term "pharmaceutical composition" denotes a mixture containing one or more compounds described herein or physiologically or pharmaceutically acceptable salts or prodrugs thereof and other chemical components, as well as other components, such as physiologically or pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

[0027] The “pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the US Food and Drug Administration to be acceptable for human or livestock use.

[0028] The term "effective amount" or "therapeutically effective amount" described in the disclosure includes an amount sufficient to ameliorate or prevent a symptom or disorder of a medical disorder. The term effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0029] The term "THF" refers to tetrahydrofuran.

[0030] The term “LiHMDS” refers to lithium bis(trimethylsilyl)amide.

[0031] The term “DCM” refers to dichloromethane.

[0032] The term “MTBE” refers to methyl tert-butyl ether.

[0033] The term “DIPEA” refers to N,N-diisopropylethylamine.

[0034] The term “TFA” refers to trifluoroacetic acid.

[0035] The term "DMAP" refers to 4-dimethylaminopyridine.

[0036] The term "DMF" refers to N,N-dimethylformamide.

[0037] The term "DCC" refers to N,N'-dicyclohexylcarbodiimide.

[0038] The term “TMSOTf” refers to trimethylsilyl trifluoromethanesulfonate.

[0039] The term “Selectfluor” refers to Selectfluor.

[0040] The term “TBAF” refers to tetrabutylammonium fluoride.

[0041] The term “LDA” refers to lithium diisopropylamide.

[0042] The term "NaHMDS" refers to sodium bis(trimethylsilyl)amide. Brief Description of the Drawings

[0043] FIG. 1 shows the effects of the compounds on neurological deficit scores in rats with permanent ischemic stroke (Mean±SD, n=6).

[0044] FIG. 2 shows the effects of the compounds on cerebral infarct areas in rats with permanent ischemic stroke (Mean±SD, n=6). Detailed Description of Embodiments

[0045] The disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the disclosure.

[0046] Experimental methods without specific conditions indicated in the examples of the disclosure are generally conducted under conventional conditions, or conditions recommended by the manufacturers of the starting materials or commercial products. Reagents for which the specific source is not specified are conventional, commercially available reagents.

[0047] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (5) is given in the unit of 10-6 (ppm). NMR is determined with a nuclear magnetic resonance spectrometer Bruker AVANCE-400. The solvents for determination are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (methanol-d4), and the internal standard is tetramethylsilane (TMS).

[0048] HPLC is performed on an Agilent1100 high pressure liquid chromatograph equipped with a GAS15B DAD ultraviolet detector and a Water Vbridge C18 150*4.6 mm 5 pm chromatographic column.

[0049] MS is performed on an Agilent6120 triple quadrupole mass spectrometer equipped with a G1315D DAD detector and a Waters Xbridge C18 4.6*50 mm, 5 pm chromatographic column. Scanning is performed in positive / negative ion mode with a mass scan range of 80-1200.

[0050] For thin layer chromatography, Yantai Huanghai HSGF254 silica gel plates are used. The specifications of silica gel plates applied in thin layer chromatography (TLC) are 0.2 mm±0.03 mm, while those used for separation and purification of products by thin layer chromatography are 0.4 mm-0.5 mm.

[0051] Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) is used for the flash column purification system.

[0052] For normal-phase chromatography, Yantai Huanghai silica gel of 200-300 mesh or 300 400 mesh silica gel is generally used as the carrier, or Santai Technologies pre-packed ultra-pure normal phase silica gel column (40-63 pm, 60 g, 24 g, 40 g, 120 g or other specifications) is used.

[0053] Known starting materials in the disclosure may be synthesized using or according to methods known in the art, or may be purchased from Shanghai Titan Scientific, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Bide Pharmatech Ltd., and other companies.

[0054] Unless otherwise specified in the examples, all reactions can be carried out under nitrogen atmosphere.

[0055] The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.

[0056] The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0057] Hydrogen is produced by QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0058] The establishment of nitrogen atmosphere or hydrogen atmosphere usually comprises: evacuating, filling with nitrogen or hydrogen, and repeating the operation three times.

[0059] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0060] Unless otherwise specified in the examples, the reaction temperature refers to room temperature, which is 20°C to 30°C.

[0061] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography and the developing solvent system for thin layer chromatography used to purify the compound, and the volume ratio of the solvent are adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment. Example 1. Preparation of Compound 1 Step 1:

[0062] Compound 1a (10.0 g, 65.69 mmol, purchased from Accela ChemBio Inc.) was added to a flask, 100 mL of toluene was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen. Triethylamine (15.95 g, 157.65 mmol) and TMSOTf (29.20 g, 131.38 mmol) were added, and the resulting mixture was heated to 125°C and refluxed until the reaction was complete. At room temperature, 100 mL of n-hexane was added, and the mixture was washed twice with saturated aqueous sodium bicarbonate solution (50 mL each time), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 13.7 g of Compound 1b (yield: 92.94%).

[0063] 1H NMR (400 MHz, CDCI3): 3 4.45 (d, 1H, J = 3.6 Hz), 1.99-2.00(m, 1H), 1.51-1.58 (m, 1H), 1.26-1.32 (m, 1H), 0.83-0.96 (m, 2H), 0.68 (s, 6H), 0.58 (s, 3H) ,0.00-0.01 (s, 9H). Step 2:

[0064] Compound 1b (12.0 g, 53.47 mmol) was added to a flask, and 100 mL of anhydrous DMF was added for dissolution. The system was protected with nitrogen. At room temperature, Selectfluor (18.94 g, 53.47 mmol) and TBAF in tetrahydrofuran (1.0 M, 53.47 mL) were added, and then the mixture was poured into 200 mL of water, stirred and reacted until the reaction was complete. The system was extracted three times with n-hexane (100 mL each time). The organic phases were combined. The combined organic phase was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=0-10%) to afford 8.1 g of Compound 1c (yield: 88.99%).

[0065] 1H NMR (400 MHz, CDCI3): § 4.36-4.96 (m, 1H), 1.25-2.30 (m, 4H), 0.84-1.12 (m, 10H). Step 3:

[0066] Compound 1c (3.0 g, 17.62 mmol) was added to a flask, 30 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, the temperature was reduced to -78C, LDA (1.0 M, 35.25 mL) was added dropwise, and a reaction was carried out until the reaction was complete. 30 mL of a saturated aqueous ammonium chloride solution was added for quenching, and the mixture was extracted three times with MTBE (30 mL each time). The organic phases were combined. The combined organic phase was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=50:1-20:1) to afford 1.5 g of Compound 1d (yield: 50%).

[0067] 1H NMR (400 MHz, CDCb): 8 4.83-4.97 (m, 1H), 2.40-2.42 (m, 1H), 1.74-1.88 (m, 3H), 1.26-1.58 (m, 1H),0.84-1.12 (m, 9H). Step 4:

[0068] Compound 1d (300 mg, 1.76 mmol) was added to a flask, 10 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, the temperature was reduced to -78C, and lithium aluminum hydride (1.0 M, 2.29 mL) was added dropwise, and a reaction was carried out until the reaction was complete. 20 mL of a saturated aqueous ammonium chloride solution was added for quenching, and the mixture was extracted three times with MTBE (30 mL each time). The organic phases were combined. The combined organic phase was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=50:1-20:1) to afford 120 mg of Compound 1 (yield: 40%).

[0069] 1H NMR (400 MHz, CDCh): 8 4.92-5.10 (m, 1H), 3.83-3.89 (m, 1H), 1.98-2.06 (m, 2H), 1.68-1.82 (m, 2H), 1.49-1.54 (m, 1H), 1.23-1.30 (m, 1H), 0.84-0.93 (m, 9H). Example 2. Preparation of Compound 2

[0070] Compound 1d (620 mg, 3.64 mmol) was added to a flask, 10 mL of anhydrous isopropanol was added, and the resulting mixture was stirred for dissolution. Aluminum isopropoxide (1.86 g, 9.11 mmol) was added, the system was protected with nitrogen, and the mixture was heated to 90C to react overnight. 20 mL of saturated aqueous sodium bicarbonate solution was added for quenching, and the mixture was extracted three times with MTBE (20 mL each time). The mixture was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=50:1) to afford 410 mg of Compound 2 (yield: 65.3%).

[0071] 1H NMR (400 MHz, CDCI3): 3 4.99-5.15 (m, 1H), 3.55-3.63 (m, 1H), 2.00 (t, 1H), 1.89 (d, 1H), 1.47-1.74 (m, 3H), 1.14-1.20 (m, 1H),1.02 (s, 3H), 0.84-0.88 (m, 6H). Example 3. Preparation of Compound 3 1c                        3 Step 1:

[0072] Compound 1c (4.45 g, 26.14 mmol) was added to a flask, 90 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, (R)-methyl-CBS-oxazaborolidine (1.45 g, 5.23 mmol, purchased from Bide) was added, the temperature was reduced to 0°C, and borane in tetrahydrofuran (1.0 M, 52.3 mL) was added. The mixture was stirred until the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution until pH=3, and the reaction solution was concentrated to remove the organic solvent. The aqueous phase was extracted three times with methyl tert-butyl ether (50 mL each time), and the organic phases were combined. The combined organic phase was washed sequentially with 50 mL of water and 50 mL of saturated saline. The resulting organic phase was dried over sodium sulfate, dried, concentrated, and purified by column chromatography (EA:PE=0-5%) to afford 170 mg of Compound 3 (yield: 4%).

[0073] 1H NMR (400 MHz, CDCl3): 3 4.40-4.22 (m, 1H), 4.20-4.08 (m, 1H), 2.00-1.88(m, 1H), 1.84-1.65 (m, 2H), 1.30-1.24 (m, 1H), 1.22-1.18 (m, 1H), 1.16-1.05 (m, 1H), 1.00 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H). Example 4. Preparation of Compound 4 1c                   4 Step 1:

[0074] Compound 1c (2.0 g, 11.75 mmol) was added to a flask, 20 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, the temperature was reduced to -60C, lithium tri-sec-butylborohydride in tetrahydrofuran (1.0 M, 15.3 mL) was added, and the reaction was continued until complete. 20 mL of 1 M aqueous hydrochloric acid solution was added to quench the reaction, and the mixture was extracted three times with MTBE (50 mL each time). The organic phases were combined. The combined organic phase was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:MTBE=100:15) to afford 633 mg of Compound 4 (yield: 30%).

[0075] 1H NMR (400 MHz, CDCI3): 3 4.70-4.54 (m, 1H), 3.69-3.63 (m, 1H), 2.04-1.99(m, 2 H), 1.73-1.69 (m, 1H), 1.50-1.44 (m, 1H), 1.10-1.08 (m, 3H), 0.97-0.91 (m, 5H), 0.83 (s, 3H). Example 5 Preparation of compounds 5 and 6 Step 1:

[0076] Compound 1a (2.0 g, 13.14 mmol) was added to a flask, 20 mL of tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, the temperature was reduced to -78C, NaHMDS (1.0 M, 22.99 mL) was added, and after the addition was completed, the mixture was heated to 0C and reacted until the reaction was complete. The system was cooled again to -78C, N-fluorobenzenesulfonimide in tetrahydrofuran (0.53 M, 100 mL) was added dropwise, and after the addition, the mixture was reacted at room temperature until the reaction was complete. 100 mL of 1 N HCl was added for quenching, 100 mL of ethyl acetate was added for extraction, 50 mL of saturated sodium bicarbonate was added for washing once, and the organic phase was dried over sodium sulfate, filtered, and concentrated. 200 mL of n-hexane was added for trituration, and the mixture was filtrated, concentrated, and purified by column chromatography (PE:EA=50:1-30:1) to afford 1.3 g of Compound 5a (yield: 53%).

[0077] 1H NMR (400 MHz, CDCl3): 3 3.87-3.94 (m, 1H), 2.04-2.07 (m, 1H), 1.89-1.94 (m, 1H), 1.67-1.77 (m, 3H), 1.20-1.30 (m, 1H), 0.89-1.00 (m, 9H). Step 2:

[0078] Compound 5a (1.08 g, 5.76 mmol) was added to a flask, 15 mL of anhydrous isopropanol was added, and the resulting mixture was stirred for dissolution. Aluminum isopropoxide (2.94 g, 14.39 mmol) was added, and the system was protected with nitrogen, and heated and reacted until the reaction was complete. 30 mL of saturated aqueous sodium bicarbonate solution was added for quenching, the mixture was extracted with MTBE (20 mL*3), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=150:1-100-1) to afford 38 mg of Compound 5 (yield 3%) and 560 mg of Compound 6 (yield 51%).

[0079] Compound 5: 1H NMR (400 MHz, CDCI3): §3.88-3.94 (m, 1H), 2.04-2.07 (m, 1H), 1.90 ~ 1.93 (m, 1H) , 1.62-1.75 (m, 3H), 1.24-1.30 (m, 1H), 0.90-1.00 (m, 9H).

[0080] Compound 6: 1H NMR (400 MHz, CDCb): d 3.60 to 3.64 (m, 1H), 2.01 to 2.04 (m, 1H), 1.96 (br s, 1H), 1.56 to 1.66 (m, 3H), 1.24 to 1.27 (m, 1H), 1.12 to 1.13 (d, 3H), 0.94(s,3H), 0.88(s,3H). Example 6 Preparation of Compound 7 1a                7a                  7 Step 1:

[0081] Compound 1a (300 mg, 1.97 mmol) was added to a flask, 6 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, and cooled to below -60C with a dry ice-ethanol bath. LDA in tetrahydrofuran (2.0 M, 1.2 mL) was added and stirred until the reaction was complete. Methyl chlorosulfonate (309 mg, 2.36 mmol) was added and stirred until the reaction was complete. 12 mL of 1 M dilute hydrochloric acid was added to the reaction solution, and the reaction solution was concentrated. The aqueous phase was extracted with petroleum ether (6 mL*3), the organic phases were combined, and the combined organic phase was washed sequentially with 3 mL of water, 3 mL of saturated aqueous sodium bicarbonate solution, and 3 mL of saturated saline. The resulting organic phase was dried over sodium sulfate, filtered, concentrated, and purified by chromatography (EA:PE=0-5%) to afford 175 mg of Compound 7a (yield 48%). Step 2:

[0082] Compound 7a (100 mg, 0.54 mmol) was added to a flask, 2 mL of anhydrous tetrahydrofuran was added, and the resulting mixture was stirred for dissolution. The system was protected with nitrogen, the temperature was reduced to -50C, lithium tri-sec-butylborohydride in tetrahydrofuran (1.0 M, 3.9 mL) was added dropwise, and the reaction was continued until complete. 10 mL of 1 M aqueous hydrochloric acid solution was added for quenching, and the mixture was extracted with MTBE (10 mL*2). The organic phases were combined. The combined organic phase was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (EA:PE=0-5%) to afford 92 mg of Compound 7 (yield: 91%).

[0083] 1H NMR (400 MHz, CDCb): 8 4.70-4.66 (m, 1H), 3.89-3.85 (m, 1H), 2.06-2.05 (m, 1H), 1.97-1.95 (m, 1H), 1.85-1.77 (m, 2H), 1.37-1.20 (m, 2H), 0.95-0.90 (m, 9H). Biological evaluation

[0084] The disclosure will be further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the disclosure. Test Example 1 Neuroprotective effects of the compounds on SD rats with cerebral ischemia-reperfusion

[0085] In this study, an SD rat middle cerebral artery occlusion (MCAO) model was used. The neuroprotective effects of the test compounds on SD rats with cerebral ischemia-reperfusion were evaluated by analyzing the cerebral infarct area and neurological deficit scores after intravenous administration of the test compounds to the animals. 1.     Experimental materials 1.1 Main instruments Name Model Manufacturer Electronic balance JCS-31001C Wuyi Zhuheng Electronics Co., Ltd. Electronic balance BSA224S-CW Sartorius Scientific Instruments (Beijing) Co., Ltd. RWD respiratory anesthesia machine R580S Shenzhen RWD Life Science Co., Ltd. Laser speckle blood flow imager SIM BFI HR PRO Wuhan Xunwei Optoelectronic Technology Co., Ltd. 1.2 Experimental animals

[0086] Male SD rats weighing 240-260 g. 2.     Experimental method 2.1 Experimental steps

[0087] Step 1): Model preparation: The method for preparing the SD rat middle cerebral artery occlusion (MCAO) model was performed with reference to Experimental Methodology of Pharmacology, 4th Edition. Adult male SD rats were subjected to 90 min of cerebral ischemia followed by reperfusion using the intraluminal suture method.

[0088] Step 2): Animal grouping: At 60 min after suture placement, rats with successful model establishment were screened on the basis of neurological deficit scores (10-11 points), and randomly divided into groups, with eight rats per group.

[0089] Step 3): Dosing regimen A single tail vein bolus injection was administered immediately after reperfusion; the experimental endpoint was set at 24 h after administration.

[0090] Step 4): Detection indicators:

[0091] Neurological deficit score: The severity of neurological deficits in animals was scored in a blinded fashion before administration and at 24 h after administration, with a total score of 16 points.

[0092] Infarct area measurement: At 24 h after administration, the animals were decapitated, and the whole brains were harvested. The brain tissues were sliced and immersed in a 1% 2,3,5-triphenyltetrazolium chloride (TTC) solution for staining, and then the cerebral infarct area was calculated. 2.2 Data analysis

[0093] The experimental data were expressed as mean±standard deviation (mean±SD) and analyzed using IBM SPSS Statistics 25.0 statistical software. Multiple-group comparisons were statistically analyzed by means of one-way analysis of variance (ANOVA). First, the data were tested for homogeneity of variances, if P<0.05, the data were considered to have unequal variances; if P>0.05, the data were considered to have equal variances. For data with equal variances, multiple comparisons were performed using the LSD test. For data with unequal variances, Dunnett's T3 test was used for statistical analysis. A value of P<0.05 was regarded as statistically significant. Test Example 2 Anti-inflammatory effects of the compounds on neuroinflammatory cell model

[0094] In this study, mouse microglial cells (BV-2 cells) were used to establish an inflammatory cell model via co-stimulation with IFN-y + TNF-a. The in vitro anti-inflammatory effect of the compound was evaluated by analyzing the inhibitory effect of the compound on the mRNA transcription levels of IL-ip and IL-6. 1.     Experimental materials 1.1 Main instruments Name Model Manufacturer Analytical balance, readability 0.1 mg BSA124S Sartorius Analytical balance, readability 0.01 mg SQP Sartorius Multipurpose low-speed centrifuge DM0636 DLAB Biological safety cabinet HFsafe-1200LC (A2) Heal Force CO2 incubator 371 Thermo Fisher Scientific Real-time fluorescence quantitative PCR instrument *Roche 480 Roche Fluorescence spectrophotometer / NULL Water bath DWB20-S DLAB 1.2 Experimental cells

[0095] BV-2 (mouse microglial cells). 2.     Experimental method 2.1 Experimental steps

[0096] Step 1): Cell culture: The old medium was removed, followed by one rinse with PBS. Then 0.25% trypsin was added, and the cells were incubated at 37C for 2-3 min. The corresponding culture medium was added to terminate digestion. The cell suspension was gently pipetted with a pipette to dissociate the aggregated cells, transferred to a sterile centrifuge tube, and centrifuged at 1000 rpm for 5 min to collect cells. After centrifugation, the supernatant was discarded. The cells were seeded in a 10 cm cell culture dish at a density of 2.5*105 cells per cell culture dish.

[0097] Step 2): Establishment of cellular inflammatory model: After cell seeding, the cells were cultured until reaching 70%-80% confluence under microscopic observation. Compounds at different concentrations were added. After 3 h, TNF-a and IFN-y solutions were added at a final concentration of 10 ng / mL each to establish the TNF-a / IFN-Y-induced cellular inflammatory model. Relevant detections were performed 24 h later.

[0098] Step 3): Detection indicators: Cells were lysed, and RNA was extracted for subsequent experiments or storage at -80C. cDNA templates were obtained by reverse transcription, and the intracellular mRNA transcription levels of IL- ip and IL-6 were detected by qPCR. 2.2 Data analysis

[0099] After data summarization, the data were analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software on the basis of the SPSS analytical results. Test Eample 3 In vivo pharmacokinetic test in Beagle dogs 1.     Sample preparation

[0100] Preparation of reference standard: A required amount of (+)-borneol (purchased from Jiangxi Xinsen Natural Vegetable Oil Co., Ltd.) was weighed, and an appropriate volume of 5% DMSO+95% normal saline was added. The (+)-borneol was fully dissolved by vortexing or sonication to obtain a clear dosing solution. After preparation, the dosing solution was filtered through a 0.22 pm microporous filter membrane for intravenous administration.

[0101] Preparation of test sample: A required amount of Compound 1 was weighed, and an appropriate volume of normal saline was added. The compound was fully dissolved by vortexing or sonication to obtain a clear dosing solution. After preparation, the dosing solution was filtered through a 0.22 pm microporous filter membrane for intravenous administration. 2.     Test animals

[0102] Beagle dogs, male, weighing about 8 to 10 kg. The animals were purchased from Jiangsu Marshall Bio-Tech Co., Ltd., with the animal production license as follows: SCXK (Jiangsu) 2021-0012. 3.     Experimental method

[0103] Dosing regimen The animals were weighed before administration, the dosage was calculated based on body weight, and the drug was administrated via intravenous injection. 0.6 to 1 mL of blood was collected from limb veins before administration and at 2 min, 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h and 8 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube (pre-cooled) and kept on wet ice. Centrifugation was completed within 30 min (3500 rpm, 10 min, 2C to 8C). Plasma was isolated and transferred to a freezer at -80°C for cryopreservation, and low-temperature conditions were maintained throughout the entire process from sample collection to aliquoting. The concentrations of (+)-borneol and Compound 1 in plasma were detected, respectively. Table 1 Dosing regimen Group Test substance Number (male) Dose (mg / kg) Concentration (mg / mL) Dosing volume (mL / kg) Route of administration* Sample collected 1 (+)-Borneol 2 0.3 0.15 2 IV Plasma 2 Compound 1 2 0.3 0.15 2 IV Plasma *The animals were fasted for more than 12 h prior to the test with free access to drinking water, and food was supplied 4 h after administration. 4.     Experimental results

[0104] The pharmacokinetic parameters of animals in each group are shown in Table 2. Table 2 Pharmacokinetic data Group                    (+)-Borneol                  Compound 1 PK data Mean SD Mean SD C2 min ng / mL 291 12.0 404 68.6 AUC0-t h*ng / mL 58.1 11.9 99.1 5.41 AUCo-» h*ng / mL 72.0 22.5 113 9.15 t1 / 2 h 0.224 0.0645 0.740 0.082 CL mL / min / kg 73.0 22.8 44.5 3.62 Vss mL / kg 1.12 0.06 1.97 0.06 Test Eample 4 In vivo pharmacodynamic test in SD rats 1.     Sample preparation

[0105] A required amount of Compound 1, Compound 5 or Compound 7 was weighed, and an appropriate volume of normal saline was added. The compound was fully dissolved by vortexing or sonication to obtain a clear dosing solution. After preparation, the dosing solution was filtered through a 0.22 pm microporous filter membrane for intravenous administration. 2.     Test animals

[0106] SD rats, male, weighing about 240 to 260 g. The animals were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with the animal production license as follows: SCXK (Beijing) 2021-0011. 3.     Experimental method 3.1 Experimental steps:

[0107] (1) Model preparation: The method for preparing the SD rat middle cerebral artery occlusion (MCAO) model was performed with reference to Experimental Methodology of Pharmacology, 4th Edition, and a permanent cerebral ischemia model was established by the intraluminal suture method.

[0108] (2) Animal grouping: At 55 min after suture occlusion, neurological deficit scoring was performed (animals with scores of 10-11 points (indicating relatively uniform deficit severity) were selected; those with excessively severe or mild deficits were excluded). Cerebral blood flow was measured using a laser speckle perfusion imager (animals with a decrease of >50% compared with the ipsilateral baseline value were eligible). Animals meeting both criteria were enrolled. Rats with successful model establishment were randomly divided into four groups, with six rats per group, and an additional sham operation group containing six rats was set up. The specific grouping information is as follows: Table 3 Grouping and dosing information Group Dose (mg / kg) n Dosing start time Route of administration / dosing frequency Sham operation - 6 60 min after ischemia IV injection / single dose Model control - 6 60 min after ischemia IV injection / single dose Compound 1 0.4 6 60 min after ischemia IV injection / single dose Compound 5 0.4 6 60 min after ischemia IV injection / single dose Compound 7 0.4 6 60 min after ischemia IV injection / single dose

[0109] (3) Dosing regimen At 60 min after suture occlusion, a single tail vein injection of the solution of Compound 1, Compound 5 or Compound 7 was performed, and a single tail vein injection of vehicle normal saline was performed in the sham operation group and the model control group. The experimental endpoint was set at 24 h after cerebral occlusion.

[0110] (4) detection indicators:

[0111] Neurological deficit score: The severity of neurological deficits in animals was scored in a blinded fashion before modeling, at 55 min after ischemia and at 24 h after modeling, with a total score of 16 points.

[0112] Infarct area measurement: At 24 h after administration, the animals were decapitated, and the whole brains were harvested. The brain tissues were sliced and immersed in a 1% 2,3,5-triphenyltetrazolium chloride (TTC) solution for staining, and then the percentage of cerebral infarct area was calculated. 3.2 Data analysis

[0113] The experimental data were expressed as mean±standard deviation (mean±SD) and analyzed using IBM SPSS Statistics 25.0 statistical software. Multiple-group comparisons were statistically analyzed by means of one-way analysis of variance (ANOVA). First, the data were tested for homogeneity of variances, if P<0.05, the data were considered to have unequal variances; if P>0.05, the data were considered to have equal variances. For data with equal variances, multiple comparisons were performed using the LSD test. For data with unequal variances, Dunnett's T3 test was used for statistical analysis. A value of P<0.05 was regarded as statistically significant. 4.     Experimental results

[0114] The neurological deficit scoring results of rats in each group are shown in FIG. 1 and Table 4. Compared with the sham operation group, rats in the model control group had significant behavioral disorders at 24 h after modeling, with a score of 9.0 at 24 h after modeling (P<0.001). Compared with the model control group, 0.4 mg / kg Compound 1, administered at 1 h after suture occlusion, significantly improved the neurological deficit scores, with an improvement rate of 24.4% (P<0.01), and 0.4 mg / kg Compound 5 and 0.4 mg / kg Compound 7 showed a trend toward improvement in neurological deficit scores, with improvement rates of 11.1% (P>0.05) and 13.0% (P>0.05), respectively. Table 4 Effects of compounds on neurological deficit scores in rats with permanent ischemic stroke (Mean ± SD, n=6) Neurological deficit score Group (mg / kg) n Score before administration Score at 24 h after model establishment Improvement rate (%) Sham operation Saline 6 0±0 0±0 - group Model control Saline 6 10.33±0.52 9.0±0.89### - group Compound 1 0.4 6 10.4±0.55 6.8±0.84** 24.4 Compound 5 0.4 6 10.33±0.52 8.0±1.1 11.1 Compound 7 0.4 6 10.5±0.55 7.83±1.17 13.0 Notes: 1. Compared with the sham operation group: ###P<0.001; 2. Compared with the model control group: **P< 0.01

[0115] The percentage infarct areas of rats in each group are shown in FIG. 2 and Table 5. Compared with the sham operation group, rats in the model control group exhibited obvious cerebral infarction, with a mean infarct area of 25.88 (P<0.001). Compared with the model control group, 0.4 mg / kg Compound 1, administered at 1 h after suture occlusion, significantly improved the cerebral infarct area, with an improvement rate of 33.0% (P<0.01), and 0.4 mg / kg Compound 5 and 0.4 mg / kg Compound 7 showed a trend toward improvement in cerebral infarct area, with improvement rates of 8.5% (P>0.05) and 9.6% (P>0.05), respectively. Compound 1 at 0.4 mg / kg had a significant improvement effect on the cerebral infarct area compared with Compound 5 or Compound 7 at the same dose (33.0% vs 8.5% vs 9.6%, P<0.05). Table 5 Effects of compounds on cerebral infarct areas in rats with permanent ischemic stroke (Mean ± SD, n=6) Group Dose (mg / kg) n Infarct area% Improvement rate (%) Sham operation Saline 6 0±0 - group Model control group Saline 6 25.88±4.09### - Compound 1 0.4 6 17.33 ± 3.68**$ 33.0 Compound 5 0.4 6 23.68±4.49 8.5 Compound 7 0.4 6 23.4±4.62 9.6 Notes: 1. Compared with the sham operation group: ###P<0.001; 2. Compared with the model control group: **P< 0.01; 3. Compared with Compound 5 or Compound 7: $P < 0.05

Claims

1. A compound or a pharmaceutically acceptable salt thereof,Hh3C oh.

2. A compound or a pharmaceutically acceptable salt thereof,3. A compound or a pharmaceutically acceptable salt thereof,HQZT'fh3C oh.

4. A compound or a pharmaceutically acceptable salt thereof,5. An isotopically substituted compound of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, preferably, the isotopically substituted compound is a deuterated compound.

6. A pharmaceutical composition, comprising a therapeutically effective amount of at least one of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the isotopically substituted compound according to claim 5, and a pharmaceutically acceptable excipient.

7. A method for treating cardiovascular and cerebrovascular diseases, comprising administering to a patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the isotopically substituted compound according to claim 5, or the pharmaceutical composition according to claim 6.

8. The method according to claim 7, characterized in that the cardiovascular and cerebrovascular diseases are selected from the group consisting of ischemic cerebrovascular disease, cerebral infarction, myocardial infarction, and coronary heart disease.

9. Use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the isotopically substituted compound according to claim 5, or the pharmaceutical composition according to claim 6 in the manufacture of a medicament for treating cardiovascular and cerebrovascular diseases.

10. The use according to claim 9, characterized in that the cardiovascular and cerebrovascular diseases are selected from the group consisting of ischemic cerebrovascular disease, cerebral infarction, myocardial infarction, and coronary heart disease.

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