Borneolum syntheticum derivative and application thereof in pharmacy

Abstract

The invention discloses a borneol derivative and application thereof in pharmacy. The borneol derivative is a compound shown as a general formula (I) and a general formula (II), and pharmaceutically acceptable salt and / or hydrate and deuterated compound thereof, and / or racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereoisomer and tautomer thereof. Experimental results show that the borneol derivative can significantly reduce the epileptic seizure grade and improve the epileptic seizure latency, shows a good anti-epileptic effect, and has a good development prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a class of borneol derivatives and their applications in pharmacy, especially their uses in anti-epileptic drugs. Background Art

[0002] Epilepsy is a common clinical neurological disease with an incidence rate of about 1%. The characteristic of epilepsy is epileptic seizures caused by abnormal synchronous discharge of neurons in the brain. If epileptic seizures are not controlled, they will cause serious harm to the patient's quality of life and even life safety. At present, drugs are mainly used clinically to control epileptic seizures. Traditional anti-epileptic drugs mainly act on ion channels or γ-aminobutyric acid receptors on neurons to reduce the excitability in the brain. However, at present, about one-third of the patients still experience ineffective treatment with a variety of different drugs and are called refractory epilepsy or intractable epilepsy. There is still a lack of effective treatment means for refractory epilepsy. Treatments such as surgical resection of lesions are only effective for some patients and are very likely to cause sequelae. Therefore, there is an urgent need to find new structural entity compounds for the treatment of epilepsy.

[0003] Borneol is a commonly used adjuvant drug in traditional Chinese medicine. Traditional Chinese medicine believes that it has the effects of resuscitating the patient from unconsciousness, clearing heat and relieving pain, and promoting granulation. Modern medical research shows that borneol has anti-inflammatory and analgesic, antibacterial, antiviral, protecting the heart and brain, bidirectionally regulating the nervous system, and improving the bioavailability of other drugs. Recently, we found that borneol has anti-epileptic effects, but borneol has a short in vivo biological half-life and poor liposolubility. In order to improve the pharmacokinetic properties and physicochemical properties of borneol and at the same time enhance the anti-epileptic effect, we designed and synthesized a class of structurally novel borneol derivatives and their pharmaceutically acceptable salts. Summary of the Invention

[0004] The present invention provides the applications of a class of borneol derivatives and their pharmaceutically acceptable salts in pharmacy. Some compounds were evaluated for anti-epileptic effects, such as the pentylenetetrazol acute seizure model (PTZ) and the maximal electroshock seizure model (MES). This class of borneol derivatives can significantly reduce the seizure grade and increase the seizure latency, showing good anti-epileptic effects and having good development prospects.

[0005] The present invention provides a borneol derivative, which is a compound represented by the general formula (I) or formula (II) and its pharmaceutically acceptable salts and / or hydrates, deuterated compounds, and / or their racemic mixtures, solvates, prodrugs, enantiomers, diastereoisomers and tautomers;

[0006]

[0007] In formula (I), X is oxygen, and R 1 is substituted or unsubstituted C 1 ~C6 Alkyl acyl, C 5 -C 8 Cycloalkyl acyl, C 5 -C 8 Heterocycloalkyl acyl, protected or unprotected amino acid ester, substituted or unsubstituted benzoyl, phosphate group, carbonic acid amide ester; or,

[0008] In formula (II), X is NH, R 1 is a hydrogen atom, substituted or unsubstituted C 1 -C 6 alkyl acyl, substituted or unsubstituted benzoyl;

[0009] In formula (II), R 2 is a deuterium atom, substituted or unsubstituted C 1 -C 6 alkyl, trifluoromethyl, substituted or unsubstituted phenyl, C 5-6 heteroaryl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted phenylacetylene, or pyridineacetylene;

[0010] The substituent on the C 1 -C 6 alkyl acyl, amino acid ester, benzoyl, C 1 -C 6 alkyl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl or phenylacetylene is selected from one or more of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester group.

[0011] Preferably, in formula (I), X is oxygen, R 1 is substituted or unsubstituted C 1 -C 6 alkyl acyl, C 5 -C 8 cycloalkyl acyl, piperidinyl acyl, N-methylpiperazinyl acyl, substituted or unsubstituted benzoyl, -PO(OH) 2 ; or,

[0012] X is NH, R 1 is a hydrogen atom, substituted or unsubstituted C 1 -C 6 alkyl acyl, substituted or unsubstituted benzoyl;

[0013] In formula (II), R 2 is a deuterium atom, a substituted or unsubstituted C 1 ~C 6 alkyl group, trifluoromethyl group, substituted or unsubstituted phenyl group, pyridyl group, substituted or unsubstituted C 2-6 alkenyl group, substituted or unsubstituted C 2-6 alkynyl group, substituted or unsubstituted phenyl ethynyl group, or pyridyl ethynyl group;

[0014] The C 1 ~C 6 alkyl acyl group, amino acid ester, benzoyl group, C 1 ~C 6 alkyl acyl group, C 1 ~C 6 alkyl group, phenyl group, C 2-6 alkenyl group, C 2-6 The substituents on the alkynyl group or phenyl ethynyl group are selected from one or more of C 1 ~C 6 alkyl group, C 1 ~C 6 alkoxy group, C 1 ~C 6 alkoxycarbonyl group, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester group.

[0015] As a further preference, the borneol derivative and its pharmaceutically acceptable salt are selected from one of the following specific compounds:

[0016]

[0017]

[0018] As a further preference, the borneol derivative is compound 8, compound 10 or compound 13 above, and most preferably compound 13.

[0019] The compounds of the present invention can be formulated into several dosage forms, such as injections, tablets, powders, granules, capsules, oral liquids, ointments, suppositories, etc. The drugs of the above various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.

[0020] The compounds of the present invention and the pharmaceutical compositions containing the compounds of the present invention can be formulated into forms suitable for intravenous, oral, rectal, parenteral, intranasal or transdermal administration, or forms suitable for administration by inhalation or by suppository. Oral and intravenous administrations are preferred.

[0021] The applications of the borneol derivatives and pharmaceutical compositions thereof of the present invention in preparing anti-epileptic drugs, drugs for treating nervous system diseases, drugs for treating cardiovascular diseases, drugs for treating metabolic diseases, drugs for treating pain diseases, drugs for reversing multidrug resistance of tumors and adjuvant drugs, anti-inflammatory drugs, drugs for treating autoimmune diseases, anti-infective drugs and drugs for treating respiratory system diseases, etc.

[0022] The nervous system diseases mentioned above include but are not limited to cerebral hemorrhage, subarachnoid hemorrhage, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, central nervous system infectious diseases, multiple sclerosis, facial neuritis, sciatica, spinal cord compression.

[0023] The cardiovascular and cerebrovascular diseases mentioned above include but are not limited to latent coronary heart disease, angina pectoris, myocardial infarction, ischemic cardiomyopathy, sudden death type coronary heart disease, sinus arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrioventricular block, heart failure, hypertension, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, pericardial diseases, stroke, thromboangiitis obliterans and varicose veins of lower extremities;

[0024] The metabolic diseases, liver and kidney diseases mentioned above include but are not limited to diabetes, gout, thyroid dysfunction, osteoporosis, hyperhomocysteinemia, hepatitis C, hepatitis E, liver cirrhosis, fatty liver, hypercholesterolemia, mixed hyperlipidemia, hyperuricemia, gouty nephropathy, metabolic syndrome, liver fibrosis, glomerulonephritis, acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis and kidney stones;

[0025] The pain diseases mentioned above include but are not limited to acute trauma, acute inflammation, postoperative pain, acute toothache, chronic back pain, fibromyalgia, arthritis, neuropathic pain, headache, chronic abdominal pain, cancer-related pain, painful menstruation, temporomandibular joint disorder, neuralgia, pain caused by cancer metastasis, bone pain and spinal cord compression;

[0026] The inflammatory diseases and autoimmune diseases mentioned above include but are not limited to rheumatoid arthritis, gouty arthritis, prostatitis, pelvic inflammatory disease, otitis media, colitis, chronic obstructive pulmonary disease, allergic rhinitis, osteomyelitis, epididymitis, pyelonephritis, bronchitis, asthma, lupus erythematosus, psoriasis, erythema nodosum, synovitis, polymyalgia rheumatica, granulomatous inflammation, systemic vasculitis, Sjogren's syndrome, scleroderma, autoimmune thyroiditis, type 1 diabetes, myasthenia gravis, autoimmune hepatitis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, sympathetic ophthalmia, autoimmune inner ear disease and multiple sclerosis;

[0027] The infectious diseases mentioned above include but are not limited to fungal infections, viral infections and parasitic infections;

[0028] The described respiratory diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, allergic rhinitis, and bronchiectasis.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] By structurally modifying borneol, the present invention obtains a class of borneol derivatives that can significantly reduce the seizure grade and increase the seizure latency, showing good antiepileptic effects and having good development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the test result of the MES model in Biological Example 1;

[0032] Figure 2 It is the test result of the PTZ model in Biological Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention will be described in detail below with reference to specific embodiments. These embodiments are only used to explain the technical solutions of the present invention and do not form any limitation to the present invention.

[0034] The borneol derivatives 1 to 30 used in the present invention can be prepared by the following method:

[0035] Synthesis Example 1

[0036] (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl dihydrogen phosphate (1)

[0037]

[0038] Dissolve dibenzyl phosphite (5.0 mmol) in 10 mL of anhydrous toluene, and then add N-chlorosuccinimide (6.0 mmol). After stirring at room temperature for 2 hours, filter the mixture to remove the white precipitate. Concentrate the filtrate to obtain pale yellow oily dibenzyl chlorophosphate. Dissolve D-(+)-borneol (4.0 mmol) in 20 mL of anhydrous tetrahydrofuran and cool to -78 °C. Then, slowly add dropwise 1.6 mL of n-butyllithium (2.5 M in hexane, 4 mmol), and continue stirring for 15 minutes. Subsequently, add the freshly prepared dibenzyl chlorophosphate. Stir the reaction solution at -78 °C for 2 hours, and quench with saturated NH 4 Cl aqueous solution. Dilute the reaction solution with water and extract three times with ethyl acetate. Combine the organic phases, wash three times with saturated NaCl, and anhydrous Na 2 SO 4Dry under reduced pressure to concentrate and remove the solvent. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the phosphate intermediate with a yield of 65%.

[0039] Dissolve the above phosphate intermediate in 30 mL of methanol, add 100 mg of Pd / C (10 wt%), evacuate and replace with hydrogen three times. After stirring at room temperature for 12 hours, filter through diatomaceous earth and collect the filtrate. Concentrate under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain Compound 1 with a yield of 87%.

[0040] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 154.7 - 154.9 °C; 1 HNMR (400 MHz, CDCl 3 ) δ 9.28 (br, 2H), 4.51 (s, 1H), 2.29 (s, 1H), 1.95 (s, 1H), 1.68 (m, 2H), 1.27 (m, 3H), 0.86 (m, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 85.01, 49.79, 47.77, 44.92, 36.76, 28.04, 26.40, 20.07, 18.90, 13.17.

[0041] Synthesis Example 2

[0042] (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl piperidine-3-carboxylic acid hydrochloride (2)

[0043]

[0044] Weigh D-(+)-borneol (1.0 mmol), DCC (1.5 mmol), DMAP (0.2 mmol) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.5 mmol), and add 4 mL of anhydrous dichloromethane. Then, stir the reaction solution at room temperature for 12 hours. Filter through diatomaceous earth and collect the filtrate. Concentrate under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain the intermediate with a yield of 89%.

[0045] Dissolve the above intermediate in an ethyl acetate solution of hydrogen chloride (4.0 M), seal the tube and react at room temperature for 5 hours. Then, filter the precipitate in the reaction solution and wash it with ether to obtain Product 2 with a yield of 76%.

[0046] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 205.3 - 205.8 °C; 1 HNMR (400 MHz, CDCl 3; diastereoisomer) δ9.67 (br, 2H), 4.89 (t, J = 10.7 Hz, 1H), 3.62 (d, J = 6.5 Hz, 1H), 3.47 (d, J = 11.4 Hz, 1H), 3.15–2.91 (m, 2H), 2.83 (t, J = 11.0 Hz, 1H), 2.42–2.19 (m, 2H), 2.15–1.50 (m, 7H), 1.37–1.15 (m, 2H), 0.83 (dd, J = 26.8, 6.3 Hz, 9H). 13 C NMR (101 MHz, CDCl 3 ; diastereoisomer) δ171.80, 171.69, 81.23, 81.05, 49.03, 48.95, 48.04, 44.96, 44.90, 44.80, 44.76, 44.05, 38.78, 38.70, 37.01, 36.70, 28.14, 28.08, 27.26, 26.23, 26.00, 21.71, 19.77, 18.92, 13.65.

[0047] Synthesis Example 3

[0048] (1R,2S,4R)-1,7,7-Trimethyldicyclo[2.2.1]heptan-2-yl 4-aminobutyrate hydrochloride (3)

[0049]

[0050] The preparation method was the same as in Example 2, and the acid used was 4-(tert-butoxycarbonyl)amino)butyric acid.

[0051] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 97.7 - 97.9 °C; 1 H NMR (400 MHz, CDCl 3 ) δ8.15 (br, 3H), 4.84 (d, J = 9.0 Hz, 1H), 3.11 (s, 2H), 2.49 (s, 2H), 2.30 (t, J = 10.9 Hz, 1H), 2.10 (s, 2H), 1.89 (t, J = 10.4 Hz, 1H), 1.78–1.60 (m, 2H), 1.34–1.16 (m, 2H), 0.95 (d, J = 13.5 Hz, 1H), 0.87 (s, 3H), 0.85 (s, 3H), 0.80 (s, 3H). 13 C NMR (101 MHz, CDCl 3)δ 173.38, 80.64, 48.86, 47.92, 44.95, 39.59, 36.85, 31.56, 28.09, 27.20, 22.91, 19.81, 18.96, 13.72. Synthesis Example 4

[0052] (S)--2-Amino-4-oxo-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)butanoic acid hydrochloride (4)

[0053]

[0054] The preparation method was the same as that of Example 2, and the acid used was (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid.

[0055] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 178.9 - 179.3 °C; 1 HNMR(500MHz, CDCl 3 )δ 8.18(br, 2H), 4.90(s, 1H), 4.54(s, 1H), 3.25(s, 2H), 2.31(s, 1H), 1.90(s, 1H), 1.78–1.60(m, 2H), 1.35–1.17(m, 2H), 1.04(d, J = 11.7Hz, 1H), 0.93–0.78(m, 9H). 13 C NMR(126MHz, CDCl 3 )δ 171.65, 170.83, 82.18, 50.31, 49.02, 47.99, 44.94, 36.55, 34.02, 28.00, 27.18, 19.82, 19.04, 13.72.

[0056] Synthesis Example 5

[0057] (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl-4-methylpiperazine-1-carboxylic acid hydrochloride (5)

[0058]

[0059] Weigh D-(+)-borneol (1.0 mmol) and CDI (1.5 mmol), and add 4 mL of anhydrous acetonitrile. React at room temperature until D-(+)-borneol is completely consumed. Then, add N-methylpiperazine (2.0 mmol), and monitor the reaction until the intermediate formed in the first step is completely consumed. Dilute the reaction solution with water and extract it three times with ethyl acetate. Combine the organic phases, wash them three times with saturated NaCl, and anhydrous Na2 SO 4 Dry, and concentrate under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the target intermediate with a yield of 58%.

[0060] Dissolve the above intermediate in EtOAc, and add an ethyl acetate solution of hydrogen chloride (4.0 M). During the addition of hydrogen chloride, a white precipitate was formed in the reaction solution, and stirring was continued for 10 minutes. Filter the precipitate in the reaction solution and wash it with ether to obtain Product 5 with a yield of 91%.

[0061] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 232.4 - 233.0 °C; 1 HNMR(400MHz,CDCl 3 ) δ 4.80 (d, J = 8.7 Hz, 1H), 4.16 (s, 2H), 3.70 (s, 2H), 3.50 (s, 2H), 2.84 (s, 5H), 2.33 (t, J = 10.0 Hz, 1H), 1.81–1.69 (m, 2H), 1.66 (s, 1H), 1.30 (t, J = 13.2 Hz, 1H), 1.19 (t, J = 9.3 Hz, 1H), 0.97 (d, J = 13.7 Hz, 1H), 0.87 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H). 13 C NMR(101MHz,CDCl 3 ) δ 155.17, 82.21, 53.52, 48.97, 47.90, 44.83, 43.91, 40.79, 36.97, 28.10, 27.44, 19.75, 18.90, 13.66.

[0062] Synthesis Example 6

[0063] (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-amine hydrochloride (6)

[0064]

[0065] Dissolve (R)-(+)-borneolamine (1.0 mmol) in EtOAc, and add an ethyl acetate solution of hydrogen chloride (4.0 M). During the addition of hydrogen chloride, a white precipitate was formed in the reaction solution, and stirring was continued for 10 minutes. Filter the precipitate in the reaction solution and wash it with ether to obtain Product 6 with a yield of 96%.

[0066] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 192.6 - 193.0 °C; 1 HNMR(400MHz,CDCl3 ) δ 6.12 (br, 3H), 3.32 (dd, J = 10.5, 2.7 Hz, 1H), 2.34–2.24 (m, 1H), 1.85–1.65 (m, 3H), 1.52–1.37 (m, 2H), 1.19 (dd, J = 13.5, 4.0 Hz, 1H), 0.97 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 57.12, 48.89, 48.83, 44.84, 35.81, 27.92, 27.38, 19.86, 18.59, 13.60. Synthesis Example 7

[0067] N-((1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl)acetamide (7)

[0068]

[0069] Dissolve (R)-(+)-borneolamine (0.5 mmol) and triethylamine (1.0 mmol) in 4.0 mL of anhydrous dichloromethane and cool to 0 °C. Then, add acetyl chloride (0.75 mmol) to the reaction solution and react at room temperature for 2 - 3 hours. Dilute the reaction solution with water and extract three times with ethyl acetate. Combine the organic phases, wash three times with saturated NaCl, and dry over anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure to remove the solvent. Purify the crude product by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 7 in a yield of 95%.

[0070] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 126.3 - 126.6 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 5.56 (s, 1H), 4.32–4.15 (m, 1H), 2.39–2.28 (m, 1H), 1.99 (s, 3H), 1.81–1.70 (m, 1H), 1.64 (t, J = 4.4 Hz, 1H), 1.51–1.32 (m, 2H), 1.20–1.10 (m, 1H), 0.93 (s, 3H), 0.86 (s, 3H), 0.83–0.72 (m, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 170.17, 53.85, 49.43, 48.23, 45.00, 37.79, 28.48, 28.10, 23.79, 19.93, 18.76, 13.75.

[0071] Synthesis Example 8

[0072] (1R,2R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol (8)

[0073]

[0074] Dissolve LiAlD 4 (10 mmol) in 30 mL of anhydrous tetrahydrofuran and cool to -78 °C. Slowly add a tetrahydrofuran solution of D-(+)-camphor (10 mmol) to the reaction system, and then slowly warm to room temperature. After the reaction is completed, quench with saturated NH 4 Cl aqueous solution. Dilute the reaction solution with water and extract three times with ethyl acetate. Combine the organic phases, wash three times with saturated NaCl, and dry over anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure to remove the solvent. Purify the crude product by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 8 in a yield of 79%.

[0075] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 208.4 - 209.0 °C; 1 HNMR (400 MHz, CDCl 3 ) δ 1.74–1.68 (m, 3H), 1.66 (s, 2H), 1.53–1.43 (m, 1H), 1.01 (s, 3H), 0.97 (t, J = 1.8 Hz, 1H), 0.89 (s, 3H), 0.81 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 79.55 (t, J = 22.6 Hz), 48.97, 46.48, 45.15, 40.40, 33.99, 27.36, 20.58, 20.23, 11.44.

[0076] Synthesis Example 9

[0077] (1R,2R,4R)-1,2,7,7-Tetramethylbicyclo[2.2.1]heptan-2-ol (9)

[0078]

[0079] Dissolve anhydrous CeCl 3(18 mmol) was dried under vacuum at 160 °C for 6 hours, cooled to room temperature, and then 20 mL of anhydrous tetrahydrofuran and D-(+)-camphor (10 mmol) were added. It was stirred at room temperature for 1 hour, and the reaction solution turned yellow. Then, methylmagnesium bromide (20 mmol) was slowly added dropwise, and the reaction continued for 24 hours. After the reaction was completed, it was quenched with saturated NH 4 Cl aqueous solution. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated NaCl, and dried over anhydrous Na 2 SO 4 . The solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 9 with a yield of 49%.

[0080] The physicochemical properties and spectral data of the product are as follows: white solid; mp: 157.7 - 158.2 °C; 1 HNMR (400 MHz, CDCl 3 ) δ 2.12–2.00 (m, 1H), 1.79–1.61 (m, 2H), 1.44–1.31 (m, 4H), 1.22 (d, J = 3.1 Hz, 3H), 1.09 (d, J = 2.7 Hz, 3H), 1.05–0.96 (m, 1H), 0.85 (d, J = 2.9 Hz, 3H), 0.83 (d, J = 3.3 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 79.74, 52.04, 49.04, 47.41, 45.54, 31.45, 27.14, 26.96, 21.56, 21.28, 10.02.

[0081] Synthesis Example 10

[0082] (1R,2R,4R)-1,7,7-Trimethyl-2-(trifluoromethyl)bicyclo[2.2.1]heptan-2-ol (10)

[0083]

[0084] D-(+)-Camphor (10 mmol) and TMSCF 3 (20 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, and CsF (5 mmol) was added at 0 °C. Then, the reaction was carried out at room temperature and monitored by TLC until the substrate disappeared. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated NaCl, and dried over anhydrous Na 2 SO 4 . The solvent was removed by concentration under reduced pressure.

[0085] Dissolve the above residue in 20 mL of tetrahydrofuran, and add tetrabutylammonium fluoride (1 M in THF, 10 mmol). After the reaction is completed (monitored by TLC), the reaction solution is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed three times with saturated NaCl, and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 10 in a yield of 28%.

[0086] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 49.2 - 49.6 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 2.05–1.90 (m, 2H), 1.90–1.78 (m, 2H), 1.78–1.69 (m, 1H), 1.67–1.56 (m, 1H), 1.54–1.43 (m, 1H), 1.22–1.14 (m, 1H), 1.11 (s, 3H), 0.99 (s, 3H), 0.88 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 127.12 (q, J=286.7 Hz), 81.80 (q, J=26.2 Hz), 52.17, 50.12, 44.73, 40.95, 28.96 (q, J=2.9 Hz), 26.44, 21.23, 20.34, 10.70. 19 F NMR (376 MHz, CDCl 3 ) δ -74.49.

[0087] Synthesis Example 11

[0088] (1R,2R,4R)-2-Ethyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (11)

[0089]

[0090] The preparation method is the same as that of Example 9, using ethylmagnesium bromide as the Grignard reagent, with a yield of 42%.

[0091] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 65.9 - 66.3 °C; 1 H NMR (400 MHz, CDCl 3) δ 1.91 (dt, J = 13.1, 3.7 Hz, 1H), 1.73–1.63 (m, 2H), 1.58–1.46 (m, 2H), 1.44–1.31 (m, 3H), 1.20 (s, 1H), 1.10 (s, 3H), 1.03–0.92 (m, 4H), 0.85 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 81.38, 52.32, 49.58, 45.30, 45.12, 31.90, 30.51, 27.17, 21.65, 21.16, 10.79, 8.77.

[0092] Synthesis Example 12

[0093] (1R,2S,4R)-1,7,7-Trimethyl-2-vinylbicyclo[2.2.1]heptan-2-ol (12)

[0094]

[0095] The preparation method was the same as that of Example 9, and the format reagent used was vinylmagnesium bromide, with a yield of 34%.

[0096] The physical and chemical properties and spectral data of the product are as follows: colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 6.02 (dd, J = 17.3, 10.7 Hz, 1H), 5.23 (dd, J = 17.3, 1.1 Hz, 1H), 5.08 (dd, J = 10.7, 1.2 Hz, 1H), 2.04–1.96 (m, 1H), 1.77 (t, J = 4.5 Hz, 1H), 1.73–1.64 (m, 2H), 1.46 (s, 1H), 1.38–1.32 (m, 2H), 1.14 (s, 3H), 1.06–0.97 (m, 1H), 0.86 (s, 3H), 0.82 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 144.09, 112.27, 81.67, 52.79, 49.20, 45.62, 44.91, 31.33, 26.94, 21.46, 21.07, 9.85.

[0097] Synthesis Example 13

[0098] (1R,2S,4R)-2-Ethynyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (13)

[0099]

[0100] Dissolve ethynyltrimethylsilane (15 mmol) in 30 mL of anhydrous tetrahydrofuran, and cool it to -78 °C. Then, slowly add n-butyllithium (2.5 M in hexane, 15 mmol), and continue the reaction for 1 hour. Subsequently, slowly add a tetrahydrofuran solution of D-(+)-camphor (10 mmol) to the reaction system, and then slowly warm it to room temperature and react overnight. After the reaction is completed, quench it with saturated aqueous NH 4 Cl. Dilute the reaction solution with water and extract it three times with ethyl acetate. Combine the organic phases, wash them three times with saturated NaCl, and dry them over anhydrous Na 2 SO 4 . Concentrate under reduced pressure to remove the solvent. Purify the crude product by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the intermediate with a yield of 59%.

[0101] Dissolve the above intermediate (5 mmol) in 10 mL of methanol, then add potassium carbonate (10 mmol), and react at room temperature for 5 hours. After the reaction is completed, remove the solvent under reduced pressure. Recrystallize the residue to obtain Compound 13 with a yield of 82%.

[0102] The physicochemical properties and spectral data of the product are as follows: white solid; mp: 57.8 - 58.1 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 2.46 (s, 1H), 2.22 (dt, J = 13.5, 3.8 Hz, 1H), 1.98 (s, 1H), 1.93–1.84 (m, 2H), 1.76 (t, J = 4.4 Hz, 1H), 1.75–1.64 (m, 1H), 1.53–1.43 (m, 1H), 1.13 (ddd, J = 12.4, 9.4, 4.8 Hz, 1H), 1.05 (s, 3H), 0.95 (s, 3H), 0.87 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 88.18, 78.03, 71.68, 53.54, 48.18, 48.03, 45.47, 32.49, 26.98, 21.45, 21.06, 10.27.

[0103] Synthesis Example 14

[0104] (1R,2S,4R)-1,7,7-Trimethyl-2-(prop-1-yn-1-yl)bicyclo[2.2.1]heptan-2-ol (14)

[0105]

[0106] The preparation method is the same as that of Example 9, and the Grignard reagent used is propargylmagnesium bromide, with a yield of 48%.

[0107] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 72.8 - 73.1 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 2.18 (d, J = 13.2 Hz, 1H), 1.93–1.76 (m, 6H), 1.75–1.70 (m, 1H), 1.70–1.61 (m, 1H), 1.43 (td, J = 12.3, 4.5 Hz, 1H), 1.16–1.07 (m, 1H), 1.04 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 83.60, 79.31, 78.33, 53.58, 48.31, 47.91, 45.51, 32.65, 27.04, 21.56, 21.14, 10.40, 3.77.

[0108] Synthesis Example 15

[0109] (1R,2S,4R)-1,7,7-Trimethyl-2-phenyldicyclo[2.2.1]heptan-2-ol (15)

[0110]

[0111] The preparation method is the same as that of Example 9, and the Grignard reagent used is phenylmagnesium bromide, with a yield of 33%.

[0112] The physical and chemical properties of the product are as follows: colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58–7.53 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.31–7.25 (m, 1H), 2.35 (d, J = 13.9 Hz, 1H), 2.26–2.17 (m, 1H), 1.93 (t, J = 4.3 Hz, 1H), 1.87 (d, J = 0.8 Hz, 1H), 1.81–1.69 (m, 1H), 1.30 (s, 3H), 1.29–1.17 (m, 2H), 0.94 (s, 6H), 0.90–0.82 (m, 1H). 13 C NMR (101 MHz, CDCl 3)δ146.25,127.70,126.93,126.89,83.73,53.61,50.59,45.76,45.61,31.37,26.70,21.79,9.97.

[0113] Synthesis Example 16

[0114] (1R,2S,4R)-2-(4-Fluorophenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (16)

[0115]

[0116] The preparation method was the same as that of Example 9, using freshly prepared Grignard reagent 4-fluorophenylmagnesium bromide, with a yield of 39%.

[0117] The physical and chemical properties and spectral data of the product are as follows: white solid; mp: 54.5 - 54.7 °C; 1 H NMR (400 MHz, CDCl 3 )δ7.49 (dd, J = 7.1, 5.8 Hz, 2H), 7.01 (t, J = 8.2 Hz, 2H), 2.27 (d, J = 13.9 Hz, 1H), 2.20 (d, J = 14.0 Hz, 1H), 1.91 (s, 1H), 1.81 (s, 1H), 1.79–1.68 (m, 1H), 1.31–1.15 (m, 5H), 0.92 (s, 3H), 0.89 (s, 3H), 0.84–0.75 (m, 1H). 13 C NMR (101 MHz, CDCl 3 )δ161.93 (d, J = 245.5 Hz), 141.89 (d, J = 2.8 Hz), 128.54 (d, J = 7.8 Hz), 114.31 (d, J = 20.9 Hz), 83.41, 53.63, 50.50, 45.90, 45.67, 31.30, 26.67, 21.81, 21.76, 9.87.

[0118] Synthesis Example 17

[0119] (1R,2R,4R)-1,7,7-Trimethyl-2-(pyridin-3-yl)bicyclo[2.2.1]heptan-2-ol (17)

[0120]

[0121] Preparation of Grignard reagent: Under a nitrogen atmosphere, 3-bromopyridine (10.0 mmol) and LiCl (10.0 mmol, vacuum dried at 160 °C for 6 hours) were dissolved in 20 mL of anhydrous tetrahydrofuran and cooled to 0 °C. Then, isopropylmagnesium chloride (2.0 M in THF, 10.0 mmol) was slowly added, and the reaction was carried out at room temperature for 3 hours.

[0122] Next, D-(+)-camphor (5.0 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and then LaCl 3 ·2LiCl (0.6 M in THF, 5.0 mmol) was added, and the mixture was cooled to -20 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was cooled to -20 °C again, and then all of the above-prepared Grignard reagent was added, and the temperature was slowly raised to room temperature and the reaction was carried out overnight. After the reaction was completed, it was quenched with a saturated NH 4 Cl aqueous solution. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated NaCl, and dried over anhydrous Na 2 SO 4 4. The solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 17 with a yield of 28%.

[0123] The physicochemical properties and spectral data of the product are as follows: white solid; mp: 123.6 - 124.0 °C; 1 1H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.42 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 2.43 (br, 1H), 2.31–2.17 (m, 2H), 1.93 (t, J = 3.8 Hz, 1H), 1.75 (td, J = 14.0, 3.8 Hz, 1H), 1.32–1.17 (m, 5H), 0.92 (s, 3H), 0.89 (s, 3H), 0.81–0.69 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 ) δ 148.38, 147.93, 141.42, 134.70, 122.56, 82.38, 53.72, 50.57, 45.75, 45.62, 31.24, 26.64, 21.74, 9.78.

[0124] Synthesis Example 18

[0125] (1R,2S,4R)-1,7,7-Trimethyl-2-(pyridin-4-yl)bicyclo[2.2.1]heptan-2-ol (18)

[0126]

[0127] The preparation method is the same as that of Example 17, with a yield of 21%.

[0128] The physicochemical properties and spectral data of the product are as follows: white solid; mp: 147.4 - 147.9 °C; 1 HNMR(400MHz,CDCl 3 )δ8.41(d,J = 4.8Hz,2H),7.38(d,J = 4.8Hz,2H),2.82(br,1H),2.20(s,2H),1.91(s,1H),1.75(t,J = 10.3Hz,1H),1.30–1.16(m,5H),0.90(s,3H),0.87(s,3H),0.79–0.69(m,1H). 13 C NMR(101MHz,CDCl 3 )δ155.44,148.93,122.23,82.69,53.53,50.80,45.59,45.57,31.06,26.67,21.68,21.60,9.76.

[0129] Synthesis Example 19

[0130] (1R,2S,4R)-2-(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (19)

[0131]

[0132] The preparation method is the same as that of Example 9, using freshly prepared phenylmagnesium bromide 4 - methoxy, with a yield of 43%.

[0133] The physicochemical properties and spectral data of the product are as follows: white solid; mp: 64.2 - 64.4 °C; 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J = 8.9Hz,2H),6.86(d,J = 8.9Hz,2H),3.81(s,3H),2.28(d,J = 13.9Hz,1H),2.22–2.15(m,1H),1.89(t,J = 4.3Hz,1H),1.78(s,1H),1.77–1.66(m,1H),1.26(s,3H),1.25–1.14(m,2H),0.91(s,3H),0.90(s,3H),0.84(ddd,J = 13.1,9.6,3.8Hz,1H). 13 CNMR(101MHz,CDCl3 ) δ 158.50, 138.43, 127.97, 112.93, 83.46, 55.37, 53.63, 50.42, 45.71, 31.41, 26.71, 21.83, 21.77, 9.99.

[0134] Synthesis Example 20

[0135] 4-Pentyl-N-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (20)

[0136]

[0137] The preparation method is the same as that of Example 7, with a yield of 93%.

[0138] The physical and chemical properties and spectral data of the product are as follows: colorless oily; 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 6.12 (d, J = 8.4 Hz, 1H), 4.50–4.40 (m, 1H), 2.64 (t, J = 7.7 Hz, 2H), 2.51–2.39 (m, 1H), 1.88–1.76 (m, 1H), 1.70 (t, J = 4.4 Hz, 1H), 1.67–1.53 (m, 3H), 1.51–1.40 (m, 1H), 1.38–1.18 (m, 5H), 1.00 (s, 3H), 0.94–0.84 (m, 10H). 13 C NMR (101 MHz, CDCl 3 ) δ 167.74, 146.74, 132.71, 128.70, 126.93, 54.18, 49.82, 48.36, 45.10, 37.99, 35.89, 31.50, 31.07, 28.58, 28.30, 22.62, 19.98, 18.82, 14.13, 13.90. Synthesis Example 21

[0139] (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate (21)

[0140]

[0141] The preparation method is the same as that of Example 2, and the acid used is isobutyric acid, with a yield of 91%.

[0142] The physical and chemical properties and spectral data of the product are as follows: colorless oily; 1¹H NMR (400 MHz, CDCl 3 ) δ 4.87 (ddd, J = 9.9, 3.2, 2.2 Hz, 1H), 2.55 (hept, J = 7.0 Hz, 1H), 2.40–2.28 (m, 1H), 2.01–1.90 (m, 1H), 1.79–1.69 (m, 1H), 1.66 (t, J = 4.6 Hz, 1H), 1.34–1.20 (m, 2H), 1.17 (d, J = 2.4 Hz, 3H), 1.16 (d, J = 2.4 Hz, 3H), 0.96–0.88 (m, 4H), 0.86 (s, 3H), 0.81 (s, 3H). 13 ¹³C NMR (101 MHz, CDCl 3 ) δ 177.52, 79.46, 48.93, 47.94, 45.02, 36.98, 34.40, 28.19, 27.22, 19.83, 19.24, 19.10, 18.99, 13.63.

[0143] Synthesis Example 22

[0144] (1R,2S,4R)-1,7,7-Trimethyldicyclo[2.2.1]heptan-2-yl benzoate (22)

[0145]

[0146] The preparation method was the same as that of Example 2, and the acid used was benzoic acid, with a yield of 95%.

[0147] The physical and chemical properties and spectral data of the product are as follows: colorless oil; 1 ¹H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.16–5.09 (m, 1H), 2.54–2.43 (m, 1H), 2.20–2.10 (m, 1H), 1.87–1.76 (m, 1H), 1.74 (t, J = 4.5 Hz, 1H), 1.48–1.37 (m, 1H), 1.37–1.27 (m, 1H), 1.13 (dd, J = 13.8, 3.4 Hz, 1H), 0.97 (s, 3H), 0.92 (s, 6H). 13 ¹³C NMR (101 MHz, CDCl 3)δ166.93,132.87,130.99,129.63,128.44,80.63,49.20,48.00,45.09,37.03,28.22,27.51,19.86,19.05,13.75.

[0148] Synthesis Example 23

[0149] (1R,2S,4R)-1,7,7-Trimethyldicyclo[2.2.1]heptan-2-yl cyclohexanecarboxylate (23)

[0150]

[0151] The preparation method was the same as that of Example 2, and the acid used was cyclohexanecarboxylic acid, with a yield of 93%.

[0152] The physical and chemical properties and spectral data of the product are as follows: colorless oil; 1 H NMR(400MHz,CDCl 3 )δ4.90–4.83(m,1H),2.39–2.23(m,2H),1.99–1.85(m,3H),1.80–1.67(m,3H),1.68–1.57(m,2H),1.52–1.37(m,2H),1.36–1.15(m,5H),0.94–0.87(m,4H),0.86(s,3H),0.81(s,3H). 13 C NMR(101MHz,CDCl 3 )δ176.46,79.29,48.91,47.91,45.02,43.52,37.02,29.28,29.09,28.18,27.26,25.94,25.60,25.56,19.81,18.97,13.62.

[0153] Synthesis Example 24

[0154] (1R,2S,4R)-2-(Cyclopropyl ethynyl)-1,7,7-trimethyldicyclo[2.2.1]hept-2-ol (24)

[0155]

[0156] The preparation method was the same as that of Example 13, and the alkyne used was cyclopropylacetylene, with a yield of 54%.

[0157] The physical and chemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3)δ2.16 (d, J = 13.2 Hz, 1H), 1.92–1.59 (m, 5H), 1.40 (td, J = 11.9, 3.5 Hz, 1H), 1.29–1.19 (m, 1H), 1.14–1.05 (m, 1H), 1.02 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H), 0.78–0.72 (m, 2H), 0.66–0.60 (m, 2H). 13 C NMR(101MHz, CDCl 3 )δ86.93, 79.52, 78.17, 53.65, 48.36, 47.89, 45.45, 32.64, 26.99, 21.55, 21.12, 10.41, 8.47, 8.40, -0.38.

[0158] Synthesis Example 25

[0159] (1R,2S,4R)-2-(3-Hydroxyprop-1-yn-1-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (25)

[0160]

[0161] The preparation method is the same as that of Example 13, and the alkyne used is pyran, with a yield of 42%.

[0162] The physical and chemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz, CDCl 3 )δ4.30 (s, 2H), 2.81–2.28 (br, 2H), 2.25–2.16 (m, 1H), 1.88–1.78 (m, 2H), 1.75 (s, 1H), 1.72–1.62 (m, 1H), 1.45 (td, J = 13.0, 4.6 Hz, 1H), 1.16–1.07 (m, 1H), 1.04 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H). 13 C NMR(101MHz, CDCl 3 )δ89.92, 81.81, 78.09, 53.60, 51.13, 48.18, 48.02, 45.40, 32.55, 26.97, 21.45, 21.07, 10.43.

[0163] Synthesis Example 26

[0164] Methyl 3-((1R,2S,4R)-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propiolate (26)

[0165]

[0166] The preparation method was the same as that of Example 13, and the alkyne used was methyl propiolate, with a yield of 71%.

[0167] The physical and chemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3 )δ3.76(s,3H),2.28–2.16(m,2H),1.92(d,J=13.6Hz,1H),1.84–1.66(m,3H),1.19–1.11(m,1H),1.05(s,3H),0.96(s,3H),0.86(s,3H). 13 C NMR(101MHz,CDCl 3 )δ154.22,91.50,77.93,75.51,54.12,52.85,48.28,47.83,45.34,32.35,26.91,21.25,20.91,10.39.

[0168] Synthesis Example 27

[0169] (1R,2S,4R)-1,7,7-Trimethyl-2-(phenylethynyl)bicyclo[2.2.1]heptan-2-ol (27)

[0170]

[0171] The preparation method was the same as that of Example 13, and the alkyne used was phenylacetylene, with a yield of 79%.

[0172] The physical and chemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3 )δ7.48–7.38(m,2H),7.34–7.27(m,3H),2.32(dd,J=13.3,3.1Hz,1H),2.09(t,J=7.1Hz,1H),2.04–1.93(m,2H),1.81(s,1H),1.78–1.68(m,1H),1.52(td,J=13.0,4.3Hz,1H),1.25–1.15(m,1H),1.11(s,3H),1.01(s,3H),0.90(s,3H). 13 C NMR(101MHz,CDCl 3)δ131.73,128.36,128.19,123.22,93.54,83.61,78.52,53.97,48.37,48.10,45.54,32.69,27.06,21.53,21.14,10.53.

[0173] Synthesis Example 28

[0174] (1R,2S,4R)-1,7,7-Trimethyl-2-(pyridin-4-yl ethynyl)bicyclo[2.2.1]heptan-2-ol (28)

[0175]

[0176] The preparation method was the same as that of Example 13, and the alkyne used was 4-ethynylpyridine, with a yield of 63%.

[0177] The physical and chemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J = 5.9Hz,2H),7.24(d,J = 5.9Hz,2H),2.71(br,1H),2.31(dt,J = 13.5,3.8Hz,1H),1.95(d,J = 13.5Hz,1H),1.89(ddd,J = 13.2,9.4,3.8Hz,1H),1.81(t,J = 4.4Hz,1H),1.79–1.68(m,1H),1.58–1.48(m,1H),1.22–1.14(m,1H),1.10(s,3H),1.00(s,3H),0.89(s,3H). 13 C NMR(101MHz,CDCl 3 )δ149.67,131.61,125.82,98.88,81.11,78.31,54.05,48.37,48.18,45.49,32.63,27.05,21.45,21.09,10.56.

[0178] Synthesis Example 29

[0179] (1R,2S,4R)-2-((4-Fluorophenyl)ethynyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (29)

[0180]

[0181] The preparation method was the same as that of Example 13, and the alkyne used was 4-fluorophenylethyne, with a yield of 74%.

[0182] The physicochemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3 )δ7.39(dd,J=8.3,5.5Hz,2H),6.99(t,J=8.5Hz,2H),2.31(dt,J=13.4,3.6Hz,1H),2.13(s,1H),2.00–1.91(m,2H),1.80(t,J=4.3Hz,1H),1.78–1.68(m,1H),1.52(td,J=12.5,4.7Hz,1H),1.23–1.14(m,1H),1.10(s,3H),1.01(s,3H),0.90(s,3H). 13 C NMR(101MHz,CDCl 3 )δ162.44(d,J=249.1Hz),133.57(d,J=8.3Hz),119.28(d,J=3.4Hz),115.59(d,J=22.0Hz),93.21,82.56,78.46,53.94,48.35,48.08,45.50,32.67,27.05,21.50,21.12,10.51.Synthesis Example 30

[0183] (1R,2S,4R)-2-((4-Methoxyphenyl)ethynyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol(30)

[0184]

[0185] The preparation method is the same as that of Example 13, using 4-methoxyphenylacetylene, with a yield of 61%.

[0186] The physicochemical properties and spectral data of the product are as follows: white solid; 1 H NMR(400MHz,CDCl 3 )δ7.35(d,J=7.6Hz,2H),6.83(d,J=7.6Hz,2H),3.81(s,3H),2.29(d,J=13.3Hz,1H),2.08–1.90(m,3H),1.83–1.77(m,1H),1.77–1.66(m,1H),1.50(td,J=12.4,4.5Hz,1H),1.24–1.14(m,1H),1.09(s,3H),1.00(s,3H),0.89(s,3H). 13 C NMR(101MHz,CDCl 3)δ159.53,133.15,115.35,113.98,92.08,83.42,78.59,55.43,53.95,48.39,48.08,45.55,32.72,27.07,21.56,21.16,10.54.

[0187] Biological Example 1

[0188] Maximal electroshock seizure model (MES): Thirty minutes after administration of the test compound, the ears of the mice were clamped with saline-containing alligator clips, and then a stimulating current (maximum output voltage 750 V, 50 Hz sine wave pulse, 0.2 s stimulation duration) was applied. The initial stimulating current intensity was 6 mA, and it was increased by 1 mA every 2 minutes. The threshold of MES refers to the maximum current intensity at which the severity of seizure reaches tonic-clonic seizure (immediate occurrence of severe tonic seizure, maximum extension of the forelegs and hind legs, and the body becomes rigid). The duration of tonic-clonic seizure and the survival rate of the mice were also recorded. The test results are shown in Figure 1 .

[0189] The experimental results showed that Compounds 1 - 5 significantly reduced the mortality rate, but did not affect the threshold of MES. In addition, Compounds 6 and 7 had no antiepileptic effect. Compounds 8 - 18 showed antiepileptic activities to varying degrees, among which Compounds 8, 10, and 13 significantly reduced the mortality rate.

[0190] Biological Example 2

[0191] Pentylenetetrazol acute seizure model (PTZ): Thirty minutes after administration of the test drug, the mice were given 100 mg / kg of PTZ to induce seizures, and then the mice were observed for seizure activities within 30 minutes after PTZ administration. The following behavioral indices were analyzed: latency to enter the second stage (head nodding), enter the fourth stage (bilateral forelimb twitching and standing), enter the sixth stage (rigidity), and the survival rate of the mice. To detect the antiepileptic effect of the compounds, the mice were tested 0.5 hour after administration. The test results are shown in Figure 2 .

[0192] The experimental results showed that compounds 1 - 5 exhibited high anticonvulsant activity in the MES model, but did not produce anticonvulsant effects in the PTZ model, indicating that these compounds may be ineffective against epilepsy caused by GABAergic dysfunction. As expected, compounds 6 and 7 also showed inactivity in reducing the severity of PTZ-induced convulsions. In addition, compound 13 exhibited high anticonvulsant activity by prolonging the latency of seizure stages 2, 4, and 6 respectively, and no mortality was observed. Overall, compound 13 demonstrated the potential to treat tonic-clonic and myoclonic epilepsy. Therefore, compound 13 was identified as a promising and effective preferred anti-epileptic compound that requires further evaluation.

Claims

1. A borneol derivative, characterized in that: A compound represented by general formula (I) or formula (II) and a pharmaceutically acceptable salt and / or hydrate, deuterated product, and / or a racemic mixture, solvate, prodrug, enantiomer, diastereomer and tautomer thereof; In formula (I), X is oxygen, R 1 is a substituted or unsubstituted C1-C6 alkyl acyl group, a C5-C8 cycloalkyl acyl group, a C5-C8 heterocycloalkyl acyl group, a protected or unprotected amino acid ester, a substituted or unsubstituted benzoyl group, a phosphate group, or a carbonate amide ester; or X is NH, R 1 is a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl acyl group, or a substituted or unsubstituted benzoyl group; In formula (II), R 2 is a deuterium atom, a substituted or unsubstituted C1-C6 alkyl group, a trifluoromethyl group, a substituted or unsubstituted phenyl group, C 5-6 Heteroaryl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted phenylethynyl, or pyridylethynyl; The C1-C6 alkyl acyl, amino acid ester, benzoyl, C1-C6 alkyl, phenyl, C 2-6 Alkenyl, C 2-6 The substituents on the alkynyl or phenylethynyl group are selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, and ester groups.

2. The borneol derivative according to claim 1, characterized in that: In formula (I), X is oxygen, R 1 is substituted or unsubstituted C1-C6 alkyl acyl, C5-C8 cycloalkyl acyl, piperidinyl acyl, N-methylpiperazinyl acyl, substituted or unsubstituted benzoyl, -PO(OH)2; or, X is NH, R 1 is a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl acyl group, or a substituted or unsubstituted benzoyl group; In formula (II), R 2 is a deuterium atom, a substituted or unsubstituted C1-C6 alkyl group, a trifluoromethyl group, a substituted or unsubstituted phenyl group, a pyridyl group, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted phenylethynyl, or pyridylethynyl; The C1-C6 alkyl acyl, amino acid ester, benzoyl, C1-C6 alkyl, phenyl, C 2-6 Alkenyl, C 2-6 The substituents on the alkynyl or phenylethynyl group are selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, and ester groups.

3. The borneol derivative according to claim 1, characterized in that: The borneol derivatives are selected from but not limited to the following compounds and their pharmaceutically acceptable salts and / or their racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers and tautomers:

4. The borneol derivative according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable salts of the borneol derivatives of the general formula (I) and (II) include salts formed with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; or organic acids such as maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, and tannic acid; or alkali metals such as lithium, sodium, and potassium; alkaline earth metals such as calcium and magnesium; and lysine and basic amino acids.

5. A pharmaceutical composition comprising the borneol derivative according to any one of claims 1 to 4, and one or more pharmaceutically acceptable carriers, diluents and optionally pharmaceutically acceptable excipients.

6. Use of the borneol derivative according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a drug; The drugs include anti-epileptic drugs, drugs for treating nervous system diseases, drugs for treating cardiovascular and cerebrovascular diseases, drugs for treating metabolic diseases, liver and kidney diseases, drugs for treating painful diseases, drugs for treating multidrug resistance reversal agents and auxiliary drugs for treating tumors, drugs for treating inflammatory diseases, autoimmune diseases, drugs for treating infectious diseases and drugs for treating respiratory diseases, preferably anti-epileptic drugs.

7. The use according to claim 6, characterized in that The nervous system diseases include, but are not limited to, cerebral hemorrhage, subarachnoid hemorrhage, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, central nervous system infectious diseases, multiple sclerosis, facial neuritis, sciatica, and spinal cord compression; The cardiovascular and cerebrovascular diseases include, but are not limited to, latent coronary heart disease, angina pectoris, myocardial infarction, ischemic cardiomyopathy, sudden death type coronary heart disease, sinus arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrioventricular block, heart failure, hypertension, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, pericardial disease, stroke, thromboangiitis obliterans, and varicose veins of the lower extremities; The metabolic diseases, liver and kidney diseases include but are not limited to diabetes, gout, thyroid dysfunction, osteoporosis, hyperhomocysteinemia, hepatitis C, hepatitis E, cirrhosis, fatty liver, hypercholesterolemia, mixed hyperlipidemia, hyperuricemia, gouty nephropathy, metabolic syndrome, liver fibrosis, glomerulonephritis, acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis and kidney stones; The painful diseases include, but are not limited to, acute trauma, acute inflammation, postoperative pain, acute dental pain, chronic back pain, fibromyalgia, arthritis, neuropathic pain, headache, chronic abdominal pain, cancer-related pain, painful menstruation, temporomandibular joint disorder, neuropathic pain, pain caused by cancer metastasis, bone pain and spinal cord compression; The inflammatory diseases and autoimmune diseases include, but are not limited to, rheumatoid arthritis, gouty arthritis, prostatitis, pelvic inflammatory disease, otitis media, colitis, chronic obstructive pulmonary disease, allergic rhinitis, osteomyelitis, epididymitis, pyelonephritis, bronchitis, asthma, lupus erythematosus, psoriasis, erythema nodosum, synovitis, polymyalgia rheumatica, granulomatous inflammation, systemic vascular inflammation, Sjögren's syndrome, scleroderma, autoimmune thyroiditis, type 1 diabetes, myasthenia gravis, autoimmune hepatitis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, sympathetic ophthalmia, autoimmune inner ear disease and multiple sclerosis; The infectious diseases include but are not limited to fungal infections, viral infections and parasitic infections; The respiratory diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, allergic rhinitis and bronchiectasis.

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