Agarofuran compound, production method thereof, and use

Abstract

The examples of the present application relate to agarofuran compounds and their preparation and use. In the examples of the present application, a novel agarofuran compound with higher activity, better therapeutic effect, and better pharmacokinetic properties is provided by modifying the structure of a main metabolic site, such as the alkyl side chain, of 4-butyl-α-agarofuran (BAF), and is used for treating mental disorders such as anxiety.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to a Chinese patent application bearing application number 202110305886.0 and title "Agarofuran Compound and Its Preparation and Use" filed with the State Intellectual Property Office of the People's Republic of China, the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The present application relates to the technical field of biopharmaceuticals, specifically to agarofuran compounds and their preparation and use. [Background technology]

[0003] Anxiety is a disease or disorder of the human central nervous system. As the rhythm of human social life and work becomes faster and the pressure increases, the incidence of anxiety disorders tends to increase day by day.

[0004] The results of many clinical epidemiological surveys on mental disorders have shown that comorbidity of mental disorders is very common, and among various types of comorbidity, the most common is anxiety disorder comorbid with depression. Many studies have shown that comorbid anxiety disorders increase the severity of depression, decrease the recovery rate, increase the rehospitalization rate, increase the risk of suicide, and decrease social and occupational functioning. Similar trends are observed in patients with anxiety disorders comorbid with other mental disorders. Therefore, the treatment of anxiety disorders is particularly important. Currently, anxiety disorders are undertreated in the world, with only 9.8% receiving adequate treatment. Only 41.3% of anxiety patients feel the need for treatment, and the corresponding proportion in China is below the global average.

[0005] The current situation of the inadequacy of treatment of anxiety, while particularly important, makes it seem like a long-term great responsibility to standardize and strengthen adequate anxiety treatment. Currently, the number of specific treatments for clinical anxiety is far less than that of antidepressants. Therefore, the treatment of anxiety is the key to treatment of mental disorders.

[0006] Among the anti-anxiety drugs that have been developed, the most representative drugs are benzodiazepine compounds, but in clinical treatment, it has been found that benzodiazepines have side effects such as tolerance, dependence, relapse after withdrawal, and delayed therapeutic effect. Therefore, it is very necessary to develop anti-anxiety drugs with better therapeutic effects and milder side effects.

[0007] Agarwood is a precious traditional herbal medicine that contains several agarofuran compounds. The agarofuran drug 4-butyl-α-agarofuran (BAF) is a known novel anxiolytic drug that is currently approved for use in phase II / III clinical trials. The compound has significant anxiolytic activity, but its side effects are very mild and adverse events are rare. However, the drug has poor pharmacokinetic properties, specifically low total exposure, low bioavailability, and short half-life, which affect the therapeutic effect to some extent. [ka]

[0008] The information disclosed in the Background section is intended to enhance understanding of the overall background of the present application and should not be construed as an admission or in any way suggesting that such information already constitutes prior art known to those skilled in the art. Summary of the Invention [Problem to be solved by the invention]

[0009] The objective of the present application is to provide a novel agarofuran compound having higher activity, better therapeutic effect, and better pharmacokinetic properties by modifying the structure of a major metabolic site, such as the alkyl side chain, of 4-butyl-α-agarofuran (BAF), and to use the same in the treatment of mental disorders such as anxiety. [Means for solving the problem]

[0010] To achieve the objectives of the present application, the embodiments of the present application provide the following technical solutions: One aspect of the present application provides an agarofuran compound represented by the general structural formula (I): [ka] In the formula, there is no double bond in ring A or there is one double bond located at the 2-3 position of ring A; R1 is a methyl group mono-, di- or trisubstituted by fluorine atoms; R2 is a C2-C9 linear hydrocarbylene group, a branched hydrocarbylene group or a cycloalkylene group which is unsubstituted or substituted by a hydroxy group or a carbonyl group, and the linear hydrocarbylene group or the branched hydrocarbylene group is an alkylene group or an alkenylene group containing 1 to 3 double bonds; m represents the number of R3 groups bonded to the 4-carbon of the A ring, and m is 1 or 2. When m is 1, R3 is selected from a hydrogen atom, a carbonyl group, and a hydroxyl group. When m is 2, R3 is a deuterium atom. R4 is selected from a hydrogen atom, a deuterium atom, a carbonyl group, or a hydroxy group.

[0011] As noted above, the A ring as a whole represents an oxa tricycle, in which R2 is attached to position 2 of the A ring, R3 is attached to position 4 of the A ring, and R4 is attached to position 12 of the A ring, and m indicates the number of R3 groups rather than the number of repeat units within the same group.

[0012] In one possible embodiment of the agarofuran compound represented by the general formula (I) above, R2 is a C2-C5 linear alkylene group that is unsubstituted or substituted by a hydroxy group or a carbonyl group.

[0013] In one possible embodiment of the agarofuran compound represented by the general formula (I) above, R2 is a C3-C4 linear alkylene group that is unsubstituted or substituted by a hydroxy group or a carbonyl group.

[0014] In one possible embodiment of the agarofuran compound shown in general formula (I) above, R2 is a C3 linear alkylene group that is unsubstituted or substituted by a hydroxy group or substituted by a carbonyl group.

[0015] In one possible embodiment of the agarofuran compound represented by the general formula (I) above, it is selected from the following compounds: [ka] TIFF2024506515000005.tif32170

[0016] Another aspect of the present application relates to a pharmaceutical composition comprising an agarofuran compound as shown in general formula (I) or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and further comprising at least one of a pharma- ceutically acceptable carrier, diluent or excipient.

[0017] Another aspect of the present application relates to the use of an agarofuran compound as shown in general formula (I) or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition containing same, in the manufacture of a medicament for the prevention and / or treatment of anxiety.

[0018] Another aspect of the present application relates to a method for treating anxiety, comprising administering to a subject in need of such treatment a therapeutically effective amount of an agarofuran compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition comprising the same.

[0019] The agarofuran compound of the present invention represented by general formula (I) or a pharmaceutical composition containing the same may be administered in the form of a unit dose, and the administration route may be enteral or non-enteral, such as oral, intramuscular, subcutaneous, intranasal, oral mucosal, transdermal, intraperitoneal or rectal, etc. The dosage form may be, for example, a tablet, capsule, drop pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, freeze-dried powder injection, etc., and may be a general preparation, sustained release preparation, controlled release preparation, and various microparticle administration systems.

[0020] The dosage of the drug is determined by many factors, including, but not limited to, the activity of the specific compound used, the nature and severity of the disease to be treated, the patient's sex, age, weight, health condition, behavior, diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method, for example, the form of treatment, the daily dose of the compound of general formula (I) can be verified based on conventional treatment plans.

[0021] Another aspect of the present application relates to a method for producing the agarofuran compound represented by general formula (I), and can refer to the method described in "Stereoselective synthesis of antianxiety drug candidate AF-5 using (+)-dihydrocarvone as a raw material" (Yin Dali et al., China Journal of Medicinal Chemistry, 2003, Vol. 13, No. 4, pp. 187-193). The method for producing the agarofuran compound is selected from any one of the following methods (1) to (5).

[0022] (1) When the A ring of the agarofuran compound represented by the general formula (I) has one double bond located at the 2-3 position of the A ring, m=1, and R3 and R4 are both hydrogen atoms, the preparation method includes the following steps: [ka] wherein the compounds of formula (Ia) and formula (Ib) undergo a substitution reaction under alkaline conditions to obtain a compound of formula (Ic), R1 is a methyl group mono-, di- or tri-substituted with fluorine atoms, R2 is a C2-C9 linear hydrocarbylene group, a branched hydrocarbylene group or a cycloalkylene group that is unsubstituted or substituted with a hydroxy group or substituted with a carbonyl group, said linear hydrocarbylene group or branched hydrocarbylene group being an alkylene group or an alkenylene group containing 1 to 3 double bonds, X is a halogen, preferably bromine, The compound of formula (Ic) is reduced in the presence of a reducing agent to obtain a compound of formula (Id); The compound of formula (Id) undergoes a cyclization reaction under acidic conditions to give the compound of formula (Ie).

[0023] (2) When there is no double bond in the A ring of the agarofuran compound represented by the general formula (I), m=1, and R3 and R4 are simultaneously hydrogen, the preparation method includes a step of obtaining a compound of formula (If) by catalytic hydrogenation using the compound of formula (Ie) of the preparation method (1). [ka]

[0024] (3) When the A ring of the agarofuran compound represented by the general formula (I) has one double bond located at the 2-3 position of the A ring, m=2, and R3 and R4 are simultaneously deuterium, the preparation method includes the following steps: [ka] wherein the compounds of formula (Ia) and formula (Ib) undergo a substitution reaction under alkaline conditions to obtain a compound of formula (Ic), R1 is a methyl group mono-, di- or tri-substituted with fluorine atoms, R2 is a C2-C9 linear hydrocarbylene group, a branched hydrocarbylene group or a cycloalkylene group that is unsubstituted or substituted with a hydroxy group or substituted with a carbonyl group, said linear hydrocarbylene group or branched hydrocarbylene group being an alkylene group or an alkenylene group containing 1 to 3 double bonds, X is a halogen, preferably bromine, The compound of formula (Ic) undergoes a deuteration reaction with a deuterated alcohol under alkaline conditions to produce a compound of formula (Ij); A compound of formula (Ij) is reduced in the presence of a reducing agent to obtain a compound of formula (Ig); The compound of formula (Ig) undergoes a cyclization reaction under acidic conditions to give the compound of formula (Ih).

[0025] (4) When there is no double bond in the A ring of the agarofuran compound represented by the general formula (I), m=2, and R3 and R4 are simultaneously deuterium, the preparation method includes a step of obtaining a compound of formula (Ii) by catalytic hydrogenation using a compound of formula (Ih) of the preparation method (3). [ka]

[0026] (5) When a double bond is present in the A ring of the agarofuran compound represented by general formula (I), m=1, R3 is a carbonyl group, and R4 is hydrogen, the production method includes a step of carrying out an oxidation reaction using the compound of formula (Ie) of production method (1) in the presence of an oxidizing agent to obtain a compound of formula (Ik). [ka]

[0027] (6) When a double bond is present in the A ring of the agarofuran compound represented by general formula (I), m=1, R3 is a hydroxy group, and R4 is hydrogen, the preparation method includes a step of carrying out a reduction reaction using the compound of formula (Ik) of preparation method (5) in the presence of a reducing agent to obtain a compound of formula (Im). [ka]

[0028] In one possible embodiment of the above-mentioned production method, R2 is a C2-C5 linear alkylene group that is unsubstituted or substituted by a hydroxy group or a carbonyl group, optionally R2 is a C3-C4 linear alkylene group that is unsubstituted or substituted by a hydroxy group or a carbonyl group, and further optionally R2 is a C3 linear alkylene group that is unsubstituted or substituted by a hydroxy group or a carbonyl group.

[0029] In one possible embodiment of the above-mentioned production method, R1 and R2 are selected from any one of the following: 1. R1 = -CF3, R2 = -CH2CH2CH2- 2. R1 = -CHF2, R2 = -CH2CH2CH2- 3. R1 = -CH2F, R2 = -CH2CH2CH2- 4. R1 = -CF3, R2 = -CH2CH2CH2CH2-

[0030] In one possible embodiment of the process, the reagent providing the alkaline conditions is primarily an inorganic base, said inorganic base comprising one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide.

[0031] In one possible embodiment of the process, the reducing agent comprises one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride.

[0032] In one possible embodiment of the method, the reagent providing an acidic environment comprises one or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid.

[0033] In one possible embodiment of the process, the metal catalyst for catalytic hydrogenation comprises one or more of palladium on carbon, rhodium on carbon, platinum dioxide, Raney nickel.

[0034] In one possible embodiment of the method, the oxidizing agent for carrying out the oxidation reaction comprises one or more of oxygen, hydrogen peroxide, peroxide, Sarrett's reagent.

[0035] In one possible embodiment of the production method, the solvents used in production method (1) include: step 1: one or more of methanol, ethanol, isopropanol, tert-butanol; step 2: one or more of diethyl ether, tetrahydrofuran; step 3: one or more of n-hexane, petroleum ether.

[0036] In one possible embodiment of the process, the solvent used in process (2) comprises one or more of ethanol, methanol, diethyl ether.

[0037] In one possible embodiment of the production method, the solvent used in production method (3) includes step 1: one or more of methanol, ethanol, isopropanol, tert-butanol; step 2: one or more of deuterated methanol, deuterated ethanol; step 3: one or more of diethyl ether, tetrahydrofuran; and step 4: one or more of n-hexane, petroleum ether.

[0038] In one possible embodiment of the process, the solvent used in process (4) comprises one or more of ethanol, methanol, diethyl ether.

[0039] In one possible embodiment of the process, the solvent used in process (5) comprises one or more of dichloromethane, toluene, benzene, pyridine.

[0040] In one possible embodiment of the process, the solvent used in process (6) comprises one or more of ethanol, methanol, diethyl ether. Effect of the Invention

[0041] The agarofuran of the general formula (I) in the examples of the present application exhibits excellent anxiolytic activity. Compared with known anxiolytic benzodiazepine compounds (e.g., diazepam), it has the characteristics of rapid onset of effect and high safety factor, and compared with 4-butyl-α-agarofuran, it has the advantages of better pharmacokinetic properties, such as more suitable half-life, higher exposure, higher bioavailability, etc. [Brief description of the drawings]

[0042] [Figure 1] The effect of intraperitoneal injection of the drug of Example 8 on the time spent in the open and closed arms of mice in an elevated plus maze (mean ± standard error, n = 13). *P < 0.05, **P < 0.01, ***P < 0.001 are compared with the vehicle, which is an additive, and #P < 0.05 are compared with the BAF (2 mg / kg) group. [Diagram 2] This shows the effect of intraperitoneal injection of the drug of Example 8 on the number of entries into the open and closed arms of mice in an elevated maze (mean ± standard error, n = 13). *P < 0.05, **P < 0.01 compared to the vehicle used as an additive. [Diagram 3] This shows the effect of intraperitoneal administration of Example 8 on the ratio of the number of entries and the time ratio into the open and closed arms in mice in an elevated maze (mean ± standard error, n = 13). *P < 0.05, **P < 0.01 compared to the vehicle used as an additive. [Figure 4]1 shows the plasma time course curve of the prototype after intraperitoneal injection of BAF (10 mg / kg) into mice in Example 8. [Diagram 5] 1 is a curve showing the plasma time course of the prototype after intraperitoneal injection (10 mg / kg) of Compound 2 in mice of Example 8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] In the following, the technical solutions of the embodiments of the present application are described clearly and completely, so as to make the objectives, technical solutions and advantages of the embodiments of the present application more clear. Needless to say, the described embodiments are not all the embodiments of the present application, but are only a part of the embodiments. All other embodiments that a person skilled in the art can obtain based on the embodiments of the present application without creative labor belong to the scope of the claims of the present application.

[0044] In addition, in order to better explain the present application, many details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present application can be practiced without some details. In some examples, materials, elements, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to enhance the scope of the present application.

[0045] Unless expressly stated otherwise, throughout the specification and claims, the term "comprises" or variations thereof, such as "comprising" or "containing," are to be understood to include the stated element or components, but not to exclude other elements or components.

[0046] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0047] The term "alkylene group" includes straight or branched chain alkylene groups containing 2 to 9 carbon atoms, such as propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, sec-pentylene, and the like, which are unsubstituted or substituted by hydroxy or carbonyl groups.

[0048] In the present application, the term "alkenylene group containing 1 to 3 double bonds" refers to a straight-chain or branched-chain alkenylene group having 1 to 3 double bonds, such as an ethenylene group, a propenylene group, a 3-butene group, a 2-butene group, a 2-pentenylene group, a 3-pentenylene group, etc., and the alkenylene group is unsubstituted or substituted with a hydroxy group or a carbonyl group.

[0049] In the examples of the present application, the structures of all compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). For NMR measurements, a Varian Mercury-400 or Bruker-600 nuclear magnetic analyzer is used, the measurement solvent is deuterated methanol (CD3OD) or deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0050] For MS measurements, an ESI mass spectrometer (manufacturer: Thermo, model number: Exactive Plus) is used.

[0051] For HPLC measurements, an Agilent 1200 high performance liquid chromatograph (C8150×4.6 mm chromatography column) is used. Qingdao GF254 silica gel plate is used as the silica gel plate for thin layer chromatography, and the specification is 0.15~0.2 mm.

[0052] In column chromatography, 300-400 mesh silica gel from Yantai Yellow Sea silica gel is used as the carrier.

[0053] Known starting materials in the present application may be synthesized using or according to methods known in the art, or may be purchased from reagent companies such as ITC, Alfa, Bidepharm, Innochem, etc. Unless otherwise specified in the examples, reactions may be carried out under argon or nitrogen.

[0054] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing system used in the reaction was mainly petroleum ether and ethyl acetate, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0055] The elution system of column chromatography used in purifying the compounds is mainly petroleum ether and ethyl acetate, and the volume ratio of the solvents is adjusted according to the polarity of the compounds.

[0056] Example 1: Step 1 Preparation of (6R,9R)6-methyl-9-(1-hydroxyisopropyl)-2-(4,4,4-trifluorobutyl)bicyclo[4.4.0]dec-1-en-3-one (1) [ka] Under argon protection, compound of formula (Ia) (1000 mg, 4.50 mmol) and KOH (343 mg, 6.117 mmol) were dissolved in tert-butanol, heated to reflux, and added dropwise to 10 mL of a solution of 4-bromo-1,1,1-trifluorobutane (1051 mg, 5.53 mmol). After the entire addition, the mixture was allowed to react for 1 hour. After cooling, 10 mL of distilled water was added, and the mixture was neutralized with 1N hydrochloric acid to pH=7, the solvent was evaporated, and the residue was dissolved in diethyl ether. The diethyl ether layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by silica gel column chromatography and eluted with a mixture of petroleum ether / ethyl acetate (10:1) to obtain the required compound 1 (745 mg, 64% yield). [α] D 20 =-66.6°(c 0.89,CHCl3),1 H NMR(600MHz,CDCl3)δ 1.21(s,3H),1.72(s,3H),1.75(s,3H),1.42-1.48(m,2H),1.50-1.56(m,2H),1.78-1.83(m,5H),1.91-1. 98(m,2H),2.05-2.13(m,2H),2.33-2.37(m,1H),2.41-2.51(m,3H),2.58-2.64(m,1H),2.67-2.71(m,1H). 13 C NMR(150MHz, CDCl3)δ 198.1,166.5,133.2,73.4,44.0,36.9,36.4,35.9,34.1,33.7,33.5,29.0,27.1,27.0,25.0,24.4,21.5,21.4,21.2. HR-MS m / z(ESI)333.2030[M+H] + ,C 18 H 28 O2F3 calculated value 333.2036.

[0057] Step 2 (1R,6S,9R) 6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-ene (2) [ka] Compound 1 (530 mg, 1.58 mmol) was dissolved in 8 mL of methanol, sodium borohydride was added to carry out the reduction reaction, and the mixture was stirred at room temperature for 3 hours. 5 mL of water was added, the pH was adjusted to 3-4 with concentrated hydrochloric acid, 10 mL of n-hexane was added, and the mixture was stirred at room temperature overnight to carry out the cyclization reaction. The n-hexane layer was separated, washed with water to neutralize it, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound 2 (300 mg, yield 60.1%). [α] D 20 =29.3°(c 1.32,CHCl3), 1H NMR(600MHz, CDCl3)δ 0.90(s,3H),1.04-1.09(m,1H),1.21-1.25(m,5H),1.36(s,3H),1.62-1.76(m,7H),1.94-2.18(m,7H),5.60-5.61(m,1H). 13 C NMR(150MHz, CDCl3)δ 135.1,127.2,85.1,81.0,44.10,37.0,34.4,33.8,33.6,32.9,32.6,30.4,30.1,24.4,22.9,22.5,21.9,21.3,21.2. HR-MS m / z(ESI)299.1990[M+H-H2O] + ,C 18 H 26 F3 calculated value 299.1981.

[0058] Example 2: Step 1 Preparation of (6R,9R)6-methyl-9-(1-hydroxyisopropyl)-2-(4-fluorobutyl)bicyclo[4.4.0]dec-1-en-3-one (3) [ka] Under argon protection, compound of formula (Ia) (500 mg, 2.25 mmol) and KOH (171 mg, 3.0 mmol) were dissolved in tert-butanol, heated to reflux, and added dropwise to 5 mL of a solution of 4-bromo-1-fluorobutane (426 mg, 2.75 mmol). After the entire addition, the mixture was allowed to react for 1 hour. After cooling, 10 mL of distilled water was added, and the mixture was neutralized with 1N hydrochloric acid to pH=7, the solvent was evaporated, and the residue was dissolved in diethyl ether. The diethyl ether layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by silica gel column chromatography and eluted with a mixture of petroleum ether / ethyl acetate (10:1) to give the required compound 3 (421 mg, 63% yield). [α] D 20 =-28.7°(c 0.195,CH3OH), 1H NMR(400MHz,CDCl3)δ 1.17(s,3H),1.21(s,3H),1.23(s,3H),1.32-1.50(m,4H),1.63-1.69(m,3H),1.71-1.79(m,2H),1.85-1.93(m,2H) ,2.23-2.30(m,1H),2.35-2.46(m,3H),2.52-2.61(m,1H),2.63-2.69(m,1H),4.34-4.38(m,1H),4.46-4.50(m,1H). 13 C NMR(100MHz,CDCl3)δ 198.3,166.6,134.2,85.0,83.3,73.6,44.1,37.0,36.6,35.8,34.3,30.6,30.3,29.0,27.2,27.0,26.0,25.0,24.9,24.8,21.3. HR-MS m / z(ESI)297.2232[M+H] + ,C 18 H 30 O2F calculated value 297.2224.

[0059] Step 2 (1R,6S,9R) 6,10,10-trimethyl-2-(4-fluorobutyl)-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-ene (4) [ka] Compound 3 (400 mg, 1.35 mmol) was dissolved in 5 mL of methanol, sodium borohydride (205 mg, 5.4 mmol) was added to carry out a reduction reaction, the mixture was stirred at room temperature for 3 hours, 2 mL of water was added, the pH was adjusted to 3-4 with concentrated hydrochloric acid, 7 mL of n-hexane was added, and the mixture was stirred at room temperature overnight to carry out a cyclization reaction. The n-hexane layer was separated, washed with water to neutralize it, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound 4 (227 mg, yield 60.0%). [α] D 20 =20.0°(c 0.5,CHCl3), 1H NMR(600MHz,CDCl3)δ 0.89(s,3H),1.02-1.07(m,1H),1.16-1.19(m,1H),1.22(s,3H),1.36(s,3H),1.41-1.68(m,2H)1.61-1.7 7(m,7H),1.93-2.03(m,5H),2.16-2.20(m,1H),4.36-4.39(m,1H),4.48-4.60(m,1H),5.60-5.61(m,1H). 13 C NMR(150MHz, CDCl3)δ 136.0,126.7,85.3,85.0,83.4,80.9,44.2,37.0,34.6,32.9,32.7,30.8,30.7,30.5,24.7,24.5,23.0,22.7,22.0. HR-MS m / z(ESI)263.2167[M+H-H2O] + ,C 18 H 28 F calculated value 263.2170.

[0060] Example 3: Step 1 Preparation of (6R,9R)6-methyl-9-(1-hydroxyisopropyl)-2-(5,5,5-trifluoropentyl)bicyclo[4.4.0]dec-1-en-3-one (5) [ka] Under argon protection, the compound of formula (Ia) (1000 mg, 4.5 mmol) and potassium tert-butoxide (758 mg, 6.75 mmol) were dissolved in 10 mL of tert-butanol, heated to reflux, and added dropwise to 10 mL of tert-butanol solution of 5-bromo-1,1,1-trifluoropentane (1.108 g, 5.40 mmol). After the entire addition, the reaction was continued for 1 hour. After cooling, 10 mL of distilled water was added, and the mixture was neutralized with 1N hydrochloric acid to pH=7, the solvent was evaporated, and the residue was dissolved in diethyl ether. The diethyl ether layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by silica gel column chromatography and eluted with a petroleum ether / ethyl acetate (10:1) mixed solvent to obtain product 5 (950 mg, 61% yield). [α]D 20 =-63.3°(c 2.4,CHCl3), 1 H NMR(600MHz,CDCl3)δ 1.16(s,3H),1.21(s,3H),1.23(s,3H),1.24-1.28(m,1H),1.30-1.45(m,4H),1.48-1.66(m,6H),1.72-1. 77(m,1H),1.85-1.93(m,2H),1.99-2.09(m,2H),2.20-2.27(m,1H),2.35-2.44(m,3H),2.52-2.67(m,2H). 13 C NMR(150MHz, CDCl3)δ 198.2,165.7,133.8,73.4,44.0,36.9,36.5,35.8,34.2,29.0,28.2,27.1,26.9,25.0,24.9,21.9,21.8,21.2. HR-MS m / z(ESI)347.2189[M+H] + ,C 19 H 30 O2F3 calculated value 347.2192.

[0061] Step 2 (1R,6S,9R)6,10,10-trimethyl-2-(5,5,5-trifluoropentyl)-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-ene (6) [ka] Product 5 (461 mg, 1.61 mmol) was dissolved in 6 mL of methanol, sodium borohydride was added to carry out the reduction reaction, and the mixture was stirred at room temperature for 3 hours. 5 mL of water was added, and the pH was adjusted to 3-4 with concentrated hydrochloric acid. 10 mL of n-hexane was added, and the mixture was stirred at room temperature overnight to carry out the cyclization reaction. The n-hexane layer was separated, washed with water to neutralize it, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain the final product 6 (258 mg, yield 55.6%). [α] D 20 =17.0°(c 2.1,CHCl3), 1H NMR(600MHz, CDCl3)δ 0.91(s,3H),1.05-1.09(m,1H),1.24-1.34(m,7H),1.37(s,3H),1.58-1.73(m,8H),1.95-2.21(m,6H),5.60(brs,1H). 13 C NMR(150MHz, CDCl3)δ 135.6,126.5,85.2,80.9,44.1,37.0,34.5,33.8,33.6,32.9,32.6,30.7,30.4,28.1,24.4,22.9,22.5,22.1,21.9. HR-MS m / z(ESI)313.2134[M+H-H2O] + ,C 19 H 28 F3 calculated value 313.2138.

[0062] Example 4: Step 1 Preparation of (6R,9R)6-methyl-9-(1-hydroxyisopropyl)-2-(4,4,4-trifluorobutyl)-4,4,10,10-tetradeuterated bicyclo[4.4.0]dec-1-en-3-one (7) [ka] Compound 1 (298 mg, 0.90 mmol) was dissolved in 3 mL of deuterated methanol, sodium methoxide (49 mg, 0.90 mmol) was added, and the mixture was stirred overnight at room temperature under argon protection, adjusted to pH=7 with 1N hydrochloric acid, evaporated completely, washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to give yellow oil 7 (290 mg, 97% yield). [α] D 20 =-66.6°(c 0.89,CHCl3), 1H NMR(600MHz,CDCl3)δ 1.21(s,3H),1.25(s,3H),1.28(s,3H),1.43-1.48(m,1H),1.50-1.68(m,8H),1.78-1. 83(m,1H),1.92-1.96(m,2H),2.06-2.12(m,2H),2.32-2.37(m,1H),2.46-2.51(m,1H). 13 C NMR(150MHz, CDCl3)δ 198.2,166.4,133.3,126.3,73.4,43.9,36.9,36.2,35.8,33.7,33.5,29.0,27.0,25.0,24.4,21.5,21.2. HR-MS m / z(ESI)337.2260[M+H] + ,C 18 H 24 Calculated value of D4O2F3 is 337.2287.

[0063] Step 2 (1R,6R,9R) 6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-4,4,10-trideutero-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-ene (8) [ka] Lithium aluminum hydride (32 mg, 0.83 mmol) was suspended in 3 mL of anhydrous tetrahydrofuran, and added dropwise to a tetrahydrofuran solution of yellow oil 7 (280 mg, 0.83 mmol) in an ice bath. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 3 hours to carry out the reduction reaction. 3 mL of water was added, the pH was adjusted to 3-4 with concentrated hydrochloric acid, 3 mL of n-hexane was added, and the mixture was stirred at room temperature overnight to carry out the cyclization reaction. The n-hexane layer was separated, washed with water to neutralize it, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain the final product 8 (200 mg, 76% yield). [α] D 20 =29.3°(c 1.32,CHCl3), 1H NMR(600MHz,CDCl3)δ 0.93(s,3H),1.08-1.10(m,1H),1.22-1.25(m,4H),1.39(s,3H),1.67-1.75(m,6H),1.96-1.98(m,1H),2.05-2.19(m,4H),5.63(s,1H). 13 C NMR(150MHz, CDCl3)δ 135.2,127.0,85.0,81.0,44.0,36.9,34.4,33.8,33.6,32.6,30.4,30.1,24.3,22.9,21.9,21.2,21.2. HR-MS m / z(ESI)302.2161[M+H-H2O] + ,C 18 H 23 D3F3 calculated value 302.2169.

[0064] Example 5: (1R,2R / S,6S,9R) 6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-11-oxatricyclo[7.2.1.0 1,6 ] Production of dodecane (9) [ka] Compound 2 (50 mg, 0.16 mmol) was dissolved in 5 mL of diethyl ether, 30 mg of 10% palladium on carbon was added, and the mixture was hydrogenated at room temperature and normal pressure for 7 hours. The palladium on carbon was filtered off, the solvent was evaporated, and the product was purified by column chromatography (petroleum ether:ethyl acetate=50:1) to obtain the final product 9 (15 mg, 30% yield). [α] D 20 =11.2°(c 0.68,CHCl3), 1 H NMR(600MHz, CDCl3)δ 0.86(s,3H),1.10-1.14(m,4H),1.20(m,3H),1.27-1.77(m,14H),1.81-2.14(m,4H),2.31-2.66(m,1H). HR-MS m / z(ESI)301.2132[M+H-H2O] + ,C 18 H 28 F3 calculated value 301.2138.

[0065] Example 6: (1R,6R,9R)6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-en-4-one (10) [ka] Compound 2 (100 mg, 0.32 mmol) was dissolved in 5 mL of dichloromethane, 100 mg of pyridinium chlorochromate (PCC) was added, stirred at room temperature overnight, filtered through a silica gel pad, the solvent was evaporated, and purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give the final product 10 (80 mg, 76% yield). [α] D 20 =28.6°(c 1.01,CHCl3), 1 H NMR(600MHz,CDCl3)δ 0.90(s,3H),1.04-1.09(m,1H),1.21-1.25(m,5H),1.36(s,3H),1.62- 1.76(m,6H),1.94-2.18(m,3H),2.38-2.45(m,3H),5.60-5.61(m,1H). MS m / z(ESI)313.2[M+H-H2O] + .

[0066] Example 7: (1R,4R / S,6R,9R) 6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-4-hydroxy-11-oxatricyclo[7.2.1.0 1,6 ] Preparation of dodec-2-ene (11) [ka] The final product 10 (50 mg, 0.15 mmol) was dissolved in 2 mL of methanol, sodium borohydride (20 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 2 h. 3 mL of distilled water was added, the pH was adjusted to 3-4 with 2 M hydrochloric acid, and the mixture was extracted with dichloromethane, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the mixture was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give the final product 11 (30 mg, 60% yield). [α] D 20 =20.7°(c 1.03,CHCl3), 1 H NMR(600MHz,CDCl3)δ 0.90(s,3H),1.04-1.09(m,1H),1.21-1.25(m,5H),1.36(s,3H),1.51-1.80(m,7) H),1.94-2.18(m,2H),2.38-2.45(m,3H),4.05-4.08(m,1H),5.60-5.61(m,1H). MS m / z(ESI)298.2[M+2H-2H2O] + .

[0067] Example 8: Biological Evaluation 1. Efficacy Testing The novel agarofuran derivative compound represented by formula (I) of the present application has shown excellent effects in animal anxiolytic models, such as the rat elevated plus maze test. The compound represented by formula (I) of the present application, which is the active ingredient used in the following pharmacological test, is the final product of Example 1 of the present application, i.e., (1R,6S,9R)6,10,10-trimethyl-2-(4,4,4-trifluorobutyl)-11-oxatricyclo[7.2.1.0 1,6]dodec-2-ene (hereinafter referred to as Compound 2). Compound 2 and excipient PVP (Povidone K30) were mixed in an ethanol solution at a mass ratio of 1:15, and rotary dried to prepare a formulation of Compound 2 (hereinafter, Compound 2 refers to the formulation of Compound 2). The formulation in which the active ingredient is 4-butyl-α-agarofuran (abbreviated as BAF) was used as the positive drug, and the manufacturing method of the formulation was the same as that of Compound 2, and hereinafter, BAF refers to the formulation of BAF. PVP was used as the blank control. The dosage was calculated based on the raw drug.

[0068] Mouse elevated plus maze (EPM) test This model is one of the most commonly used animal models in anti-anxiety drug research. The elevated plus maze is composed of open arms (30×5×0.5 cm) and closed arms (30×8×15 cm) crossed in a cross shape, and the apparatus is placed at a height of 50 cm from the floor. The open arms are narrow, in the air, and bright, so that the open arms generate internal "fear" or conflict, whereas the closed arms are in line with the habits of mice. Five minutes after administration, the mouse was placed in the center of the maze with its head facing the open arms. During the test period (usually 5 minutes), the number of times the mouse entered the open arms and the time spent in the two arms were recorded. The percentage of the number of times the mouse entered the open arms and the time spent in the open arms to the total number of times (the sum of the number of times the mouse entered the open arms and the closed arms) and the total time (the sum of the time spent in the open arms and the closed arms) were calculated, and these were used as indices to evaluate anxiety. In general, a drug is considered to have an anxiolytic effect if it increases the cumulative time spent in the open arms without decreasing the number of passes through the open and closed arms.

[0069] Male ICR mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) weighing 18-20g were used in the study. They were randomly divided into 7 groups according to body weight, with 13 mice per group. Before the study began, the mice underwent grip strength adaptability training. Before the study, the mice were fasted for 12 hours. The drugs were administered by intraperitoneal injection. 4-Butyl-α-agarofuran (abbreviated as BAF) was used as the positive drug, and PVP was used as the blank control. The specific grouping and treatment methods were as follows: [Table 1]

[0070] During the test, immediately after intraperitoneal injection of BAF / compound 2, each mouse was placed in an open field box and allowed to move freely for 5 minutes, then placed on the central platform of the elevated plus maze, with the mouse's head facing the fixed open arm. The test was started, counted for 5 minutes, and recorded with a camera using Supermaze software. After all tests were completed, the time spent in the open and closed arms by the mouse (seconds), the number of entries into the open and closed arms, and the time and number ratios of entries into the open and closed arms were recorded using Supermaze software. If the latency period was 0, 1 was added to the number of entries into the arms. The test results are shown in Table 2 and Figures 1 to 3. [Table 2] *P<0.05, **P<0.01, ***P<0.001 compared with the excipient group. # P < 0.05 compared with the BAF (2 mg / kg) group.

[0071] The test results showed that compared with BAF, intraperitoneal injection of test compound 2 at 2.4, 4.8, and 9.6 mg / kg (equimolar doses with BAF at 2, 4, and 8 mg / kg) had obvious anxiolytic effects. Compound 2 was more effective than BAF at low and medium doses, and the efficacy results were statistically significant, especially at low doses.

[0072] In addition, we evaluated the anxiolytic activity of Compound 6 and Compound 8 according to the above plan. As shown in Tables 3 and 4, compared with BAF, the time spent in the open arms and the number of times were both increased, and there was a statistically significant difference at low doses. [Table 3] *P<0.05, **P<0.01 compared with the excipient group. # P < 0.05 compared with the BAF (2 mg / kg) group. [Table 4] *P<0.05, **P<0.01 compared with the excipient group. # P < 0.05 compared with the BAF (2 mg / kg) group.

[0073] 2. Pharmacokinetic studies Plasma pharmacokinetic study of compound 2 following intraperitoneal injection in mice 1. Test Materials A positive control drug, 4-butyl-α-agarofuran (BAF) formulation and a formulation of compound 2 were administered by intraperitoneal injection at a dose of 10 mg / kg / 10 mL (calculated based on the raw drug), and suspensions were prepared by dissolving in double distilled water and grinding with ultrasonic waves.

[0074] Male ICR mice weighing 21-24 g were purchased from Schiff (Beijing) Biotechnology Co., Ltd.

[0075] 2. Test Method 1) Collecting samples Twelve mice were randomly divided into four groups, and each group was cross-bled for three parallel samples (five blood sampling points for groups 1 and 3, and six blood sampling points for groups 2 and 4), and dosed based on body weight. Blood was collected from the orbital venous plexus at 5, 10, 15, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours after dosing. Blood at each time point was collected in heparinized anticoagulated EP tubes, placed on ice, and centrifuged at 8000 rpm for 5 minutes, after which the plasma was separated.

[0076] 2) Preparation of standard curve 55 μL of acetonitrile containing an internal standard solution (200 ng / mL, the raw materials BAF and compound 2 are internal standards for each other, i.e., BAF is the internal standard for compound 2, and compound 2 is the internal standard for BAF; the same applies below) was added to 20 μL of blank mouse plasma, and 5 μL of methanol working solutions of compound BAF or compound 2 at different concentrations were added and mixed uniformly to make the final blood concentrations 0.2, 0.5, 2, 5, 10, 25, 50, 100, 200, 500, 750, and 1000 ng / mL, respectively. The mixture was centrifuged twice at 13,000 rpm for 5 minutes, and 5 μL of the supernatant was taken out for UPLC-MS / MS analysis.

[0077] 3) Sample processing 30 μL of acetonitrile containing an internal standard solution (100 ng / mL) was added to 10 μL of plasma to precipitate proteins, and the mixture was centrifuged twice at 13,000 rpm for 5 min., after which 5 μL of the supernatant was removed and subjected to UPLC-MS / MS analysis.

[0078] 4) UPLC-MS / MS measurement Chromatography column: Symmetry C8 (2.1 mm × 50 mm, 3.5 μm), column temperature: 25 ° C, mobile phase: acetonitrile (0.1% formic acid): water (0.1% formic acid) = 70:30 gradient elution, flow rate: 0.2 mL / min, PRM detection, BAF: m / z 263.2 → 245.2, compound 2: m / z 317.2 → 299.2.

[0079] The test results are shown in Tables 5 to 8, Figures 4 and 5. After intraperitoneal injection of BAF or Compound 2 (10 mg / kg) into mice, it was rapidly absorbed, reaching a peak within 5 to 15 minutes. max and AUC (0~t) were 150% and 142% of the BAF, respectively, and the exposure increased and the MRT (0~t) increased from 1.05 to 1.32 hours, and T 1 / 2 increased from 1.29 to 1.61 hours. Therefore, we believe that compound 2 has better pharmacokinetic properties than BAF.

[0080] In addition, we evaluated the pharmacokinetic properties of Compound 6 and Compound 8 according to the above method. max was 342 ng / mL, and AUC (0~t) is 142h ng / mL, and T 1 / 2 The reaction time was 1.39 hours. max is 350ng / mL, and AUC (0~t) is 148h ng / mL, and T 1 / 2 was 1.41 hours, indicating that the pharmacokinetic properties of compounds 6 and 8 are superior to BAF. [Table 5] [Table 6] [Table 7] [Table 8]

[0081] Conclusion: Compound 2, compound 6 and compound 8 of the present application all have anxiolytic activity, and compared with BAF, their internal exposure and half-life are all significantly increased, indicating that they have better pharmacokinetic properties.In addition, at low doses, they all show better efficacy, indicating that their effective doses are lower, which can be assumed to lead to a reduction in clinical doses.

[0082] In addition, in the compound represented by the structural formula (I), R2, R3 and R4 are the metabolic sites of the compound, and when it is metabolized in the body, the C2-C9 linear hydrocarbylene group, branched hydrocarbylene group or cycloalkylene group at the R2 position is easily replaced by a carbonyl group or a hydroxyl group, and R3 and R4 are also easily metabolized to a carbonyl group or a hydroxyl group. If it is proven that the prototype in which the C2-C9 linear hydrocarbylene group, branched hydrocarbylene group or cycloalkylene group at the R2 position is not replaced by a carbonyl group or a hydroxyl group and R3 and R4 are hydrogen atoms or deuterium atoms has activity or is improved in the body, those skilled in the art can presume that the metabolic form replaced by a carbonyl group or a hydroxyl group in the body also has activity or is improved in the body. [Industrial Applicability]

[0083] The present application provides an agarofuran compound and its preparation method and use, wherein the agarofuran compound is provided as a novel agarofuran compound having higher activity, better therapeutic effect, and better pharmacokinetic properties by modifying the structure of a main metabolic site, such as the alkyl side chain, of 4-butyl-α-agarofuran (BAF), and is used for treating mental disorders such as anxiety.

Claims

1. An agarofuran compound represented by the general structural formula (I): 【Chemistry 1】 (Wherein, there is no double bond in ring A or there is one double bond located at the 2-3 position of ring A; R １ is a methyl group mono-, di- or trisubstituted by fluorine atoms, R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ２ ~C ９ a straight chain hydrocarbylene group, a branched chain hydrocarbylene group or a cycloalkylene group, said straight chain hydrocarbylene group or branched chain hydrocarbylene group being an alkylene group or an alkenylene group containing 1 to 3 double bonds; m is R bonded to the 4-carbon of the A ring. ３ m represents the number of groups, m is 1 or 2, and when m is 1, R ３ is selected from a hydrogen atom, a carbonyl group, or a hydroxyl group; when m=2, R ３ is a deuterium atom, R ４ is selected from a hydrogen atom, a deuterium atom, a carbonyl group, or a hydroxyl group.

2. R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ２ ~C ５ A straight chain alkylene group, optionally R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ３ ~C ４ is a linear alkylene group, and optionally further ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ３ 2. The agarofuran compound according to claim 1, characterized in that it is a straight-chain alkylene group.

3. 2. The agarofuran compound according to claim 1, which is selected from the following compounds: 【Chemistry 2】 【change】

4. A pharmaceutical composition comprising the agarofuran compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and further comprising at least one of a pharma- ceutically acceptable carrier, diluent, or excipient.

5. Use of the agarofuran compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition containing the same, in the manufacture of a drug for preventing and / or treating anxiety.

6. A method for producing an agarofuran compound according to claim 1, comprising the steps of: In the A ring of the agarofuran compound represented by the general formula (I), there is one double bond located at the 2-3 position of the A ring, m=1, and R ３ , R ４ When is also a hydrogen atom, the method includes the steps of: 【Chemistry 3】 wherein the compounds of formula (I-a) and formula (I-b) undergo a substitution reaction under alkaline conditions to obtain a compound of formula (I-c), and R １ is a methyl group mono-, di- or trisubstituted by fluorine atoms; R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ２ ~C ９ a linear hydrocarbylene group, a branched hydrocarbylene group or a cycloalkylene group, said linear or branched hydrocarbylene group being an alkylene group or an alkenylene group containing 1 to 3 double bonds; X is a halogen, preferably bromine; The compound of formula (I-c) is reduced in the presence of a reducing agent to obtain a compound of formula (I-d); A production method (1) in which a compound of formula (I-d) is subjected to a cyclization reaction under acidic conditions to obtain a compound of formula (I-e); The agarofuran compound represented by the general formula (I) has no double bond in the A ring and m=1, and R ３ , R ４ is simultaneously hydrogen, a production method (2) comprising a step of obtaining a compound of formula (If) by catalytic hydrogenation using the compound of formula (I-e) in the production method (1); 【Chemistry 4】 In the A ring of the agarofuran compound represented by the general formula (I), there is one double bond located at the 2-3 position of the A ring, m=2, and R ３ , R ４ When is also deuterium, the method includes the steps of: 【Chemistry 5】 wherein the compounds of formula (I-a) and formula (I-b) undergo a substitution reaction under alkaline conditions to obtain a compound of formula (I-c), and R １ is a methyl group mono-, di- or trisubstituted by fluorine atoms; R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ２ ~C ９ a linear hydrocarbylene group, a branched hydrocarbylene group or a cycloalkylene group, said linear or branched hydrocarbylene group being an alkylene group or an alkenylene group containing 1 to 3 double bonds; X is a halogen, preferably bromine; The compound of formula (I-c) undergoes a deuteration reaction with a deuterated alcohol under alkaline conditions to produce a compound of formula (I-j); The compound of formula (I-j) is reduced in the presence of a reducing agent to obtain a compound of formula (I-g); A production method (3) in which a compound of formula (I-g) is subjected to a cyclization reaction under acidic conditions to obtain a compound of formula (I-h); The agarofuran compound represented by the general formula (I) has no double bond in the A ring and m=2; R ３ , R ４ is simultaneously deuterium, a production method (4) comprising a step of obtaining a compound of formula (I-i) by catalytic hydrogenation using the compound of formula (I-h) in the production method (3); 【Chemistry 6】 The agarofuran compound represented by the general formula (I) has a double bond in the A ring and m=1, and R ３ is a carbonyl group, R ４ is hydrogen, a production method (5) comprising a step of carrying out an oxidation reaction using the compound of formula (I-e) of the production method (1) in the presence of an oxidizing agent to obtain a compound of formula (I-k); 【Chemistry 7】 The agarofuran compound represented by the general formula (I) has a double bond in the A ring and m=1, and R ３ is a hydroxy group, and R ４ is hydrogen, a production method (6) comprising a step of carrying out a reduction reaction in the presence of a reducing agent using the compound of formula (I-k) of the production method (5) to obtain a compound of formula (I-m); 【Chemistry 8】 The manufacturing method is characterized in that the method is selected from any one of the following:

7. R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ２ ~C ５ A straight chain alkylene group, optionally R ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ３ ~C ４ is a linear alkylene group, and optionally further ２ is unsubstituted or substituted by a hydroxy group or a carbonyl group; ３ The method according to claim 6, characterized in that the alkylene group is a straight-chain alkylene group.

8. R １ , R ２ The method according to claim 6, characterized in that the step (a) is selected from any one of the following: 1)R １ =-CF ３ 、R ２ =-CH ２ CH ２ CH ２ - 2)R １ =-CH ２ F、R ２ =-CH ２ CH ２ CH ２ - 3)R １ =-CHF ２ 、R ２ =-CH ２ CH ２ CH ２ - 4)R １ =-CF ３ 、R ２ =-CH ２ CH ２ CH ２ CH ２ -

9. the reagent providing the alkaline conditions comprises an inorganic base, said inorganic base comprising one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide; and / or the reducing agent comprises one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride; and / or the reagent for providing an acidic environment comprises one or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and p-toluenesulfonic acid; and / or the metal catalyst for catalytic hydrogenation includes one or more of palladium on carbon, rhodium on carbon, platinum dioxide, and Raney nickel; and / or the oxidizing agent comprises one or more of oxygen, hydrogen peroxide, peroxide, Sallet's reagent.

10. The solvent used in the production method (1) includes, in step 1, one or more of methanol, ethanol, isopropanol, and tert-butanol, in step 2, one or more of diethyl ether and tetrahydrofuran, and in step 3, one or more of n-hexane and petroleum ether; And / or the solvent used in the production method (2) comprises one or more of ethanol, methanol, and diethyl ether; and / or the solvent used in the production method (3) includes step 1: one or more of methanol, ethanol, isopropanol, and tert-butanol; step 2: one or more of deuterated methanol and deuterated ethanol; step 3: one or more of diethyl ether and tetrahydrofuran; and step 4: one or more of n-hexane and petroleum ether; And / or the solvent used in the production method (4) comprises one or more of ethanol, methanol, and diethyl ether; and / or the solvent used in the production method (5) comprises one or more of dichloromethane, toluene, benzene, and pyridine; And / or the process according to claim 6, characterized in that the solvent used in the process (6) comprises one or more of ethanol, methanol, diethyl ether.

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