CN113336735B - A kind of urolithin compound, preparation method, pharmaceutical composition and use - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a urolithin compound, a preparation method, a pharmaceutical composition and use thereof. The urolithin compound is the compound represented by the general formula I or its optical isomer, enantiomer, diastereomer, racemate or racemic mixture, or a pharmaceutically acceptable salt thereof. The urolithin compounds provided by the invention have good PDE2 inhibitory activity, the enzymatic level IC ₅₀ reaches 3.67 μM, can be used for the treatment of diseases of the central nervous system and neurodegenerative process diseases of the brain, and is used as an active ingredient to prepare PDE2 inhibitory active drug.

Description

A kind of urolithin compound, preparation method, pharmaceutical composition and use

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a urolithin compound, a preparation method, a pharmaceutical composition and use thereof.

Background technique

There are 11 families of phosphodiesterases (PDEs), which are the only super-enzyme family that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate in vivo. Among them, phosphodiesterase II (PDE2) is a dual substrate enzyme that can simultaneously By hydrolyzing cyclic adenosine monophosphate and cyclic guanosine monophosphate, PDE2 is distributed in multiple organs in the human body and participates in various physiological functions, which can be used as potential drug targets for follow-up studies. Phosphodiesterase inhibitor is a drug that inhibits the activity of phosphodiesterase. It regulates the concentration of cyclic adenosine monophosphate and cyclic guanosine monophosphate in cells by inhibiting the activity of PDEs, thereby affecting the physiological process and achieving the treatment of diseases. the goal of. PDE2 inhibitors have a wide range of applications in Alzheimer's disease, blood diseases and other fields. However, due to poor pharmacological activity and low blood-brain barrier permeability, there are currently no finished PDE2 inhibitors on the market. Therefore, if a PDE2 inhibitor with good effect can be developed, it will have great social and economic benefits.

Urolithins are metabolites of ellagitannin or ellagic acid and their derivatives. There have been many literature reports on the role of urolithin compounds in brain neuroprotection. For example, the research results of Ravikanth Velagapudi (Molecular Nutrition & Food Research, 2019, 63(10): 1801237.) et al. showed that urolithin A can activate neural Protective mechanisms, such as activation of SIRT-1 in differentiated ReNcell VM human neural cells, play a protective role; Verzelloni, E (Mol. Nutr. Food Res. 2011, 55(Suppl. 1), S35.) and Liu, W (Food Funct. 2014, 5, 2996.) The research results of et al. show that urolithin A and B can reduce the ability of advanced glycation end product formation and thus participate in brain neuroprotection. Urolithins have been shown to be useful in the treatment of various disorders in the human body. However, there is no research report on urolithin and its derivatives as PDE2 inhibitors. In addition, the existing synthesis of urolithin mainly adopts microbial pharmacy, which has the disadvantages of long cycle and high cost.

SUMMARY OF THE INVENTION

In order to solve the deficiencies of the prior art, the present invention provides a urolithin compound, a preparation method, a pharmaceutical composition and an application. The urolithin compound has good PDE2 inhibitory activity, can be used for the treatment of diseases of the central nervous system and neurodegenerative process diseases of the brain, and is used as an active ingredient to prepare a medicine for inhibiting the activity of PDE2.

For solving the deficiencies in the prior art, the technical solutions provided by the present invention are:

One aspect of the present invention provides a urolithin compound, which is Compound I or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof :

in,

R ₁ is a hydrogen atom, a methoxy group or a methyl group;

R ₂ is a C ₂ -C ₉ alkyl group, a methylthio group-substituted C ₂ -C ₉ alkyl group, a cycloalkyl group-substituted C ₁ -C ₉ alkyl group, and an ethyl ester group-substituted C ₁ -C ₉ alkyl group , one of C 1 -C ₉ alkyl substituted by heterocyclic group, C ₁ -C ₉ alkyl substituted by hydroxy group, C ₁ -C ₉ alkyl substituted by aryl group or C _{2 -C 9} heterocyclic group.

Preferably, the compound I is selected from compounds represented by formulas 1a-1q, 2a-2u or 3a-3j:

Another object of the present invention is to provide a kind of preparation method of urolithin compounds, comprising:

Step S1: After compound II, 4-bromobenzene-1,3-diol, catalyst, alkaline aqueous solution and 1,2-dimethoxyethane are mixed uniformly, react at 90-100° C. under sealed conditions Compound III is obtained in 9-12h, and the synthetic route is shown in the following formula:

Wherein, R ₁ is a hydrogen atom, a methoxy group or a methyl group;

Step S2: at room temperature, dissolving compound III in anhydrous DMF, adding K ₂ CO ₃ and stirring uniformly, heating, adding dropwise a halogenated compound of general formula R ₂ Br, and reacting at 80-120 ° C for 3.5-30 h to obtain The aforementioned compound I, the synthetic route is shown in the following formula:

wherein, R ₂ is a C ₂ -C ₉ alkyl group, a methylthio group-substituted C ₂ -C ₉ alkyl group, a cycloalkyl group-substituted C ₁ -C ₉ alkyl group, and an ethyl ester group-substituted C ₁ -C ₉ alkyl group One of alkyl, C 1 -C ₉ alkyl substituted by heterocyclyl, C ₁ -C ₉ alkyl substituted by hydroxy, C ₁ -C ₉ alkyl substituted by aryl or C _{2 -C 9} heterocyclyl kind.

Preferably, in the step S1, the molar ratio of the compound II to 4-bromobenzene-1,3-diol is 1.5-1:1.

Preferably, in the step S1,

The catalyst is one of tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride or bistriphenylphosphonium palladium dichloride or variety;

The molar ratio of the catalyst to the compound II is 1-5:100.

Preferably, in the step S1, the catalyst is tetrakis(triphenylphosphine)palladium.

Preferably, in the step S1,

The alkaline aqueous solution is one of Na ₂ CO ₃ aqueous solution, K ₂ CO ₃ aqueous solution or K ₃ PO ₄ aqueous solution;

The concentration of the alkaline aqueous solution is 3 mol/L.

Preferably, in the step S2, the molar ratio of the compound III, K ₂ CO ₃ and R ₂ Br is 1:1-1.5:1-1.5.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned urolithin compounds and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Another object of the present invention is to provide the application of the aforementioned urolithin compounds in the preparation of medicines for inhibiting PDE2.

Beneficial effects of the present invention:

The urolithin compounds provided by the invention have good PDE2 inhibitory activity, the enzymatic level IC ₅₀ reaches 3.67 μM, the blood-brain barrier permeability is high, and the in vivo absorption is good, and can be used for the treatment of central nervous system diseases, such as Alzheimer's disease and schizophrenia can also be used to treat neurodegenerative process diseases of the brain, as active ingredients to prepare drugs that inhibit the activity of PDE2.

The invention provides a new method for preparing urolithin compounds, which is simple and high in yield, overcomes the current situation of single source method of urolithin compounds, and lays a foundation for better utilization of urolithin compounds.

Detailed ways

The present invention will be further described below in conjunction with the embodiments. The following embodiments are only used to illustrate the technical solutions of the present invention more clearly, and cannot be used to limit the protection scope of the present invention.

The embodiment of the present invention provides a urolithin compound, the urolithin compound is compound I or its optical isomer, enantiomer, diastereomer, racemate or racemic mixture, or its pharmaceutical Acceptable salt on:

Wherein, R ₁ is a hydrogen atom, a methoxy group or a methyl group;

R ₂ is a C ₂ -C ₉ alkyl group, a methylthio group-substituted C ₂ -C ₉ alkyl group, a cycloalkyl group-substituted C ₁ -C ₉ alkyl group, and an ethyl ester group-substituted C ₁ -C ₉ alkyl group , one of C 1 -C ₉ alkyl substituted by heterocyclic group, C ₁ -C ₉ alkyl substituted by hydroxy group, C ₁ -C ₉ alkyl substituted by aryl group or C _{2 -C 9} heterocyclic group.

In an optional embodiment of the present invention, compound I is selected from compounds represented by formulas 1a-1b, 2a-2u or 3a-3j:

The embodiment of the present invention also provides a preparation method of a urolithin compound, comprising the following steps:

Step S1: Compound II is mixed with 4-bromobenzene-1,3-diol, catalyst, alkaline aqueous solution and 1,2-dimethoxyethane evenly, and the mixture is heated at 90°C to 100°C under sealed conditions. The reaction is carried out for 9-12h to obtain compound III, and the synthetic route is shown in the following formula:

Wherein, R ₁ is a hydrogen atom, a methoxy group or a methyl group;

Step S2: at room temperature, dissolving compound III in anhydrous DMF, adding K ₂ CO ₃ and stirring uniformly, heating, adding dropwise a halogenated compound of general formula R ₂ Br, and reacting at 80-120 ° C for 3.5-30 h to obtain Compound I, the synthetic route is shown in the following formula:

wherein, R ₂ is a C ₂ -C ₉ alkyl group, a methylthio group-substituted C ₂ -C ₉ alkyl group, a cycloalkyl group-substituted C ₁ -C ₉ alkyl group, and an ethyl ester group-substituted C ₁ -C ₉ alkyl group One of alkyl, C 1 -C ₉ alkyl substituted by heterocyclyl, C ₁ -C ₉ alkyl substituted by hydroxy, C ₁ -C ₉ alkyl substituted by aryl or C _{2 -C 9} heterocyclyl kind.

In an optional embodiment of the present invention, step S1 further includes the step of separating and purifying compound III, specifically:

When the reaction was completed as monitored by thin layer chromatography, the reaction solution was added dropwise to an ice-water mixture, and the mixture was extracted with ethyl acetate, washed with water, saturated brine, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, it was recrystallized from methanol and acetic acid for 1 h, respectively, and the residue was subjected to column chromatography on silica gel (200-300 mesh) to obtain beige compound III.

In an optional embodiment of the present invention, step S2 also includes a step of separating and purifying compound I, specifically:

When the reaction was monitored by thin layer chromatography, the reaction solution was poured into ice water, and white flocculent solid was formed. After refrigerating and standing, suction filtration, and drying to obtain the target product compound I as a crude product, which is subjected to silica gel (200-300 mesh) column chromatography to obtain the pure target product compound I.

In an optional embodiment of the present invention, in step S1, the molar ratio of compound II to 4-bromobenzene-1,3-diol is 1.5-1:1.

In an optional embodiment of the present invention, in step S1, the catalyst is tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium or bistriphenylphosphine One or more of phenylphosphonium palladium dichloride, preferably tetrakis(triphenylphosphine) palladium.

In an optional embodiment of the present invention, in step S1, the molar ratio of the catalyst to the compound II is 1-5:100.

In an optional embodiment of the present invention, in step S1, the alkaline aqueous solution is one of Na ₂ CO ₃ aqueous solution, K ₂ CO ₃ aqueous solution or K ₃ PO ₄ aqueous solution, and the concentration of the alkaline aqueous solution is 3 mol/L.

In an optional embodiment of the present invention, in step S2, the molar ratio of compound III to K ₂ CO ₃ is 1:1-1.5.

In an optional embodiment of the present invention, in step S2, the molar ratio of compound III to R ₂ Br is 1:1-1.5.

The embodiments of the present invention also provide a pharmaceutical composition, comprising a therapeutically effective amount of the aforementioned urolithin compounds and a pharmaceutically acceptable carrier, adjuvant or vehicle. The pharmaceutical composition has good PDE2 inhibitory activity.

The urolithin compounds provided by the invention can be used for preparing medicines for inhibiting PDE2.

In the present invention, the enzyme level _IC50 of Compound I was tested to characterize the PDE2 inhibitory activity of Compound I. Establishment of a high-throughput screening model for inhibitor drugs targeting PDE2 using the Alphascreen kit method (Xu Huang, Xu Xiaoshuang, Gao Ying, et al. [J]. China Journal of New Drugs, 2020, 29(10): 1175-1180. ), BAY 60-7550 (CAS No.: 439083-90-6) was used as the reference compound with an _IC50 of 8.4 nM. According to the detection results, the dilution ratio of the experimental system and the formula, the inhibition rate was calculated, and the IC ₅₀ of the compound was calculated.

The reagents used in the following examples are all commercially available, wherein BAY 60-7550 is purchased from MCE Company, and the purity is greater than 98%.

Example 1:

Preparation of Intermediate IV:

2-(Methoxycarbonyl)benzeneboronic acid (60mmol), 4-bromobenzene-1,3-diol (44mmol, 8.3g), tetrakis(triphenylphosphine)palladium (2.4mmol, 2.8g), 3M Aqueous Na ₂ CO ₃ solution (100 mL) and 1,2-dimethoxyethane (200 mL) were mixed, and the reaction was stirred at 100° C. for 12 h by sealing the tube. The progress of the reaction was monitored by TLC (petroleum ether:ethyl acetate=5:1). At the end of the reaction, the reaction solution was added dropwise to an ice-water mixture, the mixture was extracted with ethyl acetate (3×50 mL), washed with water, saturated brine, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, it was recrystallized from methanol and acetic acid for 1 h, respectively. The residue was subjected to silica gel (200-300 mesh) column chromatography (petroleum ether:ethyl acetate=10:1) to obtain Intermediate IV (2.8 g). , the yield is 30.0%).

Characterization data of intermediate IV:

m.p.250–251℃;

¹ H NMR: (300 MHz, DMSO-d ₆ ) δ=10.36 (s, 1H), 8.27 (dt, J=8.0, 3.0 Hz, 1H), 8.21-8.15 (m, 2H), 7.89 (m, 1H) ,7.57(m,1H),6.85(dd,J=9.0,3.0Hz,1H),6.76(d,J=3.0Hz,1H);

¹³ C NMR: (75MHz, DMSO-d ₆ )δ=161.06, 160.32, 152.57, 135.65, 135.52, 130.11, 128.04, 125.21, 122.02, 119.39, 113.60, 109.82, 103.40;

HRMS(ESI) m/z calcd for C ₁₃ H ₉ O ₃ ⁺ [M+H] ⁺ : 213.0473; found: 213.0470;

Chromatographic purity: 98.0% (HPLC).

Example 2

Preparation of compound 3-sec-butoxy-6H-benzo[c]benzopyran-6-one (formula 1b):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate IV (9.4 mmol, 2.00 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and 2-bromobutane (12.2 mmol) were added, And the temperature was controlled at 120 ℃, and the reaction was carried out for 6 h. The reaction was monitored by TLC (petroleum: ethyl acetate = 3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by column chromatography (200-300 mesh) to give the compound of formula 1b in 71% yield.

Characterization data for 3-sec-butoxy-6H-benzo[c]benzopyran-6-one:

M.p.73.2–75.8℃;

¹ H NMR (400MHz, DMSO-d6)δ=8.36-8.19(m,3H), 7.93-7.88(m,1H), 7.62-7.57(m,1H), 7.00-6.97(m,2H), 4.60- 4.53(m,1H),1.74-1.58(m,2H),1.28(d,J=8.0Hz,3H),0.95(t,J=4.0Hz,3H);

¹³ C NMR (100MHz, DMSO-d6)δ=160.97, 160.25, 152.58, 135.73, 135.24, 130.12, 128.41, 125.19, 122.31, 119.64, 113.83, 110.83, 103.21, 75.23, 9.92;

HRMS(ESI) m/z calcd for C ₁₇ H ₁₇ O ₃ ⁺ [M+H] ⁺ : 269.1099; found: 269.1095;

Chromatographic purity: 99.2% (HPLC).

Example 3

Preparation of 3-butoxy-6H-benzo[c]benzopyran-6-one (Formula 1c):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate IV (9.4 mmol, 2.00 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and bromobutane (12.2 mmol) were added, and The temperature was controlled at 120 °C, and the reaction was carried out for 8 h. The reaction was monitored by TLC (petroleum: ethyl acetate = 3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by column chromatography (200-300 mesh) to give the compound of formula 1c in 56% yield.

Characterization data for 3-butoxy-6H-benzo[c]benzopyran-6-one:

M.p.53.6–55.5℃.

¹ H NMR (300MHz, DMSO-d6)δ=8.34-8.20(m,3H),7.91(t,J=9.0Hz,1H),7.60(t,J=9.0Hz,1H),7.01-6.99(d , J＝6.0Hz, 2H), 4.09(t, J＝6.0Hz, 2H), 1.74(t, J＝9.0Hz, 2H), 1.50–1.42(m, 2H), 0.95(t, J＝9.0Hz) ,3H);

¹³ C NMR (75MHz, DMSO-d6) δ=161.13, 160.98, 152.54, 135.78, 135.25, 130.14, 128.49, 125.16, 122.39, 119.67, 113.13, 110.98, 102.34, 68.30, 31.5;

HRMS(ESI) m/z calcd for C1 ₇ H ₁₇ O ₃ ⁺ [M+H] ⁺ : 269.1099; found: 269.1095.

Chromatographic purity: 98.7% (HPLC).

Example 4

Preparation of compound 3-((tetrahydro-2H-pyran-4-yl)methoxy)-6H-benzo[c]benzopyran-6-one (formula 1f):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate IV (9.4 mmol, 2.00 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and 4-bromomethyltetrahydropyran ( 12.2 mmol), and the temperature was controlled at 120 °C for 6 h. The reaction was monitored by TLC (petroleum: ethyl acetate = 3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by column chromatography (200-300 mesh) to give the compound of formula 1f in 55% yield.

Characterization data for compound 3-((tetrahydro-2H-pyran-4-yl)methoxy)-6H-benzo[c]benzopyran-6-one:

M.p.133.0–134.8℃.

¹ H NMR (300 MHz, CDCl ₃ ) δ=8.34 (d, J=9.0 Hz, 1H), 7.96 (dd, J=18.0, 9.0 Hz, 2H), 7.78 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5Hz, 1H), 6.91–6.82 (m, 2H), 4.04 (dd, J=12.0, 9.0Hz, 2H), 3.87 (t, J=6.0Hz, 2H), 3.46 (t, J=12.0Hz, 2H), 2.17–2.06 (m, 1H), 1.80 (d, J=3.0Hz, 2H), 1.57–4.13 (m, 2H);

¹³ C NMR (75MHz, DMSO-d6)δ=161.09, 160.97, 152.53, 135.79, 135.22, 130.15, 128.53, 125.19, 122.41, 119.69, 113.13, 111.08, 102.44, 73.00, 67.06, 34.77

HRMS(ESI) m/z calcd for C ₁₉ H ₁₉ O4 ⁺ [M+H] ⁺ : 311.1205; found: 311.1201.

Chromatographic purity: 97.3% (HPLC).

Example 5

Preparation of compound 3-cyclopentylmethoxy-6H-benzo[c]benzopyran-6-one (formula 1o):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate IV (9.4 mmol, 2.00 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and bromomethylcyclopentane (12.2 mmol) were added , and the temperature was controlled at 120 °C for 6 h. The reaction was monitored by TLC (petroleum: ethyl acetate = 3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by column chromatography (200-300 mesh) to obtain the compound of formula 1o in a yield of 77%.

Characterization data for 3-cyclopentylmethoxy-6H-benzo[c]benzopyran-6-one:

M.p.90.6–91.2℃.

¹ H NMR (300 MHz, CDCl ₃ ) δ=8.34 (dd, J=9.0, 1.5 Hz, 1H), 7.98 (dd, J=6.0, 1.2 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H) ,7.79–7.74(m,1H),7.51–7.45(m,1H),6.90(dd,J=9.0,3.0Hz,1H),6.83(d,J=3.0Hz,1H),3.89(d,J = 6.0Hz, 2H), 2.47 (m, 1H), 1.96–1.79 (m, 2H), 1.752–1.55 (m, 4H), 1.44–1.32 (m, 2H);

¹³ C NMR (75MHz, CDCl ₃ )δ=161.61, 161.19, 152.56, 135.25, 134.85, 130.52, 127.61, 123.67, 121.05, 119.89, 112.87, 110.87, 102.12, 72.67, 385.90, 29.48

HRMS(ESI) m/z calcd for C ₁₉ H ₁₉ O ₃ ⁺ [M+H] ⁺ : 295.1256; found: 295.1251.

Chromatographic purity: 98.4% (HPLC).

Example 6

Preparation of Intermediate V:

2-Methoxycarbonyl-4-methoxybenzeneboronic acid (60mmol), 4-bromobenzene-1,3-diol (44mmol, 8.3g), tetrakis(triphenylphosphine)palladium (2.4mmol, 2.8g) ), 3M Na ₂ CO ₃ aqueous solution (100 mL) and 1,2-dimethoxyethane (200 mL) were mixed, and the reaction was stirred at 100° C. for 12 h by sealing. The progress of the reaction was monitored by TLC (petroleum ether:ethyl acetate=5:1). At the end of the reaction, the reaction solution was added dropwise to an ice-water mixture, the mixture was extracted with ethyl acetate (3×50 mL), washed with water, saturated brine, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, it was recrystallized from methanol and acetic acid for 1 h, respectively, and the residue was subjected to silica gel (200-300 mesh) column chromatography (petroleum ether:ethyl acetate=10:1) to obtain Intermediate V (2.66 g) , yield 25.0%).

Characterization parameters of intermediate V:

m.p.276.2～278.8℃.

¹ H NMR: (300 MHz, DMSO-d ₆ ) δ=10.22 (s, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.60 (d, J ＝3.0Hz,1H),7.49(dd,J＝9.0,3.0Hz,1H),6.83(dd,J＝9.0,3.0Hz,1H),6.75(d,J＝3.0Hz,1H),3.89(s , 3H).

¹³ C NMR: (75MHz, DMSO-d ₆ )δ=160.97, 159.41, 158.94, 151.62, 128.97, 124.57, 124.36, 123.99, 120.48, 113.55, 111.27, 109.96, 103.30, 56.01.

HRMS(ESI) m/z calcd for C ₁₄ H ₁₀ O ₄ ⁺ [M+H] ⁺ : 243.0579; found: 243.0575.

Chromatographic purity: 97.2% (HPLC).

Example 7

Preparation of compound 3-butoxy-8-methoxy-6H-benzo[c]benzopyran-6-one (2d)

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate V (9.4 mmol, 2.28 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and bromobutane (12.2 mmol) were added, and The temperature was controlled at 80°C and the reaction was stirred for 12h. The reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain compound 2d in a yield of 65%.

Characterization data for 3-butoxy-8-methoxy-6H-benzo[c]benzopyran-6-one:

M.p.102.5–104.4°C.

¹ H NMR (300MHz, DMSO-d6)δ=8.26(d,J=9.0Hz,1H),8.19-8.15(m,1H),7.62(d,J=3.0Hz,1H),7.51(dd,J ＝9.0,3.0Hz,1H),6.98(s,1H),6.96(t,J＝4.5Hz,1H),4.07(t,J＝6.0Hz,2H),3.90(s,3H),1.78–1.68 (m, 2H), 1.52–1.3840 (m, 2H), 0.95 (t, J=7.5Hz, 3H);

¹³ C NMR (75MHz, DMSO-d6)δ=160.84, 160.25, 159.20, 151.52, 128.58, 124.43, 124.29, 124.24, 120.75, 112.99, 111.31, 111.08, 102.21, 68.21, 517.02, 4.14;

HRMS(ESI) m/z calcd for C ₁₈ H ₁₉ O ₄ ⁺ [M+H] ⁺ : 299.1205; found: 299.1201.

Chromatographic purity: 99.1% (HPLC).

Example 8

Preparation of compound 8-methoxy-3-(2-(methylthio)ethoxy)-6H-benzo[c]benzopyran-6-one (formula 2h):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate V (9.4 mmol, 2.28 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and 2-bromoethyl methyl sulfide ( 12.2 mmol) and the temperature was controlled at 120 °C and the reaction was stirred for 22 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain compound 2h in a yield of 40%.

Characterization data for 8-methoxy-3-(2-(methylthio)ethoxy)-6H-benzo[c]benzopyran-6-one:

Mp110.1–111.8℃. ¹ H NMR(300MHz,DMSO-d6)δ=8.27(d,J=9Hz,1H),8.19(d,J=9.0Hz,1H),7.62(d,J=3.0Hz ,1H),7.52(dd,J＝9.0,3.0Hz,1H),7.03–6.98(m,2H),4.26(t,J＝6.0Hz,2H),3.90(s,3H),2.89(t, J=7.5Hz, 2H), 2.18(s, 3H);

¹³ C NMR (75MHz, CDCl ₃ )δ=165.60, 164.53, 164.05, 156.28, 133.29, 129.33, 129.13, 125.61, 117.84, 116.16, 116.12, 107.21, 72.70, 60.82, 37.28, 20.45;

HRMS(ESI) m/z calcd for C ₁₇ H ₁₇ O ₄ S ⁺ [M+H] ⁺ : 317.0769; found: 317.0765.

Chromatographic purity: 97.8% (HPLC).

Example 9

Preparation of compound 8-methoxy-3-((tetrahydro-2H-pyran-4-yl)methoxy)-6H-benzo[c]benzopyran-6-one (formula 2o):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate V (9.4 mmol, 2.28 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and 4-bromomethyltetrahydropyran ( 12.2 mmol) and the temperature was controlled at 80 °C and the reaction was stirred for 24 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain compound 2o in a yield of 36%.

Characterization data for compound 8-methoxy-3-((tetrahydro-2H-pyran-4-yl)methoxy)-6H-benzo[c]benzopyran-6-one:

Mp168.1-168.5℃. ¹ H NMR (400MHz, CDCl ₃ )δ=7.94(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.78(d,J=4.0Hz ,1H),7.39(dd,J＝8.0,4.0Hz,1H),6.91(dd,J＝8.0,4.0Hz,1H),6.86(d,J＝4.0Hz,1H),4.06(dd,J＝ 12.0, 4.0Hz, 2H), 3.94 (s, 3H), 3.88 (d, J=8.0Hz, 2H), 3.51–3.45 (m, 2H), 2.19–2.0 (m, 1H), 1.82–1.78 (m ,2H),1.56–1.46(m,2H);

¹³ C NMR (75MHz, DMSO-d6)δ=160.91, 160.29, 159.31, 151.59, 128.64, 124.60, 124.45, 124.41, 120.86, 113.14, 111.41, 111.25, 102.42, 72.99, 67.0, 2, 9.6.1;

HRMS(ESI) m/z calcd for C ₂₀ H ₂₁ O ₅ ⁺ [M+H] ⁺ : 341.1311; found: 341.1307.

Chromatographic purity: 97.4% (HPLC).

Example 10

Preparation of compound 3-((4-(hydroxymethyl)phenyl)methoxy)-8-methoxy-6H-benzo[c]benzopyran-6-one (formula 2p):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate V (9.4 mmol, 2.28 g), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and 4-bromomethylbenzyl alcohol (12.2 g) were added mmol) and the temperature was controlled at 120 °C and the reaction was stirred for 4 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain compound 2p in a yield of 37%.

Characterization data for compound 3-((4-(hydroxymethyl)phenyl)methoxy)-8-methoxy-6H-benzo[c]benzopyran-6-one:

Mp192.4–194.6℃. ¹ H NMR(300MHz, DMSO-d6)δ=8.27(d,J=9.0Hz,1H),8.19(d,J=9.0Hz,1H),7.62(d,J=3.0 Hz, 1H), 7.51 (dd, J=9.0, 3.0Hz, 1H), 7.44 (dd, J=6.0, 3.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 7.08–7.03 (m , 2H), 5.20(t, J=6.0Hz, 3H), 4.51(d, J=3.0Hz, 2H), 3.90(s, 3H);

¹³ C NMR(75MHz,DMSO-d6)δ＝160.86,159.87,159.32,151.49,142.91,135.27,128.55,128.18,127.01,124.57,124.40,120.88,113.43,111.44,111.39,102.84,70.11,63.11,56.08；

HRMS(ESI) m/z calcd for C ₂₂ H ₁₉ O ₅ ⁺ [M+H] ⁺ : 363.1154; found: 363.1150.

Chromatographic purity: 98.6% (HPLC).

Example 11

Preparation of Intermediate VI:

Methyl 2-boronic acid-5-methylbenzoate (60 mmol), 4-bromobenzene-1,3-diol (44 mmol, 8.3 g), tetrakis(triphenylphosphine)palladium (2.4 mmol, 2.8 g), After mixing 3M Na ₂ CO ₃ aqueous solution (100 mL) and 1,2-dimethoxyethane (200 mL), the reaction was stirred at 100° C. for 12 h by sealing. The progress of the reaction was monitored by TLC (petroleum ether:ethyl acetate=5:1). At the end of the reaction, the reaction solution was added dropwise to an ice-water mixture, the mixture was extracted with ethyl acetate (3×50 mL), washed with water, saturated brine, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, it was recrystallized from methanol and acetic acid for 1 h, respectively, and the residue was subjected to silica gel (200-300 mesh) column chromatography (petroleum ether:ethyl acetate=10:1) to obtain Intermediate VI (2.89 g) , the yield is 28.9%).

Characterization parameters of intermediate VI:

m.p.266.8～267.5℃.

¹ H NMR: (300 MHz, DMSO-d ₆ ) δ=10.27 (s, 1H), 8.13 (dd, J=9.0, 6.0 Hz, 2H), 7.98 (s, 1H), 7.70 (dd, J=9.0, 3.0Hz, 1H), 6.83 (dd, J=9.0, 3.0Hz, 1H), 6.74 (d, J=2.4Hz, 1H), 2.44 (s, 3H).

¹³ C NMR: (75 MHz, DMSO-d ₆ ) δ = 165.87, 164.68, 157.02, 142.60, 141.62, 137.86, 134.50, 129.77, 126.90, 124.05, 118.30, 114.72, 108.11, 25.87.

HRMS (ESI) m/z calcd for C ₁₄ H ₁₀ O ₄ ⁺ [M+H] ⁺ : 227.00630; found: 227.0626.

Chromatographic purity: 98.6% (HPLC).

Example 12

Preparation of compound 8-methyl-3-pentyloxy-6H-benzo[c]benzopyran-6-one (formula 3a):

Anhydrous DMF (30 mL) was added to a 250 mL round bottom flask, Intermediate VI (9.4 mmol), anhydrous K ₂ CO ₃ (12.2 mmol, 1.7 g) and bromopentane (12.2 mmol) were added, and the temperature was controlled at The reaction was stirred for 12 h at 120 °C. The reaction was monitored by TLC (petroleum: ethyl acetate = 3:1). After the reaction was completed, the reaction solution was added to an ice-water mixture to obtain a brown solid. After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain the compound represented by formula 3a.

Characterization data for compound 8-methyl-3-pentyloxy-6H-benzo[c]benzopyran-6-one:

M.p.90.3-91.6℃;

¹ H NMR: (300 MHz, DMSO-d ₆ ) δ=8.23 (d, J=3.0 Hz, 1H), 8.21 (d, J=6.0 Hz, 1H), 8.02 (s, 1H), 7.74 (dd, J =6.0,2.1Hz,1H),6.99-6.97(m,2H),4.07(t,J=4.5Hz,2H),2.46(s,3H),1.79-1.72(m,2H),1.46-1.32( m, 4H), 0.91 (t, J=6.0Hz, 3H);

¹³ C NMR: (75MHz, DMSO-d ₆ )δ=161.04, 160.78, 152.24, 138.31, 136.92, 132.80, 129.78, 124.92, 122.45, 119.57, 113.08, 111.13, 102.34, 68.57, 22.5, 28, 2 14.39;

HRMS(ESI) m/z calcd for C ₁₈ H ₁₉ O ₃ ⁺ [M+H] ⁺ :296.1412found:296.1410.

Chromatographic purity: 98.5% (HPLC).

According to the steps of Example 2, only changing the type and reaction time of R ₂ Br, the compounds represented by formula 1a, formula 1d, formula 1e, formula 1g-1n, formula 1p, and formula 1q were prepared; according to the steps of embodiment 8, Only change the type and reaction time of R ₂ Br to prepare compounds represented by formula 2a-2c, formula 2e-2g, formula 2i-2n and formula 2q-2u; follow the steps of Example 12, only change the type of R ₂ Br, Compounds represented by formulae 3a to 3j were prepared; R ₂ Br used for preparing these compounds, reaction time and yield of compounds are shown in the following table.

Table 1 Preparation conditions and yields of urolithin compounds

The enzymatic level _IC50 test results of compounds of formulas 1a-1q, 2a-2u and 3a-3j are shown in the following table:

Table 2 Enzyme level IC ₅₀ of urolithin compounds inhibiting PDE2

Table 2 shows that the urolithin compounds provided by the present invention have good PDE2 inhibitory activity.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the technical principles of the present invention, several improvements and modifications can be made. These improvements and modifications It should also be regarded as the protection scope of the present invention.

Claims (10)

1. A urolithin compound selected from the group consisting of the compounds shown below, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof:

2. the urolithin compound of claim 1, wherein the urolithin compound is a compound of formula 1 o:

3. the method for producing a urolithin compound according to any one of claims 1 to 2, comprising:

step S1: uniformly mixing a compound II, 4-bromobenzene-1, 3-diol, a catalyst, an alkaline aqueous solution and 1, 2-dimethoxyethane, and reacting for 9-12 h at 90-100 ℃ under a sealed condition to obtain a compound III, wherein the synthetic route is shown as the following formula:

wherein R is ₁ Is one of hydrogen atom, methoxyl or methyl;

step S2, dissolving compound III in anhydrous DMF at room temperature, adding K ₂ CO ₃ After being stirred evenly, the mixture is heated and dripped with the general formula R ₂ Reacting a halogenated Br product at 80-120 ℃ for 3.5-30 h to obtain the urolithin compound as claimed in any one of claims 1-2, wherein the synthetic route is shown as the following formula:

wherein,

R ₁ when it is a hydrogen atom, R ₂ Selected from the following groups:

R ₁ when it is methoxy, R ₂ Selected from the following groups:

R ₁ when it is methyl, R ₂ Is composed of

4. The method for producing a urolithin compound according to claim 3,

in the step S1, the molar ratio of the compound II to 4-bromobenzene-1, 3-diol is 1.5-1: 1.

5. The method for preparing a urolithin compound according to claim 3, wherein in step S1,

the catalyst is one or more of tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride or bis (triphenylphosphine) palladium dichloride;

the molar ratio of the catalyst to the compound II is 1-5: 100.

6. The method for producing a urolithin compound according to claim 5,

in the step S1, the catalyst is tetrakis (triphenylphosphine) palladium.

7. The method for preparing a urolithin compound according to claim 3, wherein in step S1,

the alkaline aqueous solution is Na ₂ CO ₃ Aqueous solution, K ₂ CO ₃ Aqueous solutions or K ₃ PO ₄ One of aqueous solutions;

the concentration of the alkaline aqueous solution is 3 mol/L.

8. The method for preparing a urolithin compound according to claim 3, wherein in step S2, the compounds III and K are ₂ CO ₃ 、R ₂ The molar ratio of Br is 1: 1-1.5.

9. A pharmaceutical composition comprising a therapeutically effective amount of a urolithin compound according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

10. Use of a urolithin compound in the manufacture of a medicament for inhibiting PDE2, wherein the urolithin compound is selected from the group consisting of the compounds shown below, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof: