3-hydroxy-8-fluoro-6h-benzo[c]chromen-6-one derivatives, processes for their preparation and uses thereof

Abstract

The application discloses a 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-ketone derivative, a preparation method and application thereof, and belongs to the field of chemical medicines. The structural formula of the 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-ketone compound is shown in the description, R is one of C2-C5 alkyl, cycloalkyl-substituted C1-C3 alkyl and heterocyclic group-substituted C2-C3 alkyl. 2-bromo-5-fluoro-benzoic acid and resorcinol are used as raw materials, a cyclization reaction is catalyzed by CuI as a catalyst in the presence of sodium carbonate, the reaction temperature is 80-100 DEG C, the reaction time is greatly shortened, and the yield is improved. The 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-ketone compound provided by the application has PDE2 / 4 dual inhibition activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine, and particularly relates to a 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one derivative as a PDE2 / 4 dual inhibitor and a preparation method thereof. BACKGROUND

[0002] Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers in cells, which play an important role in physiological processes such as vision, olfaction, metabolism, muscle contraction, memory, immune response, neurotransmission, exocytosis, cell growth and differentiation. The synthesis and degradation of cAMP and cGMP are strictly regulated: adenylyl cyclase and guanylyl cyclase convert ATP and GTP into the corresponding cyclic forms, respectively, while phosphodiesterases (PDEs) catalyze the hydrolytic ring opening of cAMP and cGMP to generate inactive forms of 5'-AMP or 5'-GMP, respectively, which is the only way to degrade cAMP and cGMP in cells.

[0003] According to the principle of sequence homology, the PDEs superfamily has 11 subtypes (PDE1-11), and most of the subtypes have more than one gene product, such as PDE4 subtype has four gene products PDE4A, PDE4B, PDE4C and PDE4D. The main difference between each subtype is the close degree to two different cyclic nucleotides. For example, PDE4, 7 and 8 are cAMP-specific enzymes, PDE5, 6 and 9 are cGMP-specific enzymes, and PDE1, 2, 3, 10 and 11 are so-called dual-substrate PDEs that can act on cAMP and cGMP. Selective PDEs inhibitors can specifically act on different subtypes to produce different effects. PDEs affect the CREB phosphorylation process and the expression level of downstream genes by regulating the cAMP (cGMP) / protein kinase B (PKA) [protein kinase G (PKG)] / cAMP-responsive element binding protein (CREB) cell signaling pathway, and produce various biological effects, including anti-inflammatory, anti-depression, memory enhancement and cognitive function improvement, etc.

[0004] PDEs inhibitors can regulate the physiological processes of cAMP and cGMP by inhibiting the activity of PDEs, thereby affecting the physiological processes of cAMP and cGMP, and achieving the purpose of treating diseases. In recent years, PDEs as a new therapeutic target have attracted extensive attention from many scholars and become a new research hotspot. At present, a variety of selective inhibitors of different subtypes have been approved for clinical use. PDE1 selective inhibitors mainly include nimodipine, vinpocetine, IC86340 and IC224; PDE3 inhibitor cilostazol is used for treating heart failure, PDE4 inhibitor roflumilast is used for treating chronic obstructive pulmonary disease; PDE5 inhibitor sildenafil is used for treating erectile dysfunction and can also be used for treating PAH and improving the dyspnea of patients; PDE7 inhibitor YM-393059 is used for treating chronic inflammatory diseases, and many other PDEs inhibitors are in the clinical and preclinical research stage. However, more and more studies have shown that single PDEs inhibitors often have obvious side effects and other shortcomings in clinical use. PDE2 inhibitors such as BAY60-7550 and EHNA have not been marketed due to poor pharmacokinetic properties and difficulty in passing through the blood-brain barrier. Therefore, drugs that simultaneously inhibit multiple PDE subtypes have become one of the strategies to solve these problems. Among them, the dual-target PDEs inhibitors targeting PDE4, such as PDE3 / 4 and PDE4 / 7 dual-target inhibitors, have been reported more. The second-generation PDE4 inhibitors include roflumilast and cilomilast, among which roflumilast has been approved by FDA and the European Medicines Agency for the treatment of COPD. In addition, roflumilast also has certain therapeutic effect on other inflammatory diseases. The present application provides a novel structure of 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one PDE2 / 4 dual inhibitor, which has potential effects on treating Alzheimer's disease, depression, inflammatory diseases, cardiovascular diseases and chronic obstructive pulmonary diseases. SUMMARY

[0005] The present application provides a 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compound which has dual inhibition effect on phosphodiesterase 2 and 4 (PDE2 / 4). Meanwhile, the present application also provides a preparation method of the compound, which is simple and easy to implement.

[0006] In order to achieve the purpose of the present application, the technical solutions adopted by the present application are as follows:

[0007] The 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compound as a PDE2 / 4 dual inhibitor provided by the present application has a general formula as shown in formula (I):

[0008]

[0009] R is one of C2-C5 alkyl, cycloalkyl-substituted C1-C3 alkyl, heterocyclyl-substituted C2-C3 alkyl; wherein "cycloalkyl-substituted C1 alkyl" means R is C1 alkyl, but the C1 alkyl end is substituted by cycloalkyl.

[0010] The preparation method of the 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one derivative as a PDE2 / 4 dual inhibitor according to the present application has the following steps:

[0011]

[0012] R is one of C2-C5 alkyl, cycloalkyl-substituted C1-C3 alkyl, heterocyclyl-substituted C2-C3 alkyl; X is Cl or Br;

[0013] The preferred steps are as follows:

[0014] (1) Cyclization: 2-bromo-5-fluoro-benzoic acid, resorcinol and sodium carbonate are heated and stirred in water until completely dissolved, and CuI is added. The reaction is continued at 50-60℃. The reaction is monitored by TLC, and after the reaction is completed, the precipitate is filtered off after cooling. The precipitate is washed with 1M HCl and dried. White crystals are obtained by recrystallization in methanol.

[0015] (2) Etherification: the product obtained in step (1) is dissolved in DMF, anhydrous K2CO3 is added, stirred for 5 min, and alkyl halide is added dropwise. The reaction is carried out at 60-120℃ for 3-24h. The reaction progress is detected by spotting, and after the reaction is completed, the product is poured into ice water and filtered. The product is recrystallized in methanol for several times.

[0016] Compared with the prior art, the present application has the following beneficial effects:

[0017] The 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compounds 1d, 1h, 1l and 1r provided by the present application have good PDE2 / 4 dual inhibition activity, and can be used for preparing drugs for treating senile dementia, depression, inflammatory diseases, cardiovascular diseases and chronic obstructive pulmonary diseases. In addition, the synthesis method of the compounds is given, which is simple and has high yield. The cyclization reaction is carried out under the catalysis of CuI, the reaction is rapid, and the yield is improved from 41% to 52%. The weakly basic sodium carbonate is used, and the neutralization is more moderate, which can reduce the possibility of hydrolysis or product decomposition under alkaline conditions. The reaction time of the experiment is shortened by 1h, and the reaction condition is more mild, from 100℃ to 50℃, so that the experimental operation is safer. DETAILED DESCRIPTION

[0018] The technical solutions of the present application will be described in detail below in conjunction with the examples. The following examples are used to illustrate but not to limit the synthetic method of the compound of general formula I.

[0019] Synthetic route of 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one derivatives:

[0020]

[0021] wherein R is one of C2-C5 alkyl, cycloalkyl-substituted C1-C3 alkyl, heterocyclyl-substituted C1-C3 alkyl; X is Cl or Br;

[0022] The synthetic steps are as follows:

[0023] (1) Cyclization: 2-bromo-5-fluoro-benzoic acid, resorcinol and sodium carbonate were heated and stirred in water until completely dissolved, and CuI was added to continue the reaction at 50°C. The reaction was monitored by TLC, and after the reaction was completed, the precipitate was filtered out after cooling. The precipitate was washed with 1 M HCl and dried. White crystals were obtained by recrystallization in methanol.

[0024] (2) Etherification: the product obtained in step (1) was dissolved in DMF, anhydrous K2CO3 was added, stirred for 5 min, and the bromide was added dropwise, and the reaction was carried out at 70°C for 3-24 h. The reaction progress was detected by spotting, and after the reaction was completed, the product was poured into ice water and filtered. The product was recrystallized in methanol for several times.

[0025] In the following specific embodiments, the 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compounds include the following compounds:

[0026]

[0027] Example 1

[0028] Synthesis of 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one: resorcinol (8.9 g, 81.6 mmol) was dissolved in water, sodium carbonate (8.60 g, 81.6 mmol) was added, and the mixture was heated to 50°C until all the substances were dissolved. Then, 2-bromo-5-fluoro-benzoic acid (8.94 g, 40.8 mmol) was added, and the stirring was continued at 50°C until it was clear. CuI (0.77 g, 4.08 mmol) was added, and the reaction was stirred. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1), and after the reaction was completed, the precipitate was filtered out after cooling. The precipitate was washed with 1 M HCl several times, and dried in an oven. White solid was obtained by recrystallization in methanol.

[0029] 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one: white solid (yield 52%), m.p. 193.7-194.2°C.1 H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.33 (dd, J = 9.0, 5.0 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.87 (dd, J = 8.9, 2.8 Hz, 1H), 7.78 (td, J = 8.7, 2.9 Hz, 1H), 6.85 (dd, J = 8.7, 2.4 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H). 13 CNMR (75 MHz, DMSO-d6) δ 168.28, 162.40, 159.95, 159.55 (d, J = 3.03 Hz), 159.29, 151.37, 131.38 (d, J = 2.02 Hz), 125.11 (d, J = 8.08 Hz), 124.72, 123.33 (d, J = 22.22 Hz), 121.12 (d, J = 7.07 Hz), 114.80 (d, J = 23.23 Hz), 112.64, 110.73, 102.27.

[0030] Example 2

[0031] A solution of 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one (11.5 mmol, 2.65 g) and anhydrous potassium carbonate (27.6 mmol, 3.8 g) in anhydrous DMF (20 mL) was added dropwise with bromoethane (24.1 mmol, 2.63 g) heated to 60 °C for 5 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the reaction was poured into 200 mL of ice water solution, and after standing for 30 min, it was suction filtered and recrystallized from methanol to obtain white solid la-lr with a yield of 31-76%.

[0032] la: white solid (yield 49%), m.p. 243.7-244.2 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (dd, J = 9.0, 5.0 Hz, 1H), 8.21 (d, J = 9.6 Hz, 1H), 7.88 (dd, J = 8.8, 2.8 Hz, 1H), 7.80 (td, J = 8.7, 2.9 Hz, 1H), 6.99-6.96 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 168.28, 162.40, 159.95, 159.55 (d, J = 3.03 Hz), 159.29, 151.37, 131.38 (d, J = 2.02 Hz), 125.11 (d, J = 8.08 Hz), 124.72, 123.33 (d, J = 22.22 Hz), 121.12 (d, J = 7.07 Hz), 114.80 (d, J = 23.23 Hz), 112.64, 110.73, 102.27, 64.88, 60.79, 14.02.

[0033] 1b: White solid (yield 58%), m.p. 232.3-233.7 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1 H), 8.16 (d, J = 8.7 Hz, 1 H), 7.84 (dd, J = 8.9, 2.8 Hz, 1 H), 7.77 (td, J = 8.7, 2.9 Hz, 1 H), 6.98 - 6.89 (m, 2 H), 4.00 (t, J = 6.5 Hz, 2 H), 1.81 - 1.72 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H). 13 C NMR (100 MHz, DMSO-d6) δ 162.25, 160.45, 159.70 (d, J = 21.21 Hz), 151.51, 131.59 (d, J = 3.03 Hz), 124.96 (d, J = 8.08 Hz), 123.29 (d, J = 13.13 Hz), 120.86 (d, J = 8.08 Hz), 114.72 (d, J = 23.23 Hz), 112.67, 109.91, 101.74, 69.52, 21.85, 10.30.

[0034] 1c: White solid (yield 35%), m.p. 217.6-218.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 9.0, 5.0 Hz, 1 H), 8.18 (d, J = 8.2 Hz, 1 H), 7.86 (dd, J = 8.8, 2.8 Hz, 1 H), 7.78 (td, J = 8.7, 2.9 Hz, 1 H), 6.96 - 6.94 (m, 2 H), 4.81 - 4.72 (m, 1 H), 1.32 (d, J = 6.0 Hz, 6 H). 13C NMR (100 MHz, DMSO-d6) δ 162.25, 160.46, 159.81, 159.62 (d, J = 3.03 Hz), 151.52, 131.59 (d, J = 2.02 Hz), 124.96 (d, J = 8.08 Hz), 124.58, 123.29 (d, J = 22.22 Hz), 120.86 (d, J = 8.08 Hz), 114.72 (d, J = 23.23 Hz), 112.69, 109.90, 101.73, 67.79, 30.53, 18.67, 13.65.

[0035] 1d: White solid (yield 43%), m.p. 258.2-259.8 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.84 (dd, J = 8.8, 2.9 Hz, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 6.95 - 6.92 (m, 2H), 4.04 (t, J = 6.5 Hz, 2H), 1.78 - 1.67 (m, 2H), 1.53 - 1.39 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.25, 160.46, 159.81, 159.62 (d, J = 3.03 Hz), 151.52, 131.59 (d, J = 2.02 Hz), 124.96 (d, J = 8.08 Hz), 124.58, 123.29 (d, J = 22.22 Hz), 120.86 (d, J = 8.08 Hz), 114.72 (d, J = 23.23 Hz), 112.69, 109.90, 101.73, 67.79, 30.53, 18.67, 13.65.

[0036] 1e: White solid (yield 51%), m.p. 245.6-246.4 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 9.0, 5.0 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 7.86 (dd, J = 8.8, 2.8 Hz, 1H), 7.78 (td, J = 8.7, 2.9 Hz, 1H), 7.00 - 6.93 (m, 2H), 4.55 (h, J = 6.0 Hz, 1H), 1.76 - 1.57 (m, 2H), 1.28 (d, J = 6.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 162.24, 159.73 (d, J = 4.04 Hz), 159.64, 151.63, 131.63, (d, J = 2.02 Hz) 124.95 (d, J = 8.08 Hz), 123.31 (d, J = 23.23 Hz), 120.88 (d, J = 8.08 Hz), 114.74 (d, J = 23.23 Hz), 113.48, 109.82, 102.71, 74.75, 40.08, 28.38, 18.85, 9.43.

[0037] 1f: White solid (yield 37%), m.p. 237.9-238.6 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1 H), 8.16 (d, J = 8.6 Hz, 1 H), 7.83 (dd, J = 8.8, 2.9 Hz, 1 H), 7.77 (td, J = 8.7, 2.9 Hz, 1 H), 6.95 - 6.91 (m, 2 H), 4.02 (t, J = 6.5 Hz, 2 H), 1.77 - 1.70 (m, 2 H), 1.47 - 1.29 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H). 13 C NMR (100 MHz, DMSO-d6) δ 162.24, 159.73 (d, J = 4.04 Hz), 159.64, 151.63, 131.63, (d, J = 2.02 Hz) 124.95 (d, J = 8.08 Hz), 123.31 (d, J = 23.23 Hz), 120.88 (d, J = 8.08 Hz), 114.74 (d, J = 23.23 Hz), 113.48, 109.82, 102.71, 74.75, 40.08, 28.38, 18.85, 9.43.

[0038] 1g: White solid (yield 52%), m.p. 279.5-281.2 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1 H), 8.16 (d, J = 8.6 Hz, 1 H), 7.83 (dd, J = 8.8, 2.9 Hz, 1 H), 7.77 (td, J = 8.7, 2.9 Hz, 1 H), 6.95 - 6.91 (m, 2 H), 4.02 (t, J = 6.5 Hz, 2 H), 1.77 - 1.70 (m, 2 H), 1.47 - 1.29 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).13 C NMR (100 MHz, DMSO-d6) δ 162.26, 160.46, 159.72 (d, J = 19.19 Hz), 151.54, 131.59, 124.98 (d, J = 8.08 Hz), 124.59, 123.31 (d, J = 22.22 Hz), 120.88 (d, J = 8.08 Hz), 114.74 (d, J = 23.23 Hz), 112.75, 109.92, 101.77, 66.58, 37.19, 24.54, 22.37.

[0039] 1h: white solid (yield 71%), m.p. 277.9-279.3 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.93 (m, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.49 (td, J = 8.4, 2.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 5.52 - 5.47 (m, 1H), 4.58 (d, J = 6.7 Hz, 2H), 1.80 (dd, J = 15.2, 1.4 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 162.89, 160.68, 160.42, 152.02, 139.21, 131.77, 123.52 (d, J = 8.08 Hz), 123.16 (d, J = 23.23 Hz), 121.51 (d, J = 8.08 Hz), 118.79, 116.10 (d, J = 23.23 Hz), 113.29, 110.36, 102.35, 65.33, 25.89, 18.33.

[0040] 1i: white solid (yield 57%), m.p. 259.8-260.6 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (dd, J = 9.0, 5.0 Hz, 1H), 8.22 (d, J = 9.6 Hz, 1H), 7.87 (dd, J = 8.8, 2.8 Hz, 1H), 7.79 (td, J = 8.7, 2.9 Hz, 1H), 7.05 - 6.98 (m, 2H), 4.93 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 168.28, 162.40, 159.74 (d, J = 42.42 Hz), 159.30, 151.38, 131.40, 125.13 (d, J = 17.17 Hz), 124.74, 123.34 (d, J = 22.22 Hz), 121.10 (d, J = 8.08 Hz), 114.81 (d, J = 23.23 Hz), 112.65, 110.74, 102.28, 64.89, 60.90, 60.79, 14.02.

[0041] 1j: White solid (yield 42%), m.p. 247.9-248.6 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (dd, J = 9.0, 5.0 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.87 (dd, J = 8.8, 2.8 Hz, 1H), 7.80 (td, J = 8.7, 2.9 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 5.32 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.58, 160.12, 159.38 (d, J = 4.04 Hz), 157.78, 151.33, 131.10 (d, J = 3.03 Hz), 125.30 (d, J = 8.08 Hz), 125.08, 123.33 (d, J = 23.23 Hz), 121.37 (d, J = 8.08 Hz), 116.28, 114.86 (d, J = 23.23 Hz), 112.56, 111.80, 102.73, 53.82.

[0042] 1k: White solid (yield 46%), m.p. 264.3-265.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.9, 2.8 Hz, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 6.95 (dd, J = 8.8, 2.5 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 1.34 - 1.19 (m, 1H), 0.66 - 0.55 (m, 2H), 0.41 - 0.33 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 162.25, 160.40, 159.80, 159.62 (d, J = 4.04 Hz), 151.49, 131.59 (d, J = 3.03 Hz), 124.96 (d, J = 8.08 Hz), 124.57, 123.30 (d, J = 22.22 Hz), 120.85 (d, J = 8.08 Hz), 114.73 (d, J = 23.23 Hz), 112.69, 109.88, 101.80, 72.68, 9.93, 3.13.

[0043] 1I: White solid (yield 47%), m.p. 235.2-236.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 9.0, 5.0 Hz, 1 H), 8.16 (d, J = 8.7 Hz, 1 H), 7.84 (dd, J = 8.8, 2.8 Hz, 1 H), 7.77 (td, J = 8.7, 2.9 Hz, 1 H), 6.94 (dd, J = 8.7, 2.6 Hz, 1 H), 6.91 (d, J = 2.5 Hz, 1 H), 3.84 (d, J = 6.3 Hz, 2 H), 1.84 - 1.64 (m, 5 H), 1.33 - 0.98 (m, 4 H). 13 C NMR (100 MHz, DMSO-d6) δ 160.58, 159.72 (d, J = 17.17 Hz), 151.51, 131.60 (d, J = 2.02 Hz), 124.97 (d, J = 8.08 Hz), 124.58, 123.31 (d, J = 23.23 Hz), 120.85 (d, J = 8.08 Hz), 114.73 (d, J = 23.23 Hz), 112.69, 109.89, 101.77, 73.18, 36.91, 29.13, 25.98, 25.20.

[0044] 1m: White solid (yield 56%), m.p. 262.5-263.7 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 9.0, 5.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.8, 2.8 Hz, 1H), 7.76 (td, J = 8.7, 2.9 Hz, 1H), 6.93 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 3.84 (d, J = 6.3 Hz, 2H), 1.86 - 1.61 (m, 6H), 1.33 - 1.14 (m, 3H), 1.10 - 1.00 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.24, 160.56, 159.79, 159.61 (d, J = 3.03 Hz), 151.49, 131.59, 131.58 (d, J = 2.02 Hz), 124.94 (d, J = 8.08 Hz), 123.28 (d, J = 22.22 Hz), 120.83 (d, J = 8.08 Hz), 114.71 (d, J = 23.23 Hz), 112.67, 109.87, 101.74, 73.17, 36.90, 29.13, 25.98, 25.20.

[0045] 1n: White solid (yield 31%), m.p. 254.3-255.9 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.04 - 7.96 (m, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.51 (td, J = 8.4, 2.8 Hz, 1H), 6.97 (dd, J = 8.8, 2.6 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 5.33 (t, J = 3.9 Hz, 1H), 4.14 - 4.03 (m, 4H), 4.03 - 3.95 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 163.02, 160.39 (d, J = 30.30 Hz), 151.95, 131.59 (d, J = 2.02 Hz), 123.66, 123.64 (d, J = 8.08 Hz), 123.21 (d, J = 23.23 Hz), 121.68 (d, J = 8.08 Hz), 116.07 (d, J = 23.23 Hz), 113.03, 111.00, 102.56, 101.65, 69.06, 65.43.

[0046] 1o: White solid (yield 76%), m.p. 263.5-264.7 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.04 - 7.91 (m, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.50 (td, J = 8.5, 2.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.6 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 5.12 (t, J = 4.8 Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 4.08 - 3.86 (m, 4H), 2.232.19 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 162.93, 160.63, 160.52 (d, J = 12.12 Hz), 152.04, 131.71 (d, J = 3.03 Hz), 123.56, 123.55 (d, J = 7.07 Hz), 123.15 (d, J = 22.22 Hz), 121.57 (d, J = 8.08 Hz), 116.01 (d, J = 23.23 Hz), 112.98, 110.53, 102.29, 101.82, 65.03, 64.16, 33.55.

[0047] 1p: white solid (yield 65%), m.p. 249.5-251.4 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.95 (m, 2H), 7.87 (d, J = 8.9 Hz, 1H), 7.50 (td, J = 8.4, 2.8 Hz, 1H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 4.17 (t, J = 5.6 Hz, 2H), 3.79 - 3.72 (m, 4H), 2.85 (t, J = 5.6 Hz, 2H), 2.60 (dd, J = 5.8, 3.7 Hz, 4H). 13 C NMR (100 MHz, CDC13) δ 162.96, 160.50, 152.02, 131.65, 131.62, 123.60, 123.53, 123.17 (d, J = 23.23 Hz), 121.60 (d, J = 8.08 Hz), 116.03 (d, J = 23.23 Hz), 113.10, 110.66, 102.32, 66.91, 66.32, 57.42, 54.13.

[0048] 1q: white solid (yield 43%), m.p. 267.4-268.6 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.95 (m, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.50 (td, J = 8.4, 2.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.74 (t, J = 4.7 Hz, 4H), 2.60 - 2.43 (m, 6H), 2.03 (q, J = 6.8 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 162.91, 160.82, 160.49 (d, J = 10.10 Hz), 152.06, 131.72 (d, J = 3.03 Hz), 123.48 (d, J = 8.08 Hz), 123.54, 123.15 (d, J = 23.23 Hz), 121.55 (d, J = 8.08 Hz), 116.01 (d, J = 23.23 Hz), 113.01, 110.43, 102.21, 66.99, 66.64, 55.37, 53.76, 26.23.

[0049] 1r: white solid (yield 52%), m.p. 267.3-268.5 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.95 (m, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.50 (td, J = 8.4, 2.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.74 (t, J = 4.7 Hz, 4H), 2.60 - 2.43 (m, 6H), 2.03 (q, J = 6.8 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 162.91, 160.82, 160.49 (d, J = 10.10 Hz), 152.06, 131.72 (d, J = 3.03 Hz), 123.48 (d, J = 8.08 Hz), 123.54, 123.15 (d, J = 23.23 Hz), 121.55 (d, J = 8.08 Hz), 116.01 (d, J = 23.23 Hz), 113.01, 110.43, 102.21, 66.99, 66.64, 55.37, 53.76, 26.23.

[0050] Example 3

[0051] Phosphodiesterase inhibitory activity of the compound obtained in Example 2 was investigated

[0052] Experimental method: The PDE-Glo TM phosphodiesterase kit. The experiment used zero protein and zero inhibitor controls. The reaction was performed in 384-well white assay plates (OptiPlate) at 25 °C in a total volume of 20 μΐ^. The reaction included assay buffer (200 mM Tris-HCl (pH 7.5), 50 mM MgCl2and 0.5 mg / ml BSA), 1 μΐ^ inhibitor solution (50 μΜ), 1.5 μΐ^ enzyme, 2.5 μΐ^ cAM P (1 μΜ) / cGMP (10 μΜ), 2.5 μΐ^ stop buffer, 2.5 μΐ^ detection buffer and 10 μΐ^ luciferase-based kinase reagent. The luminescent signal was measured using a microplate reader (PerkinElmer) and the signal value is directly related to the remaining amount of ATP and thus to the phosphodiesterase activity. IC 50 values were calculated by the correlation method. The same 20 μΐ^ reaction consisting of enzyme, buffer, substrate, stop buffer, detection buffer, kinase reagent and inhibitor at a concentration range of 0.781 to 100 μΜ was incubated at 25 °C for a total of 1.5 h, with 3 sets of parallel reactions for each group. The inhibition percentage of each concentration of inhibitor was calculated according to the change in signal value, and the collected data was analyzed using GraphPad Prism software to draw the dose-response curve. BAY 60-7550 was used as the positive control for PDE2 enzyme activity detection, and Roflumilast was used as the positive control for PDE4 enzyme activity detection.

[0053]

[0054] a No inhibitory activity was detected

[0055] From the specific IC 50 values data in the above table, it can be seen that the compounds 1d, 1h, 1l and 1r of the general formula 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one all exhibit strong inhibitory effects on PDE2 and PDE4, and have potential effects for treating senile dementia, depression, inflammatory diseases, cardiovascular diseases and chronic obstructive pulmonary diseases. Although the present application is illustrated by the foregoing specific examples, it should not be construed as being limited thereto; instead, the present application encompasses the general aspects disclosed previously. Various modifications and embodiments can be made without departing from the spirit and scope of the present application.

[0056] The above description is only the preferred embodiment of the present application, and the protection scope of the present application is not limited thereto, and any person skilled in the art can make equivalent substitutions or changes to the technical solutions and concepts of the present application within the technical scope disclosed by the present application, which should be encompassed within the protection scope of the present application.

Claims

1. A 3-hydroxy-8-fluoro-6H-benzo[c]chromene-6-one compound, characterized in that, The 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compound has the following structural formula: 、 、 、 。 2. Use of the 3-hydroxy-8-fluoro-6H-benzo[c]chromen-6-one compound according to claim 1 in the preparation of a dual phosphodiesterase 2 and 4 inhibitor.

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