Preparation and application of fluorine-substituted cilostazol derivatives

Abstract

The present invention discloses a class of fluorine-substituted cilostazol derivatives and pharmaceutically acceptable salts thereof. The fluorine-substituted cilostazol derivatives of the present invention are compounds having phosphodiesterase 3A (PDE3A) inhibitory activity, have important potential therapeutic value, and are used in drugs for treating tumors, cardiovascular diseases, cerebrovascular diseases or dementia.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of fluorine-substituted cilostazol derivatives or pharmaceutically acceptable salts thereof, and their use as phosphodiesterase 3A (PDE3A) inhibitors, particularly in drugs for treating tumors, cardiovascular diseases, cerebrovascular diseases or dementia. Background Art

[0002] Cilostazol inhibits the activity of phosphodiesterase in platelets and vascular smooth muscle, thereby increasing the cAMP concentration in platelets and smooth muscle, exerting antiplatelet and vasodilatory effects. It inhibits the initial and secondary aggregation and release reactions of platelets induced by ADP, adrenaline, collagen and arachidonic acid, and has a significant antithrombotic effect on the model of cerebral circulation and peripheral circulation disorders caused by collagen, ADP, arachidonic acid and sodium laurate. It can be used to treat chronic arterial occlusive disease caused by atherosclerosis, large arteritis, thromboangiitis obliterans, diabetes, cerebrovascular disease or dementia.

[0003] The poor pharmacokinetic properties of cilostazol limit its clinical application: when a single oral dose of cilostazol 50 mg was given to healthy adult men on an empty stomach and after a meal, the Cmax and AUCinf of the post-meal administration were 2.3 times and 1.4 times those of the fasting state, respectively. Cilostazol is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 in liver microsomes, followed by CYP2D6 and CYP2C19, and metabolized into active metabolites such as OPC-13015 generated by dehydration and OPC-13213 generated by hydroxylation. When patients with severe renal dysfunction took cilostazol 0.1 g per day orally for 8 consecutive days, the Cmax and AUC of cilostazol decreased by 29% and 39%, respectively, compared with healthy adults, while the Cmax and AUC of the active metabolite OPC-13213 increased by 173% and 209%, respectively. Therefore, it is necessary to design a compound that not only satisfies the PDE3A inhibitory activity of cilostazol but also has good pharmacokinetic parameters for use in diseases related to cilostazol treatment.

[0004] In 1812, French scientists discovered a new element in HF and named it Fluorine. This was the first time that the F element appeared in front of humans. With the passage of time and the deepening of research, a large number of fluorine-containing compounds have been discovered and applied, and fluorine chemistry has also made great progress. Since the bond energy of the CF bond (487 kJ·mol−1) is higher than that of the CH bond (420 kJ·mol−1), the fluorine atom is the most commonly used blocking group. In drug design, fluorine atoms are usually introduced into small molecule compounds to block sites that are prone to oxidative metabolism, selectively prevent the occurrence of oxidative metabolism, and thus improve the metabolic stability of the compound and prolong the drug's action time in the body. Summary of the invention

[0005] The object of the present invention is to provide a fluorine-substituted cilostazol compound, which has both PDE3A inhibitory activity and good pharmacokinetic parameters, or a pharmaceutically acceptable salt thereof, for treating diseases such as tumors, cardiovascular diseases, cerebrovascular diseases or dementia.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] A fluorine-substituted cilostazol derivative as shown in Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0008]

[0009] Formula I

[0010] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 are independently hydrogen or halogen; with the additional condition that R1, R2, R3, R4, R5, R6, R7, R8, R9 or R 10 At least one of them is a halogen.

[0011] Preferably, it is characterized in that R1, R2, R3, R4, R5, R6, R7, R8, R9 and / or R 10 are each independently hydrogen or halogen, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and / or R 10 At least one of them is fluorine.

[0012] More preferably, it is characterized in that R1, R2, R3, R4, R5, R6, R7, R8, R9 and / or R 10 At least one of them is fluorine.

[0013] Most preferably, the compound of formula (I) includes but is not limited to the following specific compound examples:

[0014]

[0015] Compound 1: 6-(4-(1-((1s, 4s)-4-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S1;

[0016]

[0017] Compound 2: 6-(4-(1-((1r, 4r)-4-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S2;

[0018]

[0019] Compound 3: 6-(4-(1-(4,4-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S3;

[0020]

[0021] Compound 4: 6-(4-(1-((1R,2R)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S4;

[0022]

[0023] Compound 5: 6-(4-(1-((1S,2S)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S5;

[0024]

[0025] Compound 6: 6-(4-(1-(3,3-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S6;

[0026]

[0027] Compound 7: (R)-6-(4-(1-(2,2-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S7;

[0028]

[0029] Compound 8: (S)-6-(4-(1-(2,2-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S8.

[0030] The compounds provided by the present invention also include pharmaceutically acceptable equivalents of the compounds or a mixture of two or more.

[0031] Preferably, the compound provided by the present invention may include one or a mixture of two or more of a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite, or a prodrug.

[0032] Preferably, the compound provided by the present invention comprises an acid salt or a basic salt of the compound provided by the present invention. The pharmaceutically acceptable salt has the pharmaceutical activity of the compound and meets the requirements in biology and practical applications.

[0033] The present invention provides a fluorine-substituted cilostazol compound or a pharmaceutically acceptable salt thereof, which is used for treating diseases such as tumors, cardiovascular diseases, cerebrovascular diseases or dementia. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Dose-response curve of the compounds inhibiting PDE3A enzyme activity. DETAILED DESCRIPTION

[0035] The present invention discloses fluorine-substituted cilostazol compounds and uses thereof. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters to achieve the above. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0036] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with specific embodiments.

[0037] The general formula compound of the present invention can be synthesized via the following route:

[0038]

[0039] The compounds prepared in the examples of the present invention are as follows:

[0040]

[0041] Compound 1: 6-(4-(1-((1s, 4s)-4-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S1;

[0042]

[0043] Compound 2: 6-(4-(1-((1r, 4r)-4-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S2;

[0044]

[0045] Compound 3: 6-(4-(1-(4,4-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S3;

[0046]

[0047] Compound 4: 6-(4-(1-((1R,2R)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S4;

[0048]

[0049] Compound 5: 6-(4-(1-((1S,2S)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S5;

[0050]

[0051] Compound 6: 6-(4-(1-(3,3-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S6;

[0052]

[0053] Compound 7: (R)-6-(4-(1-(2,2-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S7;

[0054]

[0055] Compound 8: (S)-6-(4-(1-(2,2-difluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S8.

[0056] Example 1: Synthesis of Compound S1

[0057]

[0058] Step 1 Synthesis of intermediate B1

[0059] The raw material A1 (6.6 g) was dissolved in 100 mL of dichloromethane, and DAST (4.86 mL) was added dropwise in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature overnight. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution was added to quench the mixture, and the mixture was extracted with dichloromethane. After concentration, the product was dissolved in 10 mL of dichloromethane, and 2 mL of TFA was added dropwise. The mixture was stirred at room temperature for 1 hour. After TLC detection of the disappearance of the raw material, 10% NaOH solution was added to alkalize the mixture, and the mixture was extracted with dichloromethane and concentrated to obtain B1 to the amount of solvent required for the next step. ESI-MS [M+H] + =118.1.

[0060] Step 2 Synthesis of intermediate C1

[0061] Add B1 (292 mg dissolved in 5 mL of dichloromethane) and triethylamine (0.37 mL) to the reaction flask. Slowly add the acyl chloride (0.38 mL) dropwise in an ice bath, return to room temperature and stir overnight. TLC detection shows that the reaction is complete, concentrate under vacuum, and the crude product is chromatographed on a silica gel column (n-hexane: ethyl acetate = 9:1) to obtain a white solid C1 (240 mg) with a yield of 41%. ESI-MS [M+H] + =236.1.

[0062] Step 3 Synthesis of intermediate D1

[0063] Sodium azide (5.87 g), H2O (10 mL) and toluene (20 mL) were added to the reaction flask, stirred and cooled to below 5°C, 50% H2SO4 solution (9.8 g) was slowly added dropwise, and after the addition was complete, it was stirred for another 30 min. The toluene layer was separated and dehydrated with anhydrous Na2SO4 to obtain a toluene solution of hydrazoic acid, which was calibrated and used for later use. The raw material C1 (173 mg, 0.76 mmol) was dissolved in 0.74 mL of toluene, stirred, PCl5 (229 mg, 1.10 mmol) was slowly added, and stirred for another 1.5 h to obtain a crude toluene solution. It was slowly added to the toluene solution of sodium azide (0.5 ml) and stirred at room temperature for 1.5 h. The reaction progress was monitored by LC / MS. After the reaction was complete, it was diluted with water (5 mL), extracted with dichloromethane (20 mL), washed with water 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column (n-hexane: ethyl acetate = 8:2) to obtain a white solid D1 (109 g) with a yield of 55%. ESI-MS [M+H] + =261.1.

[0064] Step 4 Synthesis of S1

[0065] D1 (50 mg, 0.19 mmol) was dissolved in 0.12 mL isopropanol (solution 1), 3,4-dihydro-6-hydroxy-quinolinone (37.65 mg, 0.23 mmol) and potassium hydroxide (11.3 mg, 0.20 mmol) were dissolved in 0.16 mL isopropanol (solution 2). Solution 2 was heated to reflux, and solution 1 was added dropwise to solution 2 and heated to reflux for 4 h. After TLC monitoring, the reaction of the raw material was completed, the heating was stopped, the solvent was evaporated, and the product was dissolved in dichloromethane (15 mL), washed with 1 N NaOH solution, NH4Cl solution, and water in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (n-hexane: ethyl acetate = 8:2) to obtain 58.6 mg of the product S1 as a white solid with a yield of 40%. ESI-MS [M+H] + =388.2.

[0066] 1 H NMR (400 MHz, Chloroform- d ) δ 7.86 (s, 1H), 6.70 (dt, J = 11.9,1.7 Hz, 3H), 4.92 – 4.53 (m, 1H), 4.24 (p, J = 7.3 Hz, 1H), 3.99 (t, J = 5.9Hz, 2H), 2.93 (td, J = 7.4, 1.5 Hz, 4H), 2.72 – 2.35 (m, 2H), 2.45 – 2.18 (m,2H), 2.24 – 1.82 (m, 7H), 2.01 – 1.56 (m, 3H).

[0067] Example 2: Synthesis of Compound S2

[0068]

[0069] Step 1: Synthesis of intermediate B2: see the synthesis method of intermediate B1.

[0070] Step 2: Synthesis of intermediate C2: see the synthesis method of intermediate C1.

[0071] Step 3: Synthesis of intermediate D2: see the synthesis method of intermediate D1.

[0072] Step 4 Synthesis of S2: See the synthesis method of S1.

[0073] ESI-MS [M+H] + =388.2.

[0074] 1 H NMR (400 MHz, Chloroform- d ) δ 7.67 (s, 1H), 6.81 – 6.54 (m, 3H), 4.90 (d, J = 47.7 Hz, 1H), 4.37 – 4.10 (m, 1H), 3.98 (t, J = 6.0 Hz, 2H),2.93 (ddd, J = 8.0, 6.7, 2.1 Hz, 4H), 2.72 – 2.10 (m, 5H), 2.23 – 1.64 (m,7H), 1.82 – 1.54 (m, 1H).

[0075] Example 3: Synthesis of Compound S3

[0076]

[0077] Step 1 Synthesis of Compound B3

[0078] The raw material A3 (3.0 g, 14.08 mmol) was dissolved in 56 mL of dichloromethane, and Deoxo-Fluor (7.65 ml, 42.25 mmol) was added dropwise, and stirred at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate solution was added to quench, and the mixture was extracted with dichloromethane, dried, and concentrated. The product was dissolved in 30 mL of dichloromethane, and 5 mL of TFA was added dropwise. The mixture was stirred at room temperature for 1 h. The raw material disappeared after TLC detection. 10% NaOH solution was added to alkalize the mixture, and after dichloromethane extraction, the mixture was concentrated to obtain B3 to the amount of solvent required for the next step. ESI-MS [M+H] + =136.1.

[0079] Step 2: Synthesis of intermediate C3: see the synthesis method of intermediate C1.

[0080] Step 3: Synthesis of intermediate D3: see the synthesis method of intermediate D1.

[0081] Step 4 Synthesis of S3: See the synthesis method of S1.

[0082] ESI-MS [M+Na] + =428.2.

[0083] 1 H NMR (400 MHz, Chloroform- d ) δ 7.64 (s, 1H), 6.76 – 6.60 (m, 3H), 4.31 (d,J = 10.2 Hz, 1H), 3.99 (t, J = 5.9 Hz, 2H), 2.93 (td, J = 7.7, 2.2Hz, 4H), 2.67 – 2.54 (m, 2H), 2.37 (q, J = 10.6, 10.0 Hz, 4H), 2.15 – 1.83(m, 7H).

[0084] Example 4: Synthesis of Compound S4

[0085]

[0086] Step 1: Synthesis of intermediate B4: see the synthesis method of intermediate B1.

[0087] Step 2: Synthesis of intermediate C4: see the synthesis method of intermediate C1.

[0088] Step 3: Synthesis of intermediate D4: see the synthesis method of intermediate D1.

[0089] Step 4 Synthesis of S4: see the synthesis method of S1.

[0090] ESI-MS [M+H] + =388.2.

[0091] 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 6.82 – 6.54 (m, 3H), 4.81 (dddd, J = 49.7, 10.9, 9.4, 5.0 Hz, 1H), 4.33 – 3.84 (m, 3H), 3.10 –2.68 (m, 4H), 2.72 – 2.49 (m, 2H), 2.54 – 1.76 (m, 9H), 1.72 – 1.19 (m, 3H).

[0092] Example 5: Synthesis of Compound S5

[0093]

[0094] Step 1 Synthesis of Intermediate B5: See the synthesis method of Intermediate B1.

[0095] Step 2: Synthesis of intermediate C5: see the synthesis method of intermediate C1.

[0096] Step 3: Synthesis of intermediate D5: see the synthesis method of intermediate D1.

[0097] Step 4 Synthesis of S5: See the synthesis method of S1.

[0098] ESI-MS [M+H] + =388.2.

[0099] 1 H NMR (400 MHz, Chloroform- d ) δ 7.72 (s, 1H), 6.82 – 6.50 (m, 3H), 5.00 – 4.62 (m, 1H), 4.36 – 3.86 (m, 3H), 3.10 – 2.75 (m, 4H), 2.72 – 2.49(m, 2H), 2.48 – 2.12 (m, 2H), 2.20 – 1.76 (m, 8H), 1.72 – 1.19 (m, 2H).

[0100] Example 6: Synthesis of Compound S6

[0101]

[0102] Step 1: Synthesis of compound B6: see the synthesis method of intermediate B3.

[0103] Step 2: Synthesis of intermediate C6: see the synthesis method of intermediate C1.

[0104] Step 3: Synthesis of intermediate D6: see the synthesis method of intermediate D1.

[0105] Step 4 Synthesis of S6: see the synthesis method of S1.

[0106] ESI-MS [M+Na] + =428.2.

[0107] 1 H NMR (400 MHz, Chloroform- d ) δ 7.82 (s, 1H), 6.76 – 6.60 (m, 3H), 4.39 (tt, J = 10.7, 5.1 Hz, 1H), 3.98 (t, J = 5.9 Hz, 2H), 2.93 (dt, J= 8.0,6.4 Hz, 4H), 2.67 – 2.53 (m, 2H), 2.24 (s, 1H), 2.13 – 2.02 (m, 1H), 2.05 (s,4H), 2.10 – 1.96 (m, 1H), 2.00 – 1.75 (m, 3H), 1.68 (s, 2H).

[0108] Example 7: Synthesis of Compound S7

[0109]

[0110] Step 1: Synthesis of compound B7: see the synthesis method of intermediate B3.

[0111] Step 2: Synthesis of intermediate C7: see the synthesis method of intermediate C1.

[0112] Step 3: Synthesis of intermediate D7: see the synthesis method of intermediate D1.

[0113] Step 4 Synthesis of S7: see the synthesis method of S1.

[0114] ESI-MS [M+Na] + =428.2.

[0115] Example 8: Synthesis of Compound S8

[0116]

[0117] Step 1: Synthesis of compound B8: see the synthesis method of intermediate B3.

[0118] Step 2 Synthesis of intermediate C8: see the synthesis method of intermediate C1.

[0119] Step 3: Synthesis of intermediate D8: see the synthesis method of intermediate D1.

[0120] Step 4 Synthesis of S8: See the synthesis method of S1.

[0121] ESI-MS [M+Na] + =428.2.

[0122] Example 9: Detection of the inhibitory activity of compounds on phosphodiesterase 3A (PDE3A)

[0123] PDE3A activity was detected using the PDE3A TR-FRET Assay Kit (BPS Catalog # 60706), which is designed to identify PDE3A inhibitors using TR-FRET (time-resolved fluorescence resonance energy transfer) technology. The assay is based on FAM-labeled nucleotide monophosphates generated by phosphodiesterases. These phosphate groups bind to Tb-labeled nanoparticles, resulting in energy transfer from Tb to FAM, which emits a fluorescent signal at 520 nm. The change in fluorescence intensity can be easily measured using a multi-function microplate reader.

[0124] Experimental steps:

[0125] 1) Dilute 20 μM FAM-Cyclic-3',5'-AMP substrate stock solution 100-fold with PDE buffer to make a 200 nM solution. Use only enough to perform the assay; store the remaining stock solution in aliquots at -20°C.

[0126] 2) Add 25 μl of FAM-Cyclic-3',5'-AMP (200 nM) to each well labeled "Substrate Control," "Positive Control," and "Test Inhibitor." Add 25 μl of PDE Assay Buffer to each well designated as "Tb Only Control."

[0127] 3) Add 5 μl of inhibitor solution to each well designated as "Test Inhibitor". Add 5 μl of the same solution without inhibitor (inhibitor buffer) to the "Tb Only Control", "Substrate Control", and "Positive Control".

[0128] 4) Thaw PDE3A on ice. After the first thaw, briefly spin the tube containing the enzyme to recover the entire contents of the tube. Aliquot the PDE3A enzyme into single-use aliquots. Immediately aliquot remaining undiluted enzyme and store at -80°C.

[0129] 5) Dilute PDE3A to 0.05 ng / μl (1 ng / reaction) in PDE buffer. Start the reaction by adding 20 μl of PDE assay buffer to the wells designated as "Tb only control" and "substrate control", and 20 μl of PDE3A (0.05 ng / μl) to the wells designated as "positive control" and "test inhibitor", discarding any remaining diluted enzyme after use.

[0130] 6) Incubate at room temperature for 1 hour.

[0131] 7) Make Binding Dilution Buffer by mixing equal volumes of Binding Buffer A and Binding Buffer B.

[0132] 8) Mix the binder thoroughly and dilute the binder 1:50 with the binding dilution buffer prepared in step 1.

[0133] 9) Add Tb donor (1:1000 dilution) to the mixture.

[0134] 10) Add 100 μl to each well. Incubate at room temperature with slow shaking for 1 hour.

[0135] 11) Read the fluorescence intensity in a microtiter plate reader with TR-FRET function.

[0136] Calculation results:

[0137] (1) Calculation of fluorescence intensity

[0138]

[0139] Where S520 = sample 520 nm reading, S490 = sample 490 nm reading, Tb520 = Tb 520 nm reading only, Tb490 = Tb 490 nm reading only. When calculating percent activity, the FRET value of the substrate only control can be set to zero activity and the FRET value of the positive control can be set to 100% activity.

[0140] (2) Calculation of enzyme activity inhibition rate

[0141] × 100

[0142] Where FRETs = sample FRET, FRETSub = substrate only control FRET, FRETP = positive control FRET.

[0143] (3) Calculation of IC50 value:

[0144] With log[compound concentration] as the horizontal axis and Inhibition% as the vertical axis, fit the nonlinear curve in GraphPad Prism 7: log (inhibitor) vs. response -- Variable slope, and calculate the IC50 value.

[0145] The results are as follows Figure 1 As shown, the synthesized compounds S1-S8 all have good PDE3A enzyme inhibitory activity.

[0146] Example 10: Pharmacokinetic study of compounds S4 and S5

[0147] Pharmacokinetic study of compounds OW-846 and 847 in female SD rats

[0148] Materials and Methods

[0149] Species of experimental animals: SD rats; Grade: SPF; Gender: female; Estimated number of animals to be purchased: 16 (PK); Estimated number of animals to be used: 12 (PK); Weight: 200g-220g; Source: Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. (SPF grade), Production License No.: SCXK (Zhejiang) 2019-0001.

[0150] Feeding method: free intake; Nutritional component testing: the feed supplier shall provide a test report for each batch, including conventional nutritional component indicators: crude protein, crude fat, crude fiber, crude ash, moisture, calcium and phosphorus, amino acids, refer to the National Standard of the People's Republic of China GB14924.3-2010;

[0151] Drinking water: drinking water for experimental animals (autoclaved); water supply method: in drinking bottles, free intake; testing of routine water quality indicators: refer to the national standard of the People's Republic of China GB5749-2006, take samples and send them to relevant qualified institutions for testing, at least once a year.

[0152] Test drugs: Cilostazol (Zhejiang Jinliyuan Pharmaceutical Co., Ltd., batch number 0102220190301), compound S4, and compound S5.

[0153] Animal Grouping:

[0154] A1-3: Three female SD rats were iv-administered with S4 at a dose of 0.50 mg / kg.

[0155] A4-6: Three female SD rats were administrated S4 ig at a dose of 2.00 mg / kg.

[0156] B1-3: Three female SD rats were iv-administered with S5 at a dose of 0.50 mg / kg.

[0157] B4-6: Three female SD rats were ig-administered with S5 at a dose of 2.00 mg / kg.

[0158] C1-3: Three female SD rats were iv-administered with cilostazol at a dose of 0.50 mg / kg.

[0159] C4-6: Three female SD rats were ig-administered with cilostazol at a dose of 2.00 mg / kg.

[0160] After administration to rats, blood was collected at 5, 15, 30 min, 1, 2, 4, 6, 8, 10, and 24 h after administration. All samples were placed in EDTA-K2 anticoagulated EP tubes on ice, centrifuged at 8000 rpm at 4 °C for 5 min, and the plasma was transferred to -20 °C as soon as possible for storage for testing.

[0161] Experimental results: The average pharmacokinetic parameters of S4, S5 and cilostazol were administered by intravenous injection or oral gavage to SD rats.

[0162] Average pharmacokinetic parameters S4 intravenous injection S4 Oral S5 intravenous injection S5 Oral Cilostazol IV Cilostazol oral T1 / 2(h) 1.60 1.89 2.05 2.34 1.86 2.91 Tmax (h) 0.083 1.17 0.083 1.00 0.08 2.67 Cmax (ng / mL) 3273 5450 4287 4897 3260 1980 AUC0-24h (h*ng / mL) 6081 28569 11645 24754 8185 15246 AUC0-inf (h*ng / mL) 6219 29168 12178 24777 8221 16123 Vz(mL / kg) 194 192 134 278 168 594 Cl (mL / h / kg) 91 73.3 48.9 82.5 74.1 148 MRTlast (h) 1.94 3.77 2.58 3.80 2.56 4.85 F 117% 53% 46%

[0163] The pharmacokinetic results of oral and intravenous administration of cilostazol, S4 and S5 to female SD rats showed that compound S5 had comparable pharmacokinetic properties to cilostazol, and the oral bioavailability of compound S4 was greatly improved, which can be used for further follow-up studies.

[0164] Conclusion: Based on the above experimental results, the compound of the present invention is a compound that inhibits the activity of phosphodiesterase 3A (PDE3A), has the advantage of higher in vivo bioavailability than cilostazol, and has important potential therapeutic value in anti-tumor, treatment of cardiovascular disease, cerebrovascular disease or dementia.

[0165] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof: Compound 4: 6-(4-(1-((1R,2R)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S4; Compound 5: 6-(4-(1-((1S,2S)-2-fluorocyclohexyl)-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, as shown in S5.

2. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug having phosphodiesterase 3A inhibitory activity.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the advantage of higher in vivo bioavailability than cilostazol.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for a disease associated with inhibiting phosphodiesterase 3A activity, wherein the disease is tumor, cardiovascular disease, cerebrovascular disease or dementia.

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