CN114685449B - Preparation and application of fluorine-substituted cilostazol derivatives - Google Patents
Preparation and application of fluorine-substituted cilostazol derivatives Download PDFInfo
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Abstract
The invention discloses a fluoro-substituted cilostazol derivative and pharmaceutically acceptable salts thereof. The fluoro-substituted cilostazol derivative of the present invention is a compound with phosphodiesterase 3A (PDE 3A) inhibiting activity, has important potential therapeutic value, and is applied in the medicine for treating tumor, cardiovascular diseases, cerebrovascular diseases or dementia.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to application of fluoro-substituted cilostazol derivatives or pharmaceutically acceptable salts thereof as phosphodiesterase 3A (PDE 3A) inhibitors, in particular to application in medicaments for treating tumors, cardiovascular diseases, cerebrovascular diseases or dementia.
Background
Cilostazol exerts an antiplatelet effect and a vasodilating effect by inhibiting platelet and vascular smooth muscle phosphodiesterase activity, thereby increasing platelet and smooth muscle cAMP concentration. It can inhibit platelet initial and secondary aggregation and release reactions induced by ADP, epinephrine, collagen and arachidonic acid, and has obvious antithrombotic effect on brain circulation and peripheral circulation disorder caused by collagen, ADP, arachidonic acid and sodium laurate. Can be used for treating chronic arterial occlusive disease, cerebrovascular disease or dementia caused by atherosclerosis, arteritis, thromboangiitis obliterans, and diabetes.
Poor pharmacokinetic properties of cilostazol limit its clinical application to 50mg of cilostazol administered orally to healthy adult men on an empty stomach and once after meals, with Cmax and AUCinf being 2.3 times and 1.4 times, respectively, as compared to empty stomach. Cilostazol is metabolized mainly by cytochrome P450 isozymes CYP3A4 in hepatic microsomes, and secondarily by CYP2D6 and CYP2C19, into active metabolites such as dehydrated OPC-13015, hydroxylated OPC-13213 and the like. When cilostazol is orally taken for 1 day for 0.1g for 8 consecutive days in patients with severe renal dysfunction, the Cmax and AUC of cilostazol are reduced by 29% and 39% respectively, and the Cmax and AUC of the active metabolite OPC-13213 are increased by 173% and 209% respectively, compared with healthy adults. Therefore, there is a need to design a compound that satisfies both cilostazol PDE3A inhibitory activity and has good pharmacokinetic parameters for use in cilostazol-treated related diseases.
French scientists in 1812 found a new element in HF and named fluoroine, which was the first time element F was shown in front of humans. Over time and with intensive research, a large number of fluorine-containing compounds have been found and used, and fluorine chemistry has also advanced significantly. Since the bond energy of the C-F bond (487 kJ. Mol-1) is higher than that of the C-H bond (420 kJ. Mol-1), the fluorine atom is the most commonly used blocking group. In the drug design, fluorine atom substitution is generally introduced into a small molecular compound to seal the easy-to-oxidize metabolism site, selectively prevent the oxidation metabolism, further improve the metabolic stability of the compound and prolong the action time of the drug in vivo.
Disclosure of Invention
The invention aims to provide a fluorine substituted cilostazol compound which not only meets PDE3A inhibition activity, but also has good pharmacokinetic parameters or pharmaceutically acceptable salts thereof, and is used for treating diseases such as tumor, cardiovascular diseases, cerebrovascular diseases or dementia.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a fluoro-substituted cilostazol derivative shown in formula I or pharmaceutically acceptable salt, hydrate or solvate thereof:
I is a kind of
Wherein R 1、R2、R3、R4、R5、R6、R7、R8、R9 and R 10 are each independently hydrogen or halogen, with the proviso that at least one of R 1、R2、R3、R4、R5、R6、R7、R8、R9 or R 10 is halogen.
Preferably, it is characterized in that R 1、R2、R3、R4、R5、R6、R7、R8、R9 and/or R 10 are each independently hydrogen or halogen, wherein at least one of R 1、R2、R3、R4、R5、R6、R7、R8、R9 and/or R 10 is fluorine.
More preferably, characterized in that at least one of R 1、R2、R3、R4、R5、R6、R7、R8、R9 and/or R 10 is fluorine.
Most preferably, the compounds of formula (I) include, but are not limited to, the following specific compound examples:
compound 1:6- (4- (1- ((1S, 4S) -4-fluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S1;
Compound 2:6- (4- (1- ((1 r,4 r) -4-fluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S2;
compound 3:6- (4- (1- (4, 4-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S3;
Compound 4:6- (4- (1- ((1 r,2 r) -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;
Compound 6:6- (4- (1- (3, 3-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S6;
Compound 7, (R) -6- (4- (1- (2, 2-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S7;
compound 8, (S) -6- (4- (1- (2, 2-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S8.
The compound provided by the invention also comprises pharmaceutically acceptable equivalents of the compound or a mixture of more than two of the compounds.
Preferably, the compound provided by the invention can comprise one or more than two of pharmaceutically acceptable salts, hydrates, solvates, metabolites and prodrugs.
Preferably, the compounds provided herein comprise an acid or base salt of a compound provided herein. The pharmaceutically acceptable salts have the pharmaceutical activity of the compounds and are desirable in both biological and practical applications.
The invention provides a fluoro-substituted cilostazol compound or a pharmaceutically acceptable salt thereof, which is used for treating diseases such as tumor, cardiovascular diseases, cerebrovascular diseases or dementia.
Drawings
The compounds of fig. 1 inhibit PDE3A enzyme activity in a dose response curve.
Detailed Description
The invention discloses a fluorine substituted cilostazol compound and application thereof, and a person skilled in the art can properly improve the process parameters by referring to the content of the text. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention.
In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail with reference to specific embodiments.
The compounds of the general formula of the present invention can be synthesized via the following routes:
The compounds prepared in the examples of the present invention are as follows:
compound 1:6- (4- (1- ((1S, 4S) -4-fluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S1;
Compound 2:6- (4- (1- ((1 r,4 r) -4-fluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S2;
compound 3:6- (4- (1- (4, 4-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S3;
Compound 4:6- (4- (1- ((1 r,2 r) -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;
Compound 6:6- (4- (1- (3, 3-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S6;
Compound 7, (R) -6- (4- (1- (2, 2-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S7;
compound 8, (S) -6- (4- (1- (2, 2-difluorocyclohexyl) -1H-tetrazol-5-yl) butoxy) -3, 4-dihydroquinolin-2 (1H) -one, as shown in S8.
EXAMPLE 1 Synthesis of Compound S1
Step 1 Synthesis of intermediate B1
Raw material A1 (6.6 g) was dissolved in 100mL of dichloromethane, DAST (4.86 mL) was added dropwise under ice bath, and after stirring for 1h, it was allowed to warm to room temperature overnight. After the TLC monitoring reaction is finished, adding saturated sodium bicarbonate solution for quenching, extracting with dichloromethane, dissolving the concentrated product with 10mL dichloromethane, dripping 2 mL TFA, stirring at room temperature for 1h, detecting the disappearance of the raw materials by TLC, adding 10% NaOH solution for alkalization, extracting with dichloromethane, and concentrating to obtain the solvent amount required by the reaction from B1 to the next step. ESI-MS [ m+h ] + =118.1.
Step2 Synthesis of intermediate C1
To the reaction flask was added B1 (292 mg in 5mL of methylene chloride), triethylamine (0.37 mL). Under ice bath, add slowly acyl chloride (0.38 mL) dropwise, return to room temperature and stir overnight. TLC detection, reaction complete, concentration in vacuo, crude silica gel column chromatography (n-hexane: ethyl acetate=9:1) gave white solid C1 (240 mg), 41% yield. ESI-MS [ m+h ] + =236.1.
Step3 Synthesis of intermediate D1
Sodium azide (5.87 g), H2O (10 mL) and toluene (20 mL) are added into a reaction bottle, stirred and cooled to below 5 ℃, 50% of H 2SO4 solution (9.8 g) is slowly added dropwise, after the dropwise addition is finished, 30min is stirred again, a toluene layer is separated, anhydrous Na2SO4 is used for dehydration, and then toluene solution of the azide acid is obtained for calibration for later use. Raw material C1 (173 mg,0.76 mmol) was dissolved with 0.74 mL toluene and stirred, PCl 5 (229 mg,1.10 mmol) was slowly added and stirred for another 1.5h to give a crude toluene solution. This was slowly added to a toluene solution of sodium azide (0.5 ml) and stirred at room temperature for 1.5h. The progress of the reaction was checked by LC/MS. The reaction was completed, diluted with water (5 mL), extracted with dichloromethane (20 mL), washed 3 times with water, dried over anhydrous sodium sulfate, filtered, and concentrated. Crude silica gel column chromatography (n-hexane: ethyl acetate=8:2) gave D1 (109 g) as a white solid in 55% yield. ESI-MS [ m+h ] + = 261.1.
Synthesis of step 4 S1
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 followed by heating to reflux 4 h. After TLC monitored complete reaction of the starting materials, heating was stopped, the solvent was evaporated, dichloromethane (15 mL) was dissolved, washed sequentially with 1N NaOH solution, NH 4 Cl solution, water, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatographed on silica gel (n-hexane: ethyl acetate=8:2), separating to give product S1 as a white solid 58.6 mg in 40% yield. ESI-MS [ m+h ] + = 388.2.
1H 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 = 5.9 Hz, 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).
EXAMPLE 2 Synthesis of Compound S2
Step 1 synthesis of intermediate B2 see intermediate B1 synthesis method.
Step 2 synthesis of intermediate C2, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D2 see intermediate D1 synthesis.
Step4 S2 synthesis, see S1 synthesis method.
ESI-MS [M+H]+=388.2。
1H 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).
EXAMPLE 3 Synthesis of Compound S3
Step 1 Synthesis of Compound B3
Raw material A3 (3.0 g,14.08 mmol) was dissolved in 56mL of dichloromethane, and Deoxo-Fluor (7.65 mL,42.25 mmol) was added dropwise and stirred overnight at room temperature. After the reaction is finished, adding saturated sodium bicarbonate solution for quenching, extracting with dichloromethane, drying, dissolving the concentrated product with 30 mL dichloromethane, dripping 5mL TFA, stirring at room temperature for 1h, detecting the disappearance of the raw materials by TLC, adding 10% NaOH solution for alkalization, extracting with dichloromethane, and concentrating to obtain the solvent amount required by the reaction from B3 to the next step. ESI-MS [ m+h ] + =136.1.
Step 2 synthesis of intermediate C3, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D3 see intermediate D1 synthesis.
Step4 S3 synthesis, see S1 synthesis method.
ESI-MS [M+Na]+=428.2。
1H 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, 2.2 Hz, 4H), 2.67 – 2.54 (m, 2H), 2.37 (q, J = 10.6, 10.0 Hz, 4H), 2.15 – 1.83 (m, 7H).
EXAMPLE 4 Synthesis of Compound S4
Step 1 synthesis of intermediate B4 see intermediate B1 synthesis.
Step 2 synthesis of intermediate C4, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D4 see intermediate D1 synthesis.
Step4 S4 synthesis, see S1 synthesis method.
ESI-MS [M+H]+=388.2。
1H 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).
EXAMPLE 5 Synthesis of Compound S5
Step 1 synthesis of intermediate B5, see intermediate B1 synthesis method.
Step 2 synthesis of intermediate C5, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D5 see intermediate D1 synthesis.
Step4 S5 synthesis, see S1 synthesis method.
ESI-MS [M+H]+=388.2。
1H 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).
EXAMPLE 6 Synthesis of Compound S6
Step 1 synthesis of compound B6, see intermediate B3 synthesis method.
Step 2 synthesis of intermediate C6, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D6 see intermediate D1 synthesis.
Step 4 S6 synthesis, see S1 synthesis method.
ESI-MS [M+Na]+=428.2。
1H 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).
EXAMPLE 7 Synthesis of Compound S7
Step 1 synthesis of compound B7, see intermediate B3 synthesis method.
Step 2 synthesis of intermediate C7, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D7, see intermediate D1 synthesis method.
Step4 S7 synthesis, see S1 synthesis method.
ESI-MS [M+Na]+=428.2。
EXAMPLE 8 Synthesis of Compound S8
Step 1 synthesis of compound B8, see intermediate B3 synthesis method.
Step 2 synthesis of intermediate C8, see intermediate C1 synthesis method.
Step 3 synthesis of intermediate D8 see intermediate D1 synthesis.
Step4 S8 synthesis, see S1 synthesis method.
ESI-MS [M+Na]+=428.2。
Example 9 detection of phosphodiesterase 3A (PDE 3A) inhibiting Activity of Compounds
PDE3A Activity assay PDE3A TR-FRET ASSAY KIT (BPS catalyst # 60706) assay, the PDE3A TR-FRET assay kit is intended to identify PDE3A inhibitors using the TR-FRET (time resolved fluorescence resonance energy transfer) technique. The assay is based on FAM-labeled nucleotide monophosphates produced by phosphodiesterases. These phosphate groups bind to the Tb-labeled nanoparticle 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 multifunctional microplate reader.
The experimental steps are as follows:
1) The 20 mu MFAM-Cyclic-3',5' -AMP substrate stock was diluted 100-fold with PDE buffer to make a 200 nM solution. Only a sufficient amount of analysis was performed and the remaining stock solution was split at-20 ℃.
2) To each well labeled "substrate control", "positive control" and "test inhibitor" was added 25. Mu.l of FAM-Cyclic-3',5' -AMP (200 nM). Mu.l PDE assay buffer was added to each well designated "Tb control only".
3) To each well designated "test inhibitor" was added 5 μl of inhibitor solution. Mu.l of the same solution without inhibitor (inhibitor buffer) was added to the "Tb only control", "substrate control" and "positive control".
4) PDE3A was thawed on ice. After the first thawing, the tube containing the enzyme was briefly spun to restore the entire contents of the tube. The PDE3A enzyme is packaged for single use. The remaining undiluted enzyme was immediately aliquoted at-80 ℃.
5) PDE3A was diluted to 0.05 ng/. Mu.l (1 ng/reaction) in PDE buffer. 20 μ lPDE assay buffer was added to wells designated "Tb control only" and "substrate control" and 20 μ lPDE A (0.05 ng/. Mu.l) was added to wells designated "positive control" to initiate the reaction. "test inhibitor", all remaining diluted enzymes are discarded after use.
6) Incubate for 1 hour at room temperature.
7) The binding dilution buffer is prepared by mixing equal volumes of binding buffer A and binding buffer B.
8) The adhesive was thoroughly mixed and diluted 1:50 with the conjugate dilution buffer prepared in step 1.
9) Tb donor (1:1000 dilution) was added to the mixture.
10 100 Μl was added to each well. Incubate slowly with shaking at room temperature for 1 hour.
11 Fluorescence intensity is read in a microtiter plate reader with TR-FRET function.
Calculation results:
(1) Fluorescence intensity calculation
Where s520=sample 520 nm read, s490=sample 490 nm read, tb520=tb520 nm read only, tb490=tb490 nm read only. When calculating the percent activity, the FRET value for the substrate control alone may be set to zero activity and the FRET value for the positive control may be set to 100% activity.
(2) Enzyme activity inhibition rate calculation
× 100
Wherein FRETs = sample FRET, FRETSub = substrate only control FRET, FRETP = positive control FRET.
(3) Calculation of IC50 values:
On the abscissa, log [ compound concentration ] and on the ordinate, inhibition% was fitted to a nonlinear curve log (inhibitor) v.response- -Variable slope in GRAPHPAD PRISM, and IC50 values were calculated.
As shown in FIG. 1, the synthesized compounds S1-S8 have better PDE3A enzyme inhibition activity.
EXAMPLE 10 pharmacokinetic Studies of Compounds S4, S5
Post-administration pharmacokinetic study of compounds OW-846, 847 in female SD rats
Materials and methods
The experimental animal species were SD rats, grade SPF grade, sex female, number of animals expected to be purchased 16 (PK), number of animals expected to be used 12 (PK), body weight 200g-220g, source Zhejiang Vitolihua laboratory animal technologies Co., ltd (SPF grade), production license number SCXK (Zhejiang) 2019-0001.
The method comprises the steps of freely taking the materials, detecting the nutritional ingredients, namely providing detection reports for each batch by a feed supplier, wherein the conventional nutritional ingredient indexes comprise crude protein, crude fat, crude fiber, crude ash, moisture, calcium, phosphorus and amino acid, and referring to national standard GB14924.3-2010 of the people's republic of China;
The method comprises the steps of drinking water for experimental animals (high-pressure sterilization), water supply, water bottle filling, free intake, water quality routine index detection, sampling and delivering to units with relevant qualification detection at least 1 time per year by referring to national standard GB5749-2006 of the people's republic of China.
The test drugs include cilostazol (Zhejiang Jin Liyuan pharmaceutical Co., ltd., batch 0102220190301), compound S4 and compound S5.
Grouping animals:
A1-3 female SD rats 3, S4 was given i.v. at a dose of 0.50 mg/kg.
A4-6 female SD rats 3, i.g. S4 was given at a dose of 2.00 mg/kg.
B1-3 female SD rats 3, S5 was given i.v. at a dose of 0.50 mg/kg.
B4-6 female SD rats 3, i.g. S5 was given at a dose of 2.00 mg/kg.
C1-3 female SD rats were given cilostazol at an i.v. dose of 0.50 mg/kg.
C4-6 female SD rats 3, i.g. cilostazol was administered at a dose of 2.00 mg/kg.
After administration of rats, the blood collection time points are 5, 15, 30min, 1, 2, 4,6, 8,10, 24 h after administration, all the samples are placed in an ice bath in an EDTA-K2 anticoagulated EP tube after collection, centrifuged for 5 min at 4 ℃ and 8000 rpm, and the plasma is transferred to-20 ℃ as soon as possible for preservation and measurement.
Experimental results are that SD rats are subjected to intravenous injection, and various average drug generation parameters after S4, S5 and cilostazol are administrated by intragastric administration.
| Average drug substitution parameter | S4 intravenous injection | S4 oral administration | S5 intravenous injection | S5 oral administration | Cilostazol intravenous injection | Cilostazol oral administration |
| 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% |
The results of oral administration and intravenous injection administration of cilostazol, S4 and S5 offspring of female SD rats show that the compound S5 has the equivalent pharmacokinetic property of cilostazol, and the oral bioavailability of the compound S4 is greatly improved, so that the compound S4 can be used for subsequent further research.
The conclusion is that the compound in the invention is a compound for inhibiting phosphodiesterase 3A (PDE 3A) activity, has the advantage of higher bioavailability than cilostazol in vivo, and has important potential therapeutic value in resisting tumor, treating cardiovascular diseases, cerebrovascular diseases or dementia and other diseases.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (4)
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| KR101823405B1 (en) * | 2016-05-09 | 2018-02-01 | 가톨릭대학교 산학협력단 | Novel cilostazol salt compound and use thereof |
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