Type 5 phosphodiesterase inhibitors and their applications

A technology of phosphodiesterase and use, which is applied in the field of medicine, can solve problems such as half-life differences, and achieve good inhibitory effects and good pharmacokinetic properties

Active Publication Date: 2019-11-01
CHONGQING DIKANG ERLE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there is a huge difference between the half-lives of these three drugs

Method used

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  • Type 5 phosphodiesterase inhibitors and their applications
  • Type 5 phosphodiesterase inhibitors and their applications
  • Type 5 phosphodiesterase inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] The preparation of the compound represented by embodiment 1 formula (I) (number: DDCI01)

[0065] step 1:

[0066]

[0067] Table A

[0068]

[0069] Into a 500 mL reaction vial equipped with a reflux condenser was charged the reaction reagents and solvents shown in Table A. in N 2 In the atmosphere, the reaction was refluxed at 120°C for 6h. The reaction was monitored for completion by thin layer chromatography (TLC). After cooling the reaction solution to room temperature, the Cs was removed by filtration 2 CO 3 solid, with CH 2 Cl 2 Wash the filter cake. The filtrate was concentrated to dryness under reduced pressure, and the resulting residue was washed with CH 2 Cl 2 dissolved, followed by washing once with water and once with saturated NaCl solution, respectively. Anhydrous MgSO for organic phase 4 Dry, filter, and concentrate to dryness under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel colum...

Embodiment 2

[0087] Example 2: Inhibition of PED5

[0088] Method: Sildenafil (S1431, selleck) was used as positive control to calibrate, and homogeneous time energy transfer (Homogenous Time Resolve Fluoresce, HTF) method (Cat. ) The dose-effect relationship of inhibitory ability measured the half inhibitory concentration IC of the sample 50 .

[0089] sample IC 50 value

Cialis 111.6nM

[0090] DDCI01 33.6nM DDCI02 注

566.2nM

[0091] NOTE: The structure of compound DDCI02 is shown below:

[0092]

Embodiment 3

[0093] Embodiment 3: pharmacokinetic research

[0094] experimental method:

[0095] Stock solution preparation: Weigh 1.13 mg of Cialis, 1.15 mg of DDCI02 and 1.23 mg of DDCI01, and dissolve them in 1.13, 1.15, and 1.23 ml of dimethyl sulfoxide respectively to prepare a stock solution with a concentration of 1.00 mg / ml.

[0096] Sample preparation method: one-step protein precipitation method

[0097] Precipitating agent: Acetonitrile (with 5.00 ng / ml of verapamil)

[0098] Standard curve and QC sample preparation: Transfer 5.00 μl of standard curve or QC working solution and 45.0 μl of blank plasma to a 1.5 ml centrifuge tube. The final concentrations of the standard curve samples were 1.00, 2.50, 5.00, 10.0, 50.0, 100, 500, and 1000 ng / mL, respectively. The concentrations of quality control samples were 2.50, 5.00, 50.0 and 800 ng / ml, respectively. Dilute quality control samples to a concentration of 5000 ng / ml.

[0099] Plasma sample preparation: transfer 100 microlit...

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PUM

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Abstract

The invention discloses a compound used as a 5-type phosphodiesterase inhibitor and as shown in the formula (I) or pharmaceutically acceptable salt and application of the compound or pharmaceutically acceptable salt in treating and / or preventing 5-type phosphodiesterase-related diseases or disease state of mammals.

Description

technical field [0001] This application relates to the field of medicine, and in particular to selective phosphodiesterase type 5 (PDE5) inhibitors and their use in the treatment and / or prevention of diseases or disease states in which such inhibition is believed to be beneficial. Background technique [0002] Erectile dysfunction (ED) has an important impact on men's psychology and physiology. Studies have found that PDE5 inhibitors are effective in the treatment of ED. For example, Eli Lilly's Cialis has the following chemical structure: [0003] [0004] Studies have found that PDE5 inhibitors can improve ED caused by various reasons, and there is little difference between the compounds in terms of onset time, but there is a large difference in the half-life of the compounds. For example, the half-life of Cialis in the human body is as long as 24-36 hours, while the half-life of Viagra produced by Pfizer Pharmaceuticals and Levitra produced by Bayer Pharmaceuticals i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14A61K31/4985A61P15/10
CPCC07D471/14
Inventor 陈中祝徐志刚唐典勇
Owner CHONGQING DIKANG ERLE PHARMA CO LTD
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