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Multi-arm type PEG (Pegylation) dutasteride derivative and preparation thereof

A technique for dutasteride and its derivatives, which is applied in the field of multi-armed PEGylated dutasteride derivatives and its preparation and preparation, and preparation of anti-prostatic hyperplasia, which can solve deficiencies, feminization, compliance problems, etc. problems, to achieve the effects of reducing toxic side effects, increasing load rate, and increasing life time

Inactive Publication Date: 2018-10-23
湖南华腾医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the half-life is long, high-frequency administration is required, which has compliance problems for patients, especially elderly patients
Finally, dutasteride may cause testicular feminization of the hermaphrodites of male fetuses, and a rare type II 5α-reductase deficiency may occur with long-term exposure

Method used

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  • Multi-arm type PEG (Pegylation) dutasteride derivative and preparation thereof
  • Multi-arm type PEG (Pegylation) dutasteride derivative and preparation thereof
  • Multi-arm type PEG (Pegylation) dutasteride derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of 4arm-PEG24-Dutasteride-II

[0025] Dissolve 10mmol of 4Arm-PEG24-PA-I in 100ml of dichloromethane, add 30mmol of thionyl chloride at room temperature, and add 5mmol% of DMF to the system for catalysis, and stir at 25°C for 8h. The organic solvent and excess acid chloride in the reaction system were evaporated under reduced pressure, 100ml of dry anhydrous tetrahydrofuran solvent was added to the reaction, and 55mmol of dutasteride and 5mmol% triethylamine were added, and the reaction was carried out at 0°C for 32 hours . After the completion of the dutasteride reaction detected by TLC tracking, the pure 4arm-PEG24-dutasteride-II was obtained by recrystallization and column chromatography. Yield: 84.8%. NMR data are as follows: 1HNMR (400MHz, CDCl3) δ: 7.75 (d, J = 8.4Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.47 (d, J = 8.4Hz, 1H, ArH), 6.81 (d,J=9.6Hz,1H,CH),5.84(d,J=9.6Hz,1H,CH), 5.41(s,1H,CONH),3.58-3.542(m,96H),3.36(t,J =7.8Hz,1H,CH),2.52-2.48(m,2H,CH2),2...

Embodiment 2

[0027] Preparation of 4arm-PEG124-Dutasteride-II

[0028] Dissolve 10mmol of 4Arm-PEG124-PA-I in 100ml of chloroform, add 40mmol of thionyl chloride at room temperature, and add 1%mmol of DMF to the system for catalysis, react at 25°C and stir for 12h. The organic solvent and excess acid chloride in the reaction system were evaporated under reduced pressure, 100ml of dry chloroform solvent was added to the reaction, and 45mmol of dutasteride and 10mmol% of DIPEA were added, and the reaction was carried out at 30°C for 24 hours. After the completion of the dutasteride reaction detected by TLC tracking, the pure 4arm-PEG124-dutasteride-II was obtained by recrystallization and column chromatography. Yield: 81.5%. NMR data are as follows: 1HNMR (400MHz, CDCl3) δ: 7.75 (d, J = 8.4Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.47 (d, J = 8.4Hz, 1H, ArH), 6.81 (d,J=9.6Hz,1H,CH),5.84(d,J=9.6Hz,1H,CH),5.41 (s,1H,CONH),3.58-3.542(m,496H),3.36(t,J =7.8Hz,1H,CH),2.52-2.48(m,2H,CH2), 2.40-2.30(m,2H...

Embodiment 3

[0030] Preparation of 4arm-PEG240-Dutasteride-II

[0031]Dissolve 10mmol of 4Arm-PEG240-PA-I in 100ml of tetrahydrofuran, add 20mmol of thionyl chloride at room temperature, and add 10mmol% of DMF to the system for catalysis, and stir at 25°C for 8h. The organic solvent and excess acid chloride in the reaction system were evaporated under reduced pressure, 100ml of dry anhydrous tetrahydrofuran solvent was added to the reaction, and 60mmol of dutasteride and 10mmol% pyridine were added, and the reaction was carried out at 45°C for 16 hours. After the completion of the dutasteride reaction detected by TLC tracking, the pure 4arm-PEG240-dutasteride-II was obtained by recrystallization and column chromatography. Yield: 85.8%. NMR data are as follows: 1HNMR (400MHz, CDCl3) δ: 7.75 (d, J = 8.4Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.47 (d, J = 8.4Hz, 1H, ArH), 6.81 (d,J=9.6Hz,1H,CH),5.84(d,J=9.6Hz,1H,CH),5.41 (s,1H,CONH),3.58-3.542(m,960H),3.36(t,J =7.8Hz,1H,CH),2.52-2.48(m,2H,CH2), 2...

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Abstract

The invention discloses a multi-arm type PEG (Pegylation) dutasteride derivative.By utilizing the characteristics of no toxicity and easiness in combination of multi-arm PEG (Pegylation), four-arm PEG, six-arm PEG and the multi-arm PEG are connected with dutasteride. A prodrug of the dutasteride loaded by the multi-arm PEG has favorable water solubility and is characterized in that one multi-arm PEG chain can be connected with multiple dutasteride residues, so that the drug load rate is greatly improved, the half-life period of the drug is greatly prolonged, the existence time in plasma is remarkably prolonged, and the curative effect is improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated dutasteride derivative, its preparation, its preparation method and its application in the preparation of anti-prostatic hyperplasia. Background technique [0002] Prostatic hyperplasia (benign prostatic hyperplasia, BPH) is the most common benign disease that causes voiding disorders in middle-aged and elderly men. The incidence rate increases with age. The incidence rate of the 50-year-old group is about 40%, and the incidence rate of the 80-year-old group is as high as 70%, which seriously affects the quality of life and physical and mental health of middle-aged and elderly male patients. The diagnosis and treatment of this disease have also received more and more attention. Surgical treatment is currently the most effective treatment method. However, considering that the patients of this disease are mainly elderly people and have poor tolerance ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/337A61K47/60A61K31/58A61P13/08
CPCA61K31/58A61K47/60A61P13/08C08G65/337C08G2650/04C08G2650/30C08G2650/46C08G2650/50
Inventor 张安林邓泽平成佳
Owner 湖南华腾医药有限公司
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