Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same

A technology of polyethylene glycol and octyl conjugates, which is applied in the field of small molecule oligoethylene glycol and tamsulosin conjugates and their pharmaceutical compositions, which can solve problems such as neuropsychiatric adverse reactions and improve drug quality. Absorption, enhancing curative effect, and avoiding toxic and side effects

Active Publication Date: 2013-06-05
JENKEM TECH CO LTD TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although tamsulosin is effective, there are neuropsy...

Method used

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  • Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same
  • Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same
  • Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Preparation of Conjugate of Methoxytetraethylene Glycol and Tamsulosin (TSLX41)

[0053]

[0054] Add 9.07g p-toluenesulfonyl chloride and 32mL pyridine into a 250mL three-necked flask, and cool to 0°C. Mix 8.26gmPEG(n=4)-OH and 16mL of pyridine, dropwise into a three-necked flask, and finish dropping in two hours, controlling the temperature at 0-10°C. The reaction was continued to stir at this temperature for two hours. TLC monitored the completion of the reaction. Add 130mL of cold water and 48mL of concentrated hydrochloric acid to the reaction solution, stir slowly for half an hour, transfer the reaction solution into a 500mL separatory funnel, add ethyl acetate and extract twice (200mL+100mL). The organic layers were combined, washed with water until neutral, and dried over anhydrous sodium sulfate for two hours. The solvent was evaporated on a rotary evaporator. A total of 11.34 g of viscous liquid was obtained, which was directly used in the next reaction...

Embodiment 2

[0058] Preparation of Conjugate of Dimethoxypentaethylene Glycol and Tamsulosin (TSLX52)

[0059]

[0060] Add 356 mg of tamsulosin hydrochloride and 664 mg of potassium carbonate into a 100 mL three-necked flask containing 20 mL of acetonitrile, and stir at room temperature for 2 hours. A 10 mL acetonitrile solution dissolved with 759 mg mPEG(n=5)Br was added into the above reaction flask, and reacted under reflux overnight. TLC monitored the completion of the reaction. Column separation gave 258 mg of a colorless liquid with a yield of 36.8%. m / z[MH] + 877.8. 1 H-NMR (CDCl 3 ): 1.10(d, J=6.2Hz, 3H), 1.39-1.44(t, J=6.9Hz, 3H), 2.60(m, 1H), 2.90(m, 1H), 3.05-3.13(m, 4H) , 3.37(s, 6H), 3.45-3.55(m, 20H), 3.60-3.65(m, 20H), 3.90(s, 3H), 4.07(m, 2H), 4.17(t, J=5.2Hz, 2H ), 6.90 (m, 5H), 7.37 (dd, J=8.5Hz, J=2.2Hz, 1H), 7.74 (d, J=2.2Hz, 1H).

Embodiment 3

[0062] Preparation of Double-ended Hexaethylene Glycol and Tamsulosin Conjugate (TSLXP62)

[0063]

[0064] Add 22.9g of p-toluenesulfonyl chloride and 80mL of pyridine into a 500mL three-necked flask, and cool to 0°C. Mix 14.1g of HO-PEG(n=6)-OH with 40mL of pyridine and add it dropwise into a three-necked flask. The dropwise is completed in two hours, and the temperature is controlled at 0-10°C. The reaction was continued to stir at this temperature for two hours. TLC monitored the completion of the reaction. Add 300mL cold water and 120mL concentrated hydrochloric acid to the reaction solution, stir slowly for half an hour, transfer the reaction solution into a 1000mL separatory funnel, add ethyl acetate and extract twice (300mL+200mL). The organic layers were combined, washed with water until neutral, and dried over anhydrous sodium sulfate for two hours. The solvent was evaporated on a rotary evaporator. A total of 28.7 g of viscous liquid was obtained, which was d...

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PUM

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Abstract

The invention provides a combination of polyethylene glycol and tamsulosin and a pharmaceutical compound comprising the combination which is as shown in a general formula (II). In the combination, a P and a P' are H or polyethylene glycol, and the P and the P' cannot be the H at the same time. The tamsulosin structurally contains a sulfamide group, the low-molecular-weight polyethylene glycol is introduced through an alkylation reaction, and therefore hydrophobicity of the tamsulosin is lowered, hydrophilism of the tamsulosin is increased, and the blood-brain barrier permeability of the tamsulosin is lowered. Therefore, the toxicity of the tamsulosin is lowered.

Description

technical field [0001] The invention relates to a hydrophilic polymer-tamsulosin combination, especially a combination of small molecule oligoethylene glycol and tamsulosin and a pharmaceutical composition thereof. Background technique [0002] Benign prostatic hyperplasia (BPH) is a benign adenomatous proliferation of cells in the periurethral zone of the prostate. BPH is a common and frequently-occurring disease in middle-aged and elderly men. Clinical statistics show that the incidence rate of benign prostatic hyperplasia is about 50% during the period of 40-79 years old, and the incidence rate of men over 80 years old is as high as 80%. The human prostate is more sensitive to α-receptor agonists than the bladder, and sympathetic stimulation can lead to acute urinary retention in patients with prostatic hypertrophy, while α-receptor blockers can selectively relax prostate tissue and bladder smooth muscle without affecting The contraction of the detrusor muscle of the bla...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/18A61P13/08
CPCA61K47/48A61K31/18A61K47/48215A61K47/48107A61K47/551A61K47/60A61P13/08
Inventor 冯泽旺徐立华黄文哲赵宣
Owner JENKEM TECH CO LTD TIANJIN
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