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Pyrrolidinium derivatives as m3 muscarinic receptor antagonists and their use in pharmacy

A use and pharmaceutical technology, applied in the field of urological diseases or gastrointestinal diseases, the preparation of prevention or treatment of respiratory diseases, can solve the problems of long-lasting systemic side effects, uncertainty of efficacy and safety, etc., to reduce side effects risk, ensuring the efficacy of the drug, and the effect of high-efficiency antagonistic activity

Active Publication Date: 2018-03-02
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the glycopyrronium bromide molecule contains two chiral centers and is a mixture of two stereoisomers, and the curative effect and safety of the two stereoisomer monomers also have certain uncertainties
[0008] In summary, the existing M3 muscarinic receptor antagonists still have varying degrees of defects in efficacy or safety. Therefore, there is an urgent need to develop drugs with long duration of action, small systemic side effects, and allow daily administration. Novel M3 Muscarinic Receptor Antagonist

Method used

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  • Pyrrolidinium derivatives as m3 muscarinic receptor antagonists and their use in pharmacy
  • Pyrrolidinium derivatives as m3 muscarinic receptor antagonists and their use in pharmacy
  • Pyrrolidinium derivatives as m3 muscarinic receptor antagonists and their use in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 3R-1-methyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine

[0037] Dissolve methyl 2,2-dithienylglycolate (1.0g, 3.9mmol) in 25mL of anhydrous toluene, add 3R-3-hydroxyl-1-methylpyrrolidine (465mg, 4.6mmol), and heat up to 120 ℃, sodium hydrogen (85mg, 2.1mmol) was added in 3 batches, and reacted for 2h. The reaction solution was extracted three times with 2N hydrochloric acid, the combined aqueous layers were washed with a small amount of ethyl acetate, the aqueous layer was adjusted to alkaline with solid sodium carbonate (until no bubbles were released), the aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined , the organic layer was washed with 1N sodium hydroxide solution and saturated brine respectively, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow solid (450mg, 35%), melting point: 107°C-109°C, [α] D 25 =-7.5(c=0.42, MeOH); 1 H NMR (DMSO, 500MHz) δ7.47(m, 2H), 7.26(s, 1H), 7...

Embodiment 2

[0039] 3R-1,1-Dimethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine bromide (compound of formula I)

[0040] Dissolve 3R-1-methyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine (100mg, 0.31mmol) in 0.4mL butanone, add dropwise under ice-cooling Methyl bromide (58.8mg, 0.62mmol) was slowly warmed up to room temperature and reacted overnight. Low-boiling substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol, 40:1) to obtain an off-white solid (98 mg, 75%), [α] D 20 =-7(c=0.1, MeOH); 1 H NMR (DMSO, 500MHz) δ7.51(m, 2H), 7.48(s, 1H), 7.13(m, 2H), 7.00(m, 2H), 5.52(m, 1H), 3.93(m, 1H) , 3.73(m, 2H), 3.63(m, 1H), 3.20(s, 3H), 3.03(s, 3H), 2.74(m, 1H), 2.16(m, 1H); 13 C NMR (DMSO, 125MHz) δ170.33, 146.63, 126.69, 126.24, 125.75, 125.70, 76.24, 73.85, 69.09, 63.94, 52.66, 51.91, 29.74; m / z: 338.1 [M-Br] + ; HRMS for C 16 h 20 NO 3 S 2 Br-Br calcd338.0885, found338.0888.

Embodiment 3

[0042] 3S-1-methyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine

[0043] Dissolve methyl 2,2-dithienylglycolate (0.5g, 1.9mmol) in 13mL of anhydrous toluene, add 3S-3-hydroxyl-1-methylpyrrolidine (233mg, 2.3mmol), and heat up to 120 ℃, sodium hydrogen (33mg, 0.8mmol) was added in 3 batches, and reacted for 2h. The reaction solution was extracted three times with 2N hydrochloric acid, the combined aqueous layers were washed with a small amount of ethyl acetate, the aqueous layer was adjusted to alkaline with solid sodium carbonate (until no bubbles were released), the aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined , the organic layer was washed with 1N sodium hydroxide solution and saturated brine respectively, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow solid (217 mg, 34%), melting point: 107 ° C ~ 109 ° C, [α] D 25 =+7.7(c=0.42, MeOH); 1 H NMR (DMSO, 500MHz) δ7.47(m, 2H), 7.26(s,...

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Abstract

The invention relates to the field of pharmacy, particularly to a polymorphic substance of 3R-1,1-dimethyl-3-(2-hydroxyl-2,2-dithienyl-2-acetoxyl) pyrrolidine bromide, a preparation method of the polymorphic substance and applications of the polymorphic substance to preparation of medicines for preventing or treating respiratory system diseases, urinary system diseases or gastrointestinal tract diseases.

Description

technical field [0001] The present invention relates to the pharmaceutical field, in particular to 3R-1,1-dimethyl-3-(2-hydroxyl-2,2-dithiophen-2-ylacetoxy)pyrrolidine bromide and 3S-1,1- Dimethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine bromide and its use in the preparation of medicines for preventing or treating respiratory diseases, urinary system diseases or gastrointestinal diseases the use of. [0002] This patent application requires a Chinese patent application (application number 201310046167.7, application date: February 06, 2013, name of invention: pyrrolidinium derivatives as M3 muscarinic receptor antagonists, polymorphs and drug combinations thereof ) priority. Background technique [0003] M receptors are mainly distributed in effector cells dominated by postganglionic fibers of parasympathetic nerves, including respiratory smooth muscle, gastrointestinal smooth muscle, bladder detrusor, pupillary sphincter, cardiac muscle, etc. Nervous system f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/14A61K31/4025A61P11/00A61P13/00A61P1/00A61P11/14A61P11/06A61P11/02A61P13/10A61P1/04
CPCC07D409/14
Inventor 孙宏斌向左娟温小安
Owner JIANGSU LIANHUAN PHARMA
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