CN-121652151-B - Hyoscyamine derivative and preparation method thereof

Abstract

The invention discloses a hyoscyamine derivative and a preparation method thereof, relates to the field of medicine synthesis, and aims to provide an effective and safe medicine molecule for inhalation/local pulmonary administration. The invention introduces a linear polyethylene glycol chain containing seven ethylene glycol repeating units at the hydroxyl position of hyoscyamine, and quaternizes nitrogen atoms of the linear polyethylene glycol chain to prepare the hyoscyamine derivative. The derivative is specially designed for inhalation/local pulmonary administration, and through the structural modification, the compound systemic absorption and central penetration are reduced, the local exposure of the lung is improved, the residence time in the lung is prolonged, and meanwhile, good atomization performance is achieved.

Inventors

• LIU ZHAOHUA
• SONG YANYAN
• TIAN JINLEI
• HU MENGTING
• XIONG CHENG
• LI LINLIN

Assignees

• 成都第一制药有限公司

Dates

Publication Date

20260505

Application Date

20260206

Claims (8)

1. 1. A hyoscyamine derivative, which is characterized in that the structural formula of the hyoscyamine derivative is as follows: 。
2. 2. a process for the preparation of a scopolamine derivative according to claim 1, characterised in that it comprises the steps of: s1, carrying out etherification reaction on hyoscyamine and CH 3 (OCH 2 CH 2 ) 7 Br, and after the reaction is finished, carrying out post-treatment, purification and drying to obtain an m- (PEG 7) -hyoscyamine intermediate; And S2, carrying out methylation reaction on the nitrogen atom of the m- (PEG 7) -scopolamine intermediate prepared in the step S1, introducing methyl to form N, N-dimethyl quaternary ammonium cations and bromide, after the methylation reaction is finished, carrying out post-treatment to obtain a crude product, and pulping, purifying and drying to obtain the scopolamine derivative.
3. 3. The method for preparing the hyoscyamine derivative according to claim 2, wherein the etherification reaction in the step S1 is specifically that 1.0 molar equivalent of hyoscyamine is dissolved in DMF to prepare a solution with the concentration of 0.1g/mL, stirring is carried out, the temperature is reduced to 0 ℃ under the protection of nitrogen, 1.2 molar equivalent of strong base is added into the reaction system, the reaction temperature is kept to be not more than 20 ℃, after the addition is finished, the reaction mixture is stirred for 30 minutes at room temperature, the reaction system is cooled to 0 ℃ again, CH 3 (OCH 2 CH 2 ) 7 Br/DMF solution with the concentration of 0.2g/mL is dripped, wherein CH 3 (OCH 2 CH 2 ) 7 Br is 1.1 molar equivalent, the temperature is kept to be not more than 5 ℃, after the dripping is finished, the temperature is increased to 35 ℃, and the reaction is stirred for 12 hours until the reaction is finished.
4. 4. A process for the preparation of a hyoscyamine derivative as claimed in claim 3 wherein the strong base is sodium hydride.
5. 5. A method for preparing a scopolamine derivative according to claim 2, wherein the specific step of methylation reaction in the step S2 comprises the steps of dissolving 1.0 molar equivalent of m- (PEG 7) -scopolamine intermediate prepared in the step S1 into DMF to prepare a solution with the concentration of 0.1g/mL, stirring, reducing the temperature of the reaction solution to-10 ℃ under the protection of nitrogen, adding a methylation reagent, heating the reaction system to 50 ℃ and continuing the reaction at the temperature for 10 hours until the reaction is finished.
6. 6. The method for preparing hyoscyamine derivative as claimed in claim 5, wherein the methylating agent is gaseous bromomethane, and the reaction system is required to be fed with the methylating agent, the aeration time is controlled to be 2 hours, and the temperature of the reaction system is kept to be not more than-5 ℃.
7. 7. A method for preparing a hyoscyamine derivative as defined in claim 2, wherein the post-treatment in step S2 comprises the specific steps of cooling the reaction system to 10 ℃, stirring for 30 minutes, suction filtering, washing the filter cake with acetonitrile for 3 times to remove unreacted quaternizing agent and impurities, collecting the filter cake, and drying under reduced pressure and spin-steaming to constant weight.
8. 8. The method for preparing the hyoscyamine derivative as claimed in claim 2, wherein the specific method for pulping and purifying in the step S2 is to disperse the crude product in ethyl acetate, stir the mixture at room temperature for 2 hours, then stir the mixture at 10 ℃ for 30 minutes, and suction-filter the mixture to obtain the pure product.

Description

Hyoscyamine derivative and preparation method thereof Technical Field The invention relates to the field of medicine synthesis, in particular to a scopolamine derivative and a preparation method thereof. Background Chronic Obstructive Pulmonary Disease (COPD), asthma and allergic respiratory diseases all belong to chronic diseases with high global incidence. Clinical treatment often requires reliance on bronchodilators to rapidly or continuously alleviate dyspnea. Anticholinergic bronchodilators are an important class of drugs currently in clinical use, whose mechanism of action is to block the M3 cholinergic receptor, thereby inhibiting airway smooth muscle contraction and reducing mucus secretion. Representative varieties of such drugs include atropine, scopolamine, and their structurally engineered derivatives. In order to improve the safety of anticholinergic drugs and reduce the crossing of the blood-brain barrier (BBB), the current mainstream strategy is quaternization, namely, tertiary amine nitrogen is permanently positively charged, so that the tertiary amine nitrogen is difficult to enter the central nervous system, but the conventional quaternized anticholinergic drugs still have the defects of limited pulmonary residence time, limited solubility of part of drugs in inhalation solutions and limited means for improving the adhesion to mucous membranes. In recent years, studies have been proposed to prolong pulmonary retention by changing the hydrophilicity, hydratability and adhesiveness of molecules, but mainly focused on high molecular carriers, micelle systems or nanoparticle systems, and direct modification strategies for the bulk structure of small molecule anticholinergic agents have been lacking. In the aspect of hyoscyamine and derivatives thereof, various structure modification strategies such as quaternization, ester modification, chiral resolution and the like have been reported, but a technical scheme for simultaneously enhancing water solubility, pulmonary adhesiveness and avoiding remarkably increasing molecular weight by directly introducing short-chain PEG on hyoscyamine molecules and quaternizing has not been seen. Based on the research of anticholinergic agents, the prior art WO2018/154597A1 discloses a synthesis method of anticholinergic agents, and a representative product is quaternary ammonium anticholinergic glycopyrrolate. The technology improves receptor selectivity, reduces central penetration and improves salt forming stability of the compound by constructing tropane parent nucleus and quaternizing on nitrogen atom and introducing substituted alkyl or cycloalkyl side chain. Although the quaternized derivatives have remarkable advantages in terms of safety, structural means for enhancing the adhesion of the lung are lacking, residence time of the drug in the local part of the airway is limited, hydration capacity and hydrophilicity are insufficient, and performance of inhalation solution preparation is not optimized pertinently. In view of the above, designing an anticholinergic agent with a hyoscyamine derivative to improve water solubility, moderately enhance adhesiveness and prolong local residence time, and simultaneously has low BBB permeability and good atomization performance, is a technical problem to be solved in the art. Disclosure of Invention The invention aims to provide a scopolamine derivative and a preparation method thereof, and the scopolamine molecule is subjected to the double structural modification, so that a long-acting local bronchodilator which is more excellent in physicochemical property and suitable for inhalation administration is obtained, safer and more effective treatment options are provided for respiratory diseases such as asthma, COPD and the like, and the potential risks of limited residence time and central side effects of the existing anticholinergic agent for inhalation in the lung are overcome. The specific technical scheme is as follows: The hyoscyamine derivative is subjected to covalent modification on the basis of the hyoscyamine skeleton structure, and is characterized in that the covalent modification is to covalently bond polyether polymer chain segments at hydroxyl positions of the hyoscyamine skeleton and simultaneously carry out quaternization treatment on nitrogen atoms of the hyoscyamine skeleton. Further, the scopolamine derivative is m- (PEG 7) -scopolamineThe quaternary ammonium bromide is a quaternary ammonium bromide containing a linear PEG7 chain, wherein the linear PEG7 chain is a linear polymer chain containing 7 ethylene glycol repeating units, and the quaternary ammonium salt is N, N-dimethyl quaternary ammonium cation formed by methylation of hyoscyamine nitrogen atoms. Further, the structural formula of the scopolamine derivative is shown as follows: 。 further, the preparation method of the hyoscyamine derivative comprises the following steps: S1, carrying out etherification reaction on hyoscyamine and a PEG