EP-3828168-B1 - TWO-QUATERNARY AMMONIUM COMPOUND AND PREPARATION METHOD AND USE THEREOF

Inventors

• YANG, JUN
• LIU, JIN
• Zhang, Weiyi
• ZHANG, WENSHENG
• ZHOU, CHENG
• KE, Bowen
• TANG, LEI

Dates

Publication Date

20260506

Application Date

20190724

Claims (3)

1. A bisquaternary ammonium compound selected from the group consisting of the following compounds:
2. The bisquaternary ammonium compound according to claim 1, a stereoisomer or a mixtures of stereoisomers, a pharmaceutically acceptable salt, solvate, crystal, thereof, for use as muscle relaxant.
3. A pharmaceutical preparation, characterized in that it comprises the bisquaternary ammonium compound according to claim 1 as active ingredient, with the addition of pharmaceutically acceptable adjuvents.

Description

Technical field The present invention belongs to bisquaternary ammonium compounds as well as the preparative method and the use thereof. Background art During surgical anesthesia, neuromuscular blockers (also known as muscle relaxants) can produce muscle relaxation and are used to relax skeletal muscles during surgery and tracheal intubation. The above-mentioned muscle relaxants are classified into depolarization and non-depolarization types according to their action mechanism, and can be divided into four categories: ultra-short-acting, short-acting, medium-acting and long-acting according to their duration of action (Anesthesiology, 82(1), 33a, 1995). Among depolarizing muscle relaxants, only succinylcholine is still used in clinical. Due to its special action mechanism, succinylcholine has serious side effects, such as elevated blood potassium, malignant hyperthermia, arrhythmia, increased intraocular pressure, and gastric tension, etc. The advantage of succinylcholine is that it has a short action time, such as it lasts for 10 minutes and has a rapid effect in the human body, and thus it is used as an ultra-short-acting muscle relaxant in clinical practice. Its feature is particularly suitable for emergency treatment, because in emergency situations, using muscle relaxants with longer acting time may cause severe brain damage and even death. At present, the depolarizing muscle relaxant succinylcholine is the most suitable muscle relaxant for emergency. EP 3 828 169 A1 discloses a dicationic compound, its preparation and in the preparation of muscle relaxants. CN 108 250 143 A discloses a benzylisoquinoline derivative and a pharmaceutical composition thereof formed with a pharmaceutically acceptable carrier, which can produce a nerve Muscle joint blockage, and which is used in the field of preparing muscle relaxants. In addition to not having ultra-short-acting effects, non-depolarizing muscle relaxants are considered as safer muscle relaxants. Clinicians have been seeking for non-depolarizing muscle relaxants with ultra-short-actions (Anesthesia and Analgsia, 61(9), 721, 1982; Cueernt opinion in anaethesiology, 8, 362, 1995). However, all non-depolarizing muscle relaxants currently used in clinical do not have ultra-short-acting characteristics (meaning the muscle relaxant duration < 10 min after single dose). For example, after single administration, the duration of muscle relaxation for micuronium is 15-20 min, while the action times for cisatracurium and rocuronium are 40-60 minutes, but the action time of pancuronium is longer than 60 min. CN101588803A discloses a non-depolarizing muscle relaxant, and cysteine at 200× the dose of the drug can be administrated to quickly reverse its muscle relaxant effect. Although the rapid regression of muscle relaxant is achieved, a large amount of sulfhydryl amino acids (such as semi-cystine) must be used, which will obviously increase medical procedures, and a large number of sulfhydryl amino acids will also increase uncertainty in safety, such as excessive cysteine results in tracheal spasm and vomiting. Therefore, the ultra-short-acting and non-depolarizing muscle relaxants that do not require reversal agents are more meet the clinical needs, and can reduce the economic burden of patients, increase the safety of patient, reduce operations of medical personnels, and save medical resources. Content of the invention The object of the present invention is to provide bisquaternary ammonium compounds as well as the preparative method and the use thereof. The present invention first provides a bisquaternary ammonium compound selected from the group consisting of and The present invention further provides the use of bisquaternary ammonium compound mentioned above in the preparation of muscle relaxants. The present invention further provides a pharmaceutical preparation, which comprises the bisquaternary ammonium compound as disclosed herein above as active ingredients, with the addition of pharmaceutically acceptable adjuvents. The bisquaternary ammonium compound has a rapid effect after single administration, and provides 2 to 10 min of complete muscle relaxation. These compounds only need to rely on the body's own metabolism, and can achieve ultra-short-acting non-depolarizing muscle relaxation. After exerting ultra-short-acting effect on muscle relaxation, it is cleared up quickly by itself. Based on above-mentioned characteristics, the bisquaternary ammonium compounds, the stereoisomers or the mixtures of stereoisomers, or the pharmaceutically acceptable salts, or the solvates or the co-crystals and the combinations thereof, and their combinations with pharmaceutically acceptable can be used in the field of preparation of muscle relaxants, to provide fast, ultra-short-acting, and non-depolarizing muscle relaxant and meet the clinical needs. By following specific examples of said embodiments, above content of the present invention is further illustrated. Bu