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EP-4151622-B1 - AROMATIC COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF IN DRUG

EP4151622B1EP 4151622 B1EP4151622 B1EP 4151622B1EP-4151622-B1

Inventors

  • TONG, Rongsheng
  • SHI, Jianyou
  • LIU, LIMING
  • QIU, Dan

Dates

Publication Date
20260506
Application Date
20210428

Claims (10)

  1. A compound, or pharmaceutically acceptable salt of the formula (I): wherein: R 1 is selected from the group consisting of C1-5 alkyl, halogen; R 2 is selected from the group consisting of C1-4 alkyl; R 3 is selected from the group consisting of C1-4 alkyl; R 4 is selected from the group consisting of C1-4 alkyl; R 5 is H; X is HN; Y is O; L is carbonyl; m=1; n is an integer from 0 to 4; and R 6 is C1-12 alkyl; any carbon atom in the skeleton of R 1 -R 7 can be replaced by N atom or O atom; the skeleton of R 1 -R 7 can be substituted by one or more hydroxyl; and M is a pharmaceutically acceptable anion, such as chloride ion, bromide ion, sulfate ion, acetate ion, and sulfonate ion; or a compound, or pharmaceutically acceptable salt of the formula (I): wherein: R 1 is selected from the group consisting of C1-2 alkyl; R 2 is selected from the group consisting of C1-3 alkyl; R 3 is selected from the group consisting of C1-3 alkyl; R 4 is selected from the group consisting of C1-3 alkyl; R 5 is H; X is HN; Y is O; L is carbonyl; m=1; n is an integer from 0 to 4; and R 6 is the following specified structure: in the above specified structure, p is an integer from 1-10, R 7 is C1-4 alkyl, R 8 is H or C1-2 alkyl, Z is methylene or O; any carbon atom in the skeleton of R 1 -R 7 can be replaced by O atom or N atom; the skeleton of R 1 -R 7 can be substituted by one or more hydroxyl; and M is a pharmaceutically acceptable anion, such as chloride ion, bromide ion, sulfate ion, acetate ion, and sulfonate ion.
  2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following specific compounds:
  3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following specific compounds:
  4. The compound, or pharmaceutically acceptable salt according to any one of claims 1 to 3 for use as a local anesthetic, analgesic or antipruritic drug, which locally produces a fast, lasting and safe nerve blocking effect.
  5. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 3 and lidocaine or lidocaine salt.
  6. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 3 and bupivacaine, levobupivacaine, tetracaine or salt thereof.
  7. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 3 and ion channel agonists such as tetrodotoxin and capsaicin.
  8. The pharmaceutical composition according to any one of claims 5 to 7 for use as a local anesthetic, analgesic or antipruritic drug, which locally produces a fast, lasting and safe nerve blocking effect.
  9. A sustained-release preparation, comprising the compound, or pharmaceutically acceptable salt according to any one of claims 1 to 3 and sustained-release materials.
  10. The sustained-release preparation according to claim 9 for use as a long-acting local anesthetic, analgesic or antipruritic drug.

Description

FIELD The present invention relates to an aromatic compound, a production method and use in medicine. The compound can be used in the production of local anesthesia drugs to produce long-term local nerve block effect. BACKGROUND Most of the moderate-to-severe pain caused by surgical wounds will last for 48-72 hours, so postoperative pain is usually managed with systemic opioid analgesic drugs, but the resulting problems such as addiction, constipation, and respiratory depression plague patients. How to ensure safe and effective postoperative analgesia while reducing the use of opioids has become a major clinical problem that needs to be solved. Clinically, local anesthetic drugs can be used to control pain in some surgery with minor wounds, thereby avoiding or reducing the use of systemic opioid anesthetic drugs. Local anesthesia is a common clinical medical operation, which refers to the application of local anesthetic drugs to parts of the body when the patient is awake, so that the sensory nerve conduction function of a certain part of the body is temporarily blocked to produce analgesic effect, and the motor nerve conduction remains intact or is blocked of varying degrees simultaneously. This block should be fully reversible. The advantages of local anesthesia lie in its simplicity, safety, patient awareness, few complications and little impact on the patient's physiological function. Local anesthesia is achieved through the use of local anesthetic drugs, and the duration and intensity of the action of local anesthetic drugs determine the duration and analgesic intensity of local anesthesia. Due to the continuous diffusion of the drug from the administration site, the local concentration of the drug decreases. All local anesthetic drugs currently used in clinical use produce a duration of local anesthesia within 6 hours after a single administration. Even if the local anesthetic drugs are used in combination with drugs such as vasoconstrictor dexamethasone, and the diffusion loss of local anesthetic drugs is reduced at the administration site, the duration of local anesthesia can still not exceed 10 hours (Kyle Robert Kirkham et al, 2018, Anesthesia & Analgesia. 126(1):270-279). In 2011, a liposomal sustained-release preparation containing bupivacaine was launched in the United States. Although the preparation was alleged to produce a 72-hour local anesthetic effect, it has been reported to demonstrate its unstable dose-drug dependence (Christopher Wahal, Indian J Anaesth. 2018; 62(2): 94-102.) and limited analgesic effect (Malik O et al, J Anaesthesiol Clin Pharmacol. 2017;33(2):151-156), suggesting that the preparation cannot cope with pain independently for 48 to 72 hours after surgery and can only reduce the use of systemic opioid analgesic drugs. In some subsequent clinical trials, liposome of bupivacaine was shown to provide only 24 hours of postoperative analgesic effect, but there was no statistical difference in pain intensity between the administration group and the placebo group during the 24-72 hour period (Uskova A et al, Curr Opin Anaesthesiol. 2015;28(5):593-7.). It can be seen that if local anesthetic drugs have sufficient analgesic intensity and action duration, it is expected to greatly reduce the use of opioids and avoid or reduce various systemic side effects caused by opioids. Another challenge with long-acting local anesthetic drugs is drug safety, including both local and systemic safety. Local safety mainly refers to whether the degree of tissue damage (especially nerve damage) at the administration site is within a clinically acceptable range. The systemic safety refers to whether the drug will have a toxic effect on the heart if it diffuses or is mistakenly injected into the systemic blood circulation, and whether it will have a toxic effect on the central nervous system if it passes through the blood-brain barrier. All local anesthetic drugs currently used clinically have systemic toxicity, and if they are administrated in a too large dosage or injected into the blood by mistake, they can cause arrhythmia, abnormal central nervous activity and even death (Wadlund DL. AORN J.2017 Nov;106(5):367 -377). In order to obtain longer-acting local anesthetic drugs, some improved molecules for traditional local anesthetic drugs that do not have lasting efficacy due to diffusion have appeared one after another, such as QX-314 and QX-314-OH, which are the quaternary ammonium salt derivatives of the traditional local anesthetic drug lidocaine, having a similar structure to lidocaine. However, the molecules of the QX-314 and QX-314-OH have a permanent positive charge, which slows the diffusion of the molecules, enabling them to produce local anesthesia for a significantly longer duration than lidocaine (2 hours VS 6-8hours). It is worth noting that although the introduction of cations prolongs the duration of local anesthesia of the molecules, the ability of the molecules to diffuse from th