Amide compound, preparation method and application thereof

Abstract

The invention discloses an amide compound, a preparation method and application thereof, and particularly provides a compound as shown in a formula (I), or a salt thereof, or an isotope replacement form thereof, or an optical isomer thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof. According to the invention, the local anesthetic effect duration of the compound provided by the invention is obviously longer than that of a contrast drug bupivacaine; and compared with bupivacaine, the compound provided by the invention is higher in titer and better in safety, can bedecomposed and removed from plasma more quickly, and has a very good application prospect in preparation of local anesthetic drugs or local analgesic drugs.

Description

technical field [0001] The invention belongs to the field of pharmaceutical inventions, and relates to a class of amide compounds with local analgesic effect and its preparation and application. Background technique [0002] Local anesthetics can produce a reversible nerve block effect at the drug site, hindering the conduction of pain, thereby exerting a local analgesic effect. All local anesthetics currently used clinically will not produce local anesthesia in animals or humans for more than 6 hours without the aid of slow-release preparations. But in most cases, the duration of local pain is much longer than 6 hours, such as neuropathic pain, pain after joint surgery, cancer pain, pain caused by trauma, etc. For the above-mentioned long-term local pain, due to the lack of local anesthetic drugs with a long enough time-effectiveness, the clinic has to use opioid central analgesics for a long time and in large doses, which makes patients face systemic symptoms such as addi...

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Problems solved by technology

[0003] In order to meet the above needs, various studies on increasing the nerve block time of local anesthetic drugs have been carried out, but none of them are ideal.

If lidocaine quaternary ammonium salt QX314 is used in combination with surfactants, although the nerve block time can be significantly prolonged, the nerve damage caused by surfactants cannot be ignored (Itay Sagie and Daniel S. Kohane, PNAS, 2010 , 107(8), 3740–3745); another example is that QX314 is derivatized and prepared into cationic long-chain derivatives, although the nerve block time can be prolonged, but this type of molecule itself is a surfactant (CN 105315170B), and it is also unavoidable Nerve and tissue damage caused by surface activity; another example is the combined use of hydroxy derivatives of QX314 and levobupivacaine, although the local nerve block time is prolonged to a certain extent, but it cannot exceed 12 hours (WenLing Zhao et al, European Journal of Pharmaceutical Sciences. 2018, 111, 418–424)

In addition, a bupivacaine sustained-release liposome has been marketed in the United States in recent years. Although the local analgesic effect it can produce can last for 96 hours, it is limited by the safety of bupivacaine. The total amount of bupivacaine is limited, and its sustained analgesic effect is weak, so the use of opioid analgesics cannot be completely withdrawn (Zhang X et al, Medicine (Baltimore). 2017; 96(49):e8433)

[0004] Therefore, at present, there is no local anesthetic with strong effect (can completely avoid the use of opioid receptor agonists), long acting time (24-72 hours strong analgesia) and safety (good local tissue and systemic safety) Local Nerve Blockers, Unmet need for prolonged postoperative local analgesia

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