Long-acting local anesthetic compounds, methods of making, using and pharmaceutical compositions thereof

Abstract

The application discloses a long-acting local anesthetic compound, a preparation method, application and a pharmaceutical composition thereof. The long-acting local anesthetic compound is prepared by the following steps: reacting a local anesthetic with bromoethanol to generate a quaternary ammonium salt intermediate, and then condensing the quaternary ammonium salt intermediate with a non-steroidal anti-inflammatory drug. The preparation method is simple and suitable for large-scale production. The prepared long-acting local anesthetic compound has a long duration and an anesthetic time of more than 24 hours, and has nerve block selectivity. The long-acting local anesthetic compound can reduce the frequency of administration, increase the compliance of patients, greatly reduce the risk of anesthesia, and has a very good application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to a long-acting local anesthetic compound, and also relates to the preparation, use and pharmaceutical composition of the long-acting local anesthetic compound. BACKGROUND

[0002] Local anesthetics are a class of drugs that reversibly block the generation and conduction of sensory nerve impulses at the site of administration, and are simply referred to as "local anesthetics". In the case of keeping the consciousness clear, local anesthetics reversibly cause the disappearance of pain sensation in local tissues. Generally, the effect of local anesthetics is limited to the administration site and disappears rapidly as the drug diffuses from the administration site. Local anesthetics bind to voltage-gated sodium channels in the cell membrane to block the inward flow of sodium ions, thereby blocking the conduction of nerve impulses and ultimately achieving anesthetic effect. The emergence and development of anesthetic drugs have had a very important influence on modern medicine. Anesthesia can effectively relieve the pain of patients during surgery and create good conditions for surgery.

[0003] Due to the easy diffusion and dissociation of traditional local anesthetics, the action maintenance time is relatively short, and it is necessary to use analgesic pumps to maintain nerve block, adopt catheterization of intraspinal, nerve root, subcutaneous and other sites, which greatly increases the medical cost and the incidence of infection. Moreover, the anesthetic effect of local anesthetics is non-selective: while blocking sensory nerves, it can also cause motor nerve paralysis and sympathetic nerve block. Therefore, patients receiving intraspinal anesthesia or nerve block anesthesia usually experience limb paralysis for several hours after surgery, and circulatory fluctuations, thereby increasing the risk of anesthesia and medical costs. The prior art has improved traditional local anesthetics, for example, ethyl substitution of the tertiary amine N atom of lidocaine will obtain a quaternary ammonium salt compound called QX-314 (Figure a), the structural formula is: N-diethylaminoacetyl-2, 6-dimethylaniline (Strichartz GR. J Gen Physiol. 1973 Jul; 62(1): 37-57). QX-314 can enter nerve cells smoothly through the activation of TRPV1 channel with the assistance of capsaicin (TRPV1 Agonist), thereby producing long-term nerve block; but the strong irritability of capsaicin makes it difficult to have application prospects. A single small dose of lidocaine quaternary ammonium salt cannot penetrate the cell membrane to produce local anesthetic effect, and only a large dose can produce efficacy.

[0004]

[0005] To prolong the duration of analgesia, one method is to use long-acting bupivacaine liposomes, which are expensive and not easy to obtain. Another is to place a catheter and continuously infuse drugs through the catheter, but there is a possibility of secondary failure such as catheter obstruction, displacement and infection.

[0006] In addition, the effect of local anesthetics is also related to its liposolubility, and generally increasing the alkyl substituent group increases lipophilicity, and the anesthetic effect is stronger. For example, tetracaine has a butyl group on the aromatic ring more than procaine, and the liposolubility is significantly increased, and the toxicity is also significantly increased. The amino group of etidocaine has 3 carbon atoms more than lidocaine, but its liposolubility is increased by 50 times, and the anesthetic effect and duration are also increased, about 4 hours or so. However, these simple chemical structure modifications cannot achieve the ideal long-acting local anesthetic effect.

[0007] In order to achieve better analgesic effect, a multi-modal analgesic treatment method is developed in clinic, and local anesthetics are mixed with non-steroidal anti-inflammatory drugs for use as postoperative analgesia after small surgery or as a supplement when local analgesia is insufficient, and are combined with opioid drugs or tramadol or used for multi-modal analgesia for postoperative analgesia of patients undergoing major surgery. However, the mixture of local anesthetics and non-steroidal anti-inflammatory drugs may form a precipitate, which may cause phlebitis, thrombosis or injection site adverse reactions after local injection, and may cause serious consequences; for example, the use of lidocaine and lornoxicam together can shorten the onset time, improve postoperative analgesia, and prolong the analgesia time, but the mixture of local anesthetics and non-steroidal anti-inflammatory drugs may precipitate; the mixture of diclofenac solution and bupivacaine, levobupivacaine or ropivacaine is incompatible, and precipitates even in the presence of sodium bicarbonate. Therefore, anesthetic drugs with long duration, good selectivity, small side effects and specific inhibition of pain without affecting motor nerves and autonomic nerves are urgently needed to be developed. SUMMARY

[0008] The purpose of the present application is to provide a long-acting local anesthetic compound with long anesthetic duration and nerve block selectivity, and to provide a preparation method, application and pharmaceutical composition of the long-acting local anesthetic compound.

[0009] Technical scheme: The present application discloses a long-acting local anesthetic compound, as shown in formula I:

[0010]

[0011] A is NSAIDs is a non-steroidal anti-inflammatory drug, X - is an anion.

[0012] The compound is

[0013] The non-steroidal anti-inflammatory drug is a COX inhibitor, specifically aspirin, ibuprofen, naproxen, flurbiprofen, diclofenac, ketoprofen, indomethacin or sulindac.

[0014] X is -halogen ion, sulfate, sulfite, bicarbonate, sulfonic acid, methyl sulfonic acid or organic acid.

[0015] The halogen ion is fluoride ion, chloride ion, bromide ion or iodide ion.

[0016] The compound is a lidocaine quaternary ammonium salt derivative.

[0017] The compound is selected from any one of the compounds shown in 1-12.

[0018]

[0019] The preparation method of the long-acting local anesthetic compound comprises the following steps: reacting a local anesthetic with bromoethanol to form a quaternary ammonium salt intermediate, and then condensing with a non-steroidal anti-inflammatory drug to obtain the long-acting local anesthetic compound.

[0020]

[0021] The local anesthetic is procaine, lidocaine, ropivacaine, etidocaine or bupivacaine.

[0022] The long-acting local anesthetic compound can also be applied to the preparation of a local anesthetic drug.

[0023] The application further discloses a pharmaceutical composition containing the long-acting local anesthetic compound shown in formula I or a pharmaceutically acceptable salt or isomer, solvent, metabolite thereof, and a pharmaceutically acceptable carrier.

[0024] The pharmaceutical composition can also be applied to the preparation of a local anesthetic drug.

[0025] The local anesthetic drug contains 10-70 mM of the long-acting local anesthetic compound in a single dose; preferably 70 mM.

[0026] The local anesthetic drug is a long-acting local anesthetic and / or a selective local anesthetic, and the anesthetic time is more than 24 hours; the local anesthetic drug has nerve block selectivity, and the sensory nerve block time is longer than the motor nerve block time.

[0027] The long-acting local anesthetic compound of the application has a long-term local anesthetic effect after a single administration, and has a long-acting local anesthetic effect and a selective local anesthetic effect, and overcomes the precipitation caused by physically mixing a non-steroidal anti-inflammatory drug as an anesthetic adjuvant in clinical application.

[0028] The long-acting local anesthetic compound of this invention, through optimization of its drug structure, can fully leverage the local anesthetic and pain-relieving effects of both local analgesics and local anesthetics, achieving a synergistic effect. Local analgesics exert their effects by reducing the transduction (of nonsteroidal anti-inflammatory drugs) or transmission (of local anesthetics) of noxious signals; local anesthetics block voltage-gated sodium receptors on nerve cell membranes. + The pathway blocks nerve impulse transmission, thereby producing a local anesthetic effect and reversibly causing the loss of pain sensation in the local tissue. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their analgesic and anti-inflammatory effects by inhibiting cyclooxygenase activity, thereby reducing prostaglandins. They have good analgesic effects on both acute and chronic pain. Local NSAIDs allow for a more concentrated site of drug action, and local formulations can reduce systemic absorption and adverse reactions after administration. Therefore, synthesizing quaternary ammonium salt derivatives of local anesthetics with NSAIDs and optimizing their structures makes the long-acting local anesthetic compound of this invention highly promising for clinical applications.

[0029] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The long-acting local anesthetic compound of the present invention has good local anesthetic selectivity and long duration, with an anesthetic time exceeding 24 hours; (2) The preparation method of the long-acting local anesthetic compound of the present invention is simple and suitable for large-scale production; (3) The nerve block time of the long-acting local anesthetic compound of the present invention is longer than that of motor nerve block, has nerve block selectivity, reduces the number of administrations, increases patient compliance, greatly reduces the risk of anesthesia, and has great application prospects. Attached Figure Description

[0030] Figure 1 The 1H NMR spectrum of intermediate 1a;

[0031] Figure 2 The 1H NMR spectrum of compound 1;

[0032] Figure 3 The 1H NMR spectrum of compound 2;

[0033] Figure 4 The 1H NMR spectrum of compound 3;

[0034] Figure 5 The 1H NMR spectrum of compound 4;

[0035] Figure 6 The 1H NMR spectrum of compound 5;

[0036] Figure 7 The 1H NMR spectrum of compound 6;

[0037] Figure 8 The 1H NMR spectrum of compound 7;

[0038] Figure 9The 1H NMR spectrum of compound 8;

[0039] Figure 10 The 1H NMR spectrum of compound 9;

[0040] Figure 11 The carbon NMR spectrum of compound 1;

[0041] Figure 12 The carbon NMR spectrum of compound 2;

[0042] Figure 13 The carbon NMR spectrum of compound 3;

[0043] Figure 14 The carbon NMR spectrum of compound 4;

[0044] Figure 15 The carbon NMR spectrum of compound 5;

[0045] Figure 16 The carbon NMR spectrum of compound 6;

[0046] Figure 17 The carbon NMR spectrum of compound 7;

[0047] Figure 18 The carbon NMR spectrum of compound 8;

[0048] Figure 19 The carbon NMR spectrum of compound 9;

[0049] Figure 20 The 1H NMR spectrum of compound 10;

[0050] Figure 21 The 1H NMR spectrum of compound 11;

[0051] Figure 22 The 1H NMR spectrum of compound 12;

[0052] Figure 23 The diagram shows the results of the local anesthesia experiment of compound 1, where A is the duration of motor blockade in mice, B is the duration of sensory blockade in mice, C is the duration of motor blockade in rats, and D is the duration of sensory blockade in rats.

[0053] Figure 24 The diagram shows the results of the local anesthesia experiment of compound 4, where A is the duration of motor blockade in mice, B is the duration of sensory blockade in mice, C is the duration of motor blockade in rats, and D is the duration of sensory blockade in rats.

[0054] Figure 25The diagram shows the results of the local anesthesia experiment of compound 5, where A represents the duration of motor blockade in mice, B represents the duration of sensory blockade in mice, C represents the duration of motor blockade in rats, and D represents the duration of sensory blockade in rats. Detailed Implementation

[0055] The technical solution of the present invention will be further described below with reference to the embodiments. The test materials used in the embodiments can all be obtained through conventional means.

[0056] Example 1

[0057] Preparation of 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-((2-(4-isobutylphenyl)propanoyl)oxy)ethyl)-2-oxoethan-1-aminium (compound 1):

[0058]

[0059] 2.35 g of active pharmaceutical ingredient a and 2.5 g of bromoethanol were added to a 100 mL round-bottom flask. The mixture was stirred at 100 °C and allowed to stand for about 15 hours until a brown, viscous substance was formed. EA was added and stirred, resulting in the precipitation of a large amount of solid. After stirring for another hour, the mixture was filtered, washed with EA while being vacuum filtered, and dried to obtain 2.37 g of a light pink powder intermediate, 1a, which was used in the next step of the reaction in Examples 1-9. Yield: 65.83%. 1 HNMR(500MHz,Methanol-d4)δ9.85–9.83(s,1H),δ7.21–7.08(m,3H),4.53(s,2H),4.13–4.03(m,2H),3. 92–3.72(m,6H),3.37(s,1H),2.27(s,6H),1.44(t,6H).(+)-ESI-MS:m / z279.2070(calcd.279.2067for C 16 H 27 N2O2 + [M–Br] + ).

[0060]

[0061] In a 100 mL round-bottom flask, add 0.36 g (1 mmol, 1.0 eq) of intermediate 1a, 0.21 g (1 mmol, 1.0 eq) of intermediate 1b, 13 mg (0.1 mmol, 0.1 eq) of DMAP, and 15 mL of dichloromethane. After stirring, add 0.23 g (1.2 mmol, 1.2 eq) of EDCI and react at room temperature for 7 h. Treat successively with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated brine. Dry the extract with anhydrous sodium sulfate and evaporate to dryness to obtain 0.56 g of a transparent oil. Elute the product with (DCM:MeOH = 15:1), and evaporate to dryness to obtain 0.47 g of milky white product 1, which is the long-acting local anesthetic compound 1 of this invention. Yield: 85.59%. 1 H NMR(500MHz,Chloroform-d)δ10.96(s,1H),7.14(d,J=7.8Hz,2H),7.09(d,J=7.9Hz,2H),7.06-6.98(m,3H),4. 89(s,2H),4.63(s,1H),4.53(d,J=6.9Hz,1H),3.92(dd,J=15.8,5.4Hz,1H),3.78(d,J=10.5Hz,1H),3.69(q,J= 7.1Hz,1H),3.45(q,J=7.2Hz,2H),3.36(dt,J=13.8,7.0Hz,2H),2.42(d,J=7.1Hz,2H),2.22(s,6H),1.80(dq,J =13.5, 6.8Hz, 1H), 1.48 (d, J = 7.1Hz, 3H), 1.29 (t, J = 7.2Hz, 3H), 1.23 (t, J = 7.2Hz, 3H), 0.87 (d, J = 6.6Hz, 6H). 13 C NMR(126MHz,Chloroform-d)δ173.76,161.72,141.26,136.85,135.02,132.98,129.69,128.15,127.48,127.19,5 7.80,57.42,56.63,44.99,44.92,30.16,22.34,18.83,8.29,8.27.(+)-ESI-MS:m / z467.3275(calcd.467.3268for C 29 H 43 N2O3 + [M–Br] + ).

[0062] Example 2

[0063] Preparation of (N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium compound 2):

[0064]

[0065] In a 100 mL round-bottom flask, add 0.36 g (1 mmol, 1.0 eq) of intermediate 1a, 0.3 g (1 mmol, 1.0 eq) of intermediate 2b, 13 mg (0.1 mmol, 0.1 eq) of DMAP, and 15 mL of dichloromethane. After stirring, add 0.23 g (1.2 mmol, 1.2 eq) of EDCI and react at room temperature for 5 h. Treat successively with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated brine. Dry the extract with anhydrous sodium sulfate and evaporate to dryness to obtain 0.43 g of a pale yellowish-brown transparent oil. Elute with (DCM:MeOH = 40:1) to remove impurities, then elute with (DCM:MeOH = 15:1) to obtain 0.2 g of a white solid product 2, which is the long-acting local anesthetic compound 2 of this invention. Yield: 31.35% 1 H NMR(500MHz,Chloroform-d)δ10.90(s,1H),7.34(d,J=8.1Hz,2H),7.17(d,J=9.2Hz,1 H),7.12(t,J=7.8Hz,1H),7.08-6.98(m,4H),6.93(t,J=8.0Hz,1H),6.50(d,J=8.0Hz,1 H),6.37(s,1H),4.95(s,2H),4.69(dd,J=6.3,3.4Hz,2H),3.96(t,J=5.0Hz,2H),3.84 (s,2H),3.59(tq,J=13.6,6.9Hz,4H),2.53(s,3H),2.25(s,6H),1.37(t,J=7.1Hz,6H). 13C NMR(126MHz,Chloroform-d)δ171.41,161.81,161.78,142.63,137.34,134.98,133.07,131.07,129.90,128.98,128. 51,128.14,127.44,124.70,122.90,122.10,118.05,58.21,57.70,57.54,56.45,38.24,18.82,8.25.(+)-ESI-MS:m / z 556.2131(calcd.556.2128forC 30 H 36 Cl2N3O3 + [M–Br]+).

[0066] Example 3

[0067] Preparation of 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanoyl)oxy)ethyl)-2-oxoethan-1-aminium (compound 3):

[0068]

[0069] In a 100 mL round-bottom flask, add 0.36 g (1 mmol, 1.0 eq) of compound 1a, 0.24 g (1 mmol, 1.0 eq) of compound 3b, 10 mg (0.1 mmol, 0.1 eq) of DMAP, and 20 mL of dichloromethane. After stirring, add 0.23 g (1.2 mmol, 1.2 eq) of EDCI and react at room temperature for 1 h. Treat successively with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated brine. Dry the extract with anhydrous sodium sulfate and evaporate to dryness. Elute with (DCM:MeOH = 40:1) to remove impurities, then elute with (DCM:MeOH = 15:1) to obtain 0.3 g of product 3, which is the long-acting local anesthetic compound 3 of this invention. Yield: 51.11%. 1 H NMR(500MHz,Chloroform-d)δ10.97(s,1H),7.55-7.50(m,2H),7.48-7.37(m,4H),7.18-7.01(m,5H),4.99(s ,2H),4.73-4.62(m,2H),4.00(m,1H),3.92-3.78(m,2H),3.56(m,4H),2.26(s,6H),1.56(d,3H),1.37(m,6H).13 C NMR(126MHz,Chloroform-d)δ173.13,161.77,160.73,158.75,140.86,140.80,134.97,133.02,131.21,128.87,128.85,128.60,128.1 6,127.97,127.48,123.67,115.36,115.17,58.04,57.67,57.45,56.53,56.34,53.44,44.82,18.78,18.07,8.25,8.21.(+)-ESI-MS:m / z 505.2862(calcd.505.2861for C 31 H 38 FN2O3 + [M–Br] + ).

[0070] Example 4

[0071] Preparation of (R)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-((2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethyl)-2-oxoethan-1-aminium (compound 4):

[0072]

[0073] In a 100 mL round-bottom flask, 0.54 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.35 g (0.15 mmol, 1.0 eq) of 4b, 20 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane were added. After stirring, 0.35 g (0.18 mmol, 1.2 eq) of EDCI was added, and the mixture was reacted at room temperature for 1 h. The mixture was washed successively with saturated NaHCO3 and 1 mol / L HCl, then with water and saturated brine. After drying with anhydrous sodium sulfate, the product was evaporated to dryness to obtain 0.81 g of a light brown transparent oil. Purification was achieved by column chromatography (DCM:MeOH = 30:1) to obtain 0.4 g of a transparent oil, product 4, which is the long-acting local anesthetic compound 4 of this invention. Yield: 46.51%. 1H NMR(500MHz,Chloroform-d)δ10.89(s,1H),7.72(m,2H),7.65(d,1H),7.35(m,1H),7.17(m,1H),7.12(d,1H),7.07(m,1H),7.02(d,2H),4.86(s,2 H),4.68(m,1H),4.54(m,1H),3.93(s,3H),3.92-3.84(m,2H),3.77(m,1H ),3.38-3.24(m,3H),3.16(m,1H),2.23(s,6H),1.61(d,3H),1.10(m,6H). 13 C NMR(126MHz,Chloroform-d)δ173.67,161.66,158.02,134.98,134.59,133.83,132.99,129.10,128.83,128.14,127.63,12 7.46,126.19,125.79,119.65,105.62,57.90,57.83,57.37,56.52,56.22,55.36,45.30,17.94,8.09,8.05.(+)-ESI-MS:m / z 491.2904(calcd.491.2904for C 30 H 39 N2O4 + [M–Br] + ).

[0074] Example 5

[0075] Preparation of N-(2-((2-(3-benzoylphenyl)propanoyl)oxy)ethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium (compound 5):

[0076]

[0077] In a 100 mL round-bottom flask, 0.36 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.225 g (0.15 mmol, 1.0 eq) of 5b, 13 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane were added. After stirring, 0.23 g (0.18 mmol, 1.2 eq) of EDCI was added, and the mixture was reacted at room temperature for 2 h. The mixture was washed successively with saturated NaHCO3 and 1 mol / L HCl, then with water and saturated brine. After drying with anhydrous sodium sulfate, the product was evaporated to dryness to obtain 0.66 g of a light brown transparent oil. Purification was achieved by column chromatography (DCM:MeOH = 25:1) to obtain 0.31 g of a transparent oil, product 5, which is the long-acting local anesthetic compound 5 of this invention. Yield: 53.06%. 1 H NMR(500MHz,Chloroform-d)δ10.96(s,1H),7.78-7.73(m,2H),7.70(t,J=1.8Hz,1H),7 .63-7.56(m,2H),7.47(ddt,J=23.7,15.3,7.7Hz,4H),7.06-6.96(m,3H),4.92(s,2H), 4.61 (s, 2H), 3.94 (d, J = 11.5 Hz, 1H), 3.84 (q, J = 6.9 Hz, 2H), 3.57-3.44 (m, 4H), 2.57 (s, 1H) water peak, 2.21 (s, 6H), 1.53 (d, J = 7.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR(126MHz,Chloroform-d)δ196.27,173.16,161.79,161.74,140.28,138.37,137.08,135.04,135.02,132.98,132.85,131.57,130.05 ,129.39,128.85,128.68,128.47,128.15,127.47,58.04,57.63,57.40,56.59,56.37,45.23,18.77,18.20,8.24,8.21.(+)-ESI-MS:m / z 515.2916(calcd.515.2904forC 32 H 39 N2O4 + [M–Br] + ).

[0078] Example 6

[0079] Preparation of N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium (compound 6):

[0080]

[0081] In a 25 mL round-bottom flask, 0.36 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.358 g (0.15 mmol, 1.0 eq) of 6b, 13 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane were added. After stirring, 0.23 g (0.18 mmol, 1.2 eq) of EDCI was added, and the mixture was reacted at room temperature for 1 h. The product was washed successively with saturated NaHCO3 and 1 mol / L HCl, then with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 0.68 g of a pale yellow solid. Elution by column chromatography (DCM:MeOH = 30:1) yielded 0.3 g of a pale yellow solid, product 6, which is the long-acting local anesthetic compound 6 of this invention. Yield: 42.81%. 1 H NMR(500MHz,Chloroform-d)δ10.94(s,1H),7.63(d,J=8.6Hz,2H),7.45(d,J=6.6Hz,2H),7.0 7-7.02(m,1H),7.00(d,J=7.4Hz,2H),6.92(d,J=2.5Hz,1H),6.86(d,J=9.0Hz,1H),6.66(dd, J=9.1,2.5Hz,1H),4.92(s,2H),4.68-4.58(m,2H),3.90-3.84(m,2H),3.78(s,3H),3.74(s,2 H), 3.48 (hept, J = 7.0Hz, 4H), 2.45 (s, 1H) water peak, 2.32 (s, 3H), 2.22 (s, 6H), 1.28 (t, J = 7.1Hz, 6H). 13C NMR(126MHz,Chloroform-d)δ170.07,168.32,161.87,156.20,139.59,136.22,135.04,133.52,133.02,131.21,130.78,130.35,129.23 ,128.15,127.48,115.03,111.60,111.45,101.47,59.13,58.04,57.60,57.41,56.28,55.89,30.05,18.74,13.29,8.10.(+)-ESI-MS:m / z 618.2751(calcd.618.2729for C 35 H 41 ClN3O5 + [M–Br] + ).

[0082] Example 7

[0083] Preparation of N-(2-((2-(3-benzoylphenyl)propanoyl)oxy)ethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium (compound 7):

[0084]

[0085] In a 25 mL round-bottom flask, add 0.36 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.18 g (0.15 mmol, 1.0 eq) of 7b, 13 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane. After stirring, add 0.23 g (0.18 mmol, 1.2 eq) of EDCI and react at room temperature for 1 h. Wash successively with saturated NaHCO3, 1 mol / L HCl, water, and saturated brine. Dry the product on anhydrous sodium sulfate and evaporate to dryness to obtain 0.28 g of a pale yellow solid. Elute by column chromatography (DCM:MeOH = 30:1). Elute the product again with (DCM:MeOH = 15:1) to obtain 0.09 g of a transparent oily substance, product 7, which is the long-acting local anesthetic compound 7 of this invention. Yield: 18.20%. 1¹H NMR (500 MHz, Chloroform-d) δ 11.13 (s, 1H), 7.93 (dd, J = 7.9, 1.7 Hz, 1H), 7.60 (td, J = 7.8, 1.7 Hz, 1H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (dd, J = 8.1, 1.2 Hz, 1H), 7.09 - 7.03 (m, 1H), 7.02 (d, J = 6.3 Hz, 2H), 5.08 (s, 2H), 4.90 - 4.83 (m, 2H), 4.07 - 4.00 (m, 2H), 3.72 (qq, J = 14.1, 7.1 Hz, 4H), 2.34 (s, 3H), 2.25 (s, 6H), 1.48 (t, J = 7.2 Hz, 6H). 13 ¹³C NMR (126 MHz, Chloroform-d) δ 169.73, 163.70, 161.85, 150.84, 135.07, 134.79, 133.07, 131.18, 128.15, 127.47, 126.30, 123.84, 122.00, 57.81, 57.77, 57.57, 56.43, 21.11, 18.76, 8.31. (+)-ESI-MS: m / z 414.2387 (calcd. 414.2384 for C 25 H 33 ​​​​​​​​​​​​​​​​In a 25 mL round-bottom flask, 0.36 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.356 g (0.15 mmol, 1.0 eq) of 8b, 13 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane were added. After stirring, 0.23 g (0.18 mmol, 1.2 eq) of EDCI was added, and the mixture was reacted at room temperature for 1 h. The product was washed successively with saturated NaHCO3 and 1 mol / L HCl, then with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 0.73 g of a yellow solid. Elution by column chromatography (DCM:MeOH = 30:1) yielded 0.54 g of a yellow solid, product 8, which is the long-acting local anesthetic compound 8 of this invention. Yield: 77.16%. 1 H NMR(500MHz,Chloroform-d)δ10.86(s,1H),7.71(d,J=8.1Hz,2H),7.63(d,J=8.1Hz, 2H),7.21-7.14(m,2H),7.08-7.03(m,1H),7.00(d,J=6.5Hz,2H),6.84(dd,J=8.7,2. 4Hz,1H),6.57(t,J=9.9Hz,1H),4.96(s,2H),4.65(s,2H),3.91(s,2H),3.64(s,2H), 3.54(d,J=6.8Hz,4H),2.80(s,3H),2.21(s,6H),2.18(s,3H),1.33(t,J=7.1Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ169.91,162.35,162.07,147.25,147.17,146.92,140.65,139. 14,138.87,135.43,134.06,131.79,131.77,130.60,130.39,129.80,129.78,128.33,1 27.51,124.45,123.76,123.69,111.19,111.01,106.75,106.56,58.60,57.44,57.05,5 6.02,43.63,31.07,18.68,10.78,8.13.(+)-ESI-MS:m / z617.2841(calcd.617.2844for C 36 H 42 FN2O4S + [M–Br] + ).

[0090] Example 9

[0091] Preparation of N-(2-(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)acetoxy)ethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium (compound 9):

[0092]

[0093] In a 25 mL round-bottom flask, 0.36 g (0.15 mmol, 1.0 eq) of intermediate 1a, 0.354 g (0.15 mmol, 1.0 eq) of 9b, 13 mg (0.015 mmol, 0.1 eq) of DMAP, and 10 mL of dichloromethane were added. After stirring, 0.23 g (0.18 mmol, 1.2 eq) of EDCI was added, and the mixture was reacted at room temperature for 1 h. The product was washed successively with saturated NaHCO3 and 1 mol / L HCl, then with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 0.69 g of a white solid. Elution by column chromatography (DCM:MeOH = 20:1) yielded 0.65 g of a yellowish-white solid, product 9, which is the long-acting local anesthetic compound 9 of this invention. Yield: 93.28%. 1 H NMR(500MHz,Chloroform-d)δ10.91(s,1H),7.32(d,J=8.0Hz,2H),7.23(d,J=6.0Hz, 1H),7.13(t,J=8.5Hz,1H),7.07-7.02(m,1H),6.99(dd,J=15.9,7.9Hz,4H),6.62(s, Dichloromethane peaks: 1H, 6.54 (d, J = 8.0 Hz, 1H), 5.28 (s, 1H), 4.96 (s, 2H), 4.70 (d, J = 13.6 Hz, 4H), 3.88 (s, 4H), 3.62 (t, J = 6.8 Hz, 4H), 2.68 (s, 1H), 2.23 (s, 6H), 1.40 (t, J = 7.2 Hz, 6H). 13C NMR (126MHz, DMSO-d6) δ171.45,167.70,162.34,143.38,137.62,135.45,134.00,131.38,131.30,129.65,128.38,128.34 ,127.54,126.52,123.27,121.21,116.53,61.51,58.79,58.74,57.23,57.09,56.02,36.96,18.63,8.15.(+)-ESI-MS:m / z 614.2171(calcd.614.2183forC 32 H 38 Cl2N3O5 + [M–Br] + ).

[0094] Example 10

[0095] Preparation of (2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-((2-(4-isobutylphenyl)propanoyl)oxy)ethyl)-1-propylpiperidin-1-ium (compound 10):

[0096]

[0097] 0.42 g of active pharmaceutical ingredient c (1.5 mmol, 1.0 eq) and 0.46 g of bromoethanol (3.75 mmol, 2.5 eq) were added to a 100 mL Erlenmeyer flask. The mixture was heated to reflux at 120 °C, and the reaction was monitored by thin-layer chromatography. After seven hours, the ropivacaine reaction was complete. After evaporation (to remove excess bromoethanol), 0.6 g of a black viscous substance was obtained. The product was eluted by column chromatography, first with PE:EA = 1:5, then with DCM:MeOH = 1:1. The product was then evaporated to dryness to obtain 0.3 g of a brown solid intermediate, 1c. This intermediate was used in the next step of the reactions in Examples 10-12. Yield: 49.17%.

[0098]

[0099] In a 100 mL round-bottom flask, add 0.4 g of intermediate 1c (1 mmol, 1.0 eq), 0.165 g (0.8 mmol, 0.8 eq) of 1b, 13 mg of DMAP (0.01 mmol, 0.1 eq), and 15 mL of dichloromethane. After stirring, add 0.23 mg of EDCI (1.2 mmol, 1.2 eq). React at room temperature for 4 hours, then perform TLC. The reactants have largely reacted. The mixture is treated sequentially with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated saline solution. The extract is dried over anhydrous sodium sulfate and evaporated to dryness to obtain 0.38 g of a transparent oily, brown, viscous product. Elute by column chromatography, first with a solvent of PE:EA = 1:1, then with a solvent of DCM:MeOH = 5:1. Elute to dryness to obtain 0.38 g of a yellowish-brown, viscous product, which is the long-acting local anesthetic compound 10 of this invention. Yield: 64.53%. 1 H NMR(500MHz,Chloroform-d)δ10.96(s,1H),7.67(dt,J=15.4,7.5Hz,2H),7.60(s,1H),7.30(d,J=8.5Hz,1H),7.15( d,J=6.4Hz,1H),7.10(s,1H),7.07-6.96(m,3H),5.79(s,1H),4.71-4.56(m,1H),4.54-4.39(m,2H),3.91(s,3H),3.8 5(q,J=7.0Hz,1H),3.70(s,1H),3.45(s,1H),3.34-3.26(m,2H),3.12(s,1H),2.33(s,2H),2.19(s,7H),2.00(s,1H), 1.77(d,J=35.6Hz,4H),1.57(d,J=7.1Hz,3H),0.81(t,J=7.1Hz,3H).(+)-ESI-MS:m / z507.3598(calcd.507.3581for C 32 H 47 N2O3 + [M–Br] + ).

[0100] Example 11

[0101] Preparation of (2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethyl)-1-propylpiperidin-1-ium (compound 11):

[0102]

[0103] In a 100 mL round-bottom flask, 0.4 g of intermediate 1c (1 mmol, 1.0 eq) and 0.21 g (1 mmol, 0.9 eq) of 4b, 13 mg of DMAP (0.1 mmol, 0.1 eq), and 15 mL of dichloromethane were added. After stirring, 0.23 g (1.2 mmol, 1.2 eq) of EDCI was added. The reaction was carried out at room temperature for 7 hours, and the reaction was recorded on a TLC plate. The product was treated successively with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated saline solution. The product was dried over a small amount of anhydrous sodium sulfate and evaporated to dryness to give 0.4 g of a brown viscous substance. The product was eluted by column chromatography and evaporated to dryness to give 0.32 g of a brown solid, which is the long-acting local anesthetic compound 11 of this invention. Yield: 52.19%. 1 H NMR(500MHz,Chloroform-d)δ10.96(s,1H),7.67(dt,J=15.4,7.5Hz,3H),7.60(s,1H),7.30(d,J=8.5Hz,1H),7.15(d,J=6.4Hz,1 H),7.10(s,1H),7.07-6.96(m,4H),5.79(s,1H),4.73-4.56(m,1H),4.54-4.39(m,2H),3.91(s,3H),3.85(q,J=7.0Hz,1H),3.70(s ,2H),3.45(s,1H),3.34-3.26(m,2H),3.12(s,1H),2.90-2.30(m,6H),2.19(s,6H),2.00(s,2H),1.77(d,J=35.6Hz,4H),1.57(d,J =7.1Hz,3H),1.45(t,J=6.0Hz,2H),1.21(d,J=31.3Hz,2H),0.81(t,J=7.1Hz,3H).(+)-ESI-MS:m / z531.3227(calcd.531.3217for C 33 H 43 N2O4 + [M–Br] + ).

[0104] Example 12

[0105] Preparation of (2S)-1-(2-((2-(3-benzoylphenyl)propanoyl)oxy)ethyl)-2-((2,6-dimethylphenyl)carbamoyl)-1-propylpiperidin-1-ium (compound 12):

[0106]

[0107] In a 100 mL round-bottom flask, add 0.4 g of intermediate 1c (1 mmol, 1.0 eq), 0.23 g (0.9 mmol, 0.9 eq) of 5b, 13 mg of DMAP (0.1 mmol, 0.1 eq), and 15 mL of dichloromethane. After stirring, add 0.23 g (1.2 mmol, 1.2 eq) of EDCI and react at room temperature for 5 hours. Treat successively with saturated sodium bicarbonate, 1 mol / L hydrochloric acid, water, and saturated brine. Dry with a small amount of anhydrous sodium sulfate and evaporate to dryness to obtain 0.45 g of a brown viscous substance. Elute the product by column chromatography and evaporate to dryness to obtain 0.38 g of a brown oily substance. This is the long-acting local anesthetic compound 12 of this invention, with a yield of 59.64%. 1 H NMR(500MHz,Chloroform-d)δ10.94(s,1H),7.76(d,J=7.6Hz,2H),7.69(s,1H),7.60(dd,J=17.5,7.2Hz ,2H),7.55-7.37(m,3H),7.13-6.92(m,3H),5.77(s,1H),4.66-4.40(m,2H),3.89-3.60(m,3H),3.46-3. 35(m,4H),3.24(s,1H),2.41(s,1H),2.20(s,7H),1.95-1.85(m,2H),1.82-1.64(m,2H),1.53(d,J=7.3H z,3H),1.32-1.06(m,2H),0.94(dt,J=30.0,8.1Hz,3H).(+)-ESI-MS:m / z555.3236(calcd.555.3217for C 35 H 43 N2O4 + [M–Br] + ).

[0108] Experiments were conducted on the local anesthetic effect of the long-acting local anesthetic compound of the present invention:

[0109] Dosage concentrations: The lidocaine group was 2% (70 mM), and the test drugs were the quaternary ammonium salt compound QX-314 and the long-acting local anesthetic compound of the present invention, with concentrations of 10 mM, 30 mM, and 70 mM (corresponding to 0.5%, 1%, and 2% of lidocaine concentrations, respectively). Data are expressed as mean ± SEM; the specific experiments included the following.

[0110] Experiment on the effect of local anesthesia in a mouse sensory blockade model:

[0111] Healthy, qualified ICR mice were used, n=6. Mice were placed in a restraint tube, and the tip of their tail (2 cm) was immersed in a 50°C water bath. Tail-flick latency was measured, and animals with a latency of less than 3 seconds were selected. Two 20 μL injections were administered into the tail. The needle was inserted obliquely inward until the tip touched the tail vertebrae, and then withdrawn 1 mm before injection. Tail-flick latency was measured at 1, 10, 20, 30, 45, 60, 90, and 120 minutes after injection, and hourly after injection, until the end time was determined. The maximum water bath time was 4 seconds per sampling. A tail-flick latency greater than 4 seconds was defined as sensory block. Because mice tend to struggle in the restraint tube, sensory block was defined as the start of two consecutive readings with a tail-flick latency greater than 4 seconds, and similarly, the end of sensory block was defined as two consecutive readings with a tail-flick latency less than 4 seconds.

[0112] Table 1. Sensory blocking effects of the compounds of the present invention in mice.

[0113]

[0114]

[0115] The results are shown in Table 1. Compared with lidocaine, compounds 1, 3, 4, and 5 of this invention exhibited a longer duration of anesthetic effect at a concentration of 70 mM. Compared with QX-314, compounds 1 and 4 exhibited a longer duration of anesthetic effect and a shorter onset time at a concentration of 70 mM.

[0116] Experiment on the effect of local anesthesia in a mouse model of motor blockade:

[0117] Healthy, qualified ICR mice (n=8) were used. The mice were placed in the center of a 20×25 cm inverted net. Before administration, all mice were able to climb the inverted net on all fours. The mice were placed in a restraint tube for injection, administered via a needle into the popliteal fossa of the left hind limb. After injection, the mice were removed from the restraint tube and placed on the inverted net. The time it took for the hind limb to lose its ability to hang on the inverted net after injection was measured at 1, 5, 10, 20, 30, 45, and 60 minutes post-injection, and hourly. Animals were tested on the inverted net for at least 60 minutes. After this period, only mice whose injected hind limbs could not hang on the inverted net were monitored.

[0118] Table 2. Motor blocking effect of the compounds of the present invention in mice.

[0119]

[0120]

[0121] The results are shown in Table 2. Compared with lidocaine, compounds 1-6 had a longer duration of anesthetic effect at a concentration of 70 mM. Compared with QX-314, compounds 1-6 had a longer duration of anesthetic effect at a concentration of 70 mM.

[0122] Experiment on the effect of local anesthesia in a rat sensory blockade model:

[0123] Healthy rats were used, with each rat receiving 0.2 ml of the drug or control injection, injected near the sciatic nerve. Hyperalgesia was assessed using MWTs (Multiple Motion Thromboscopy) and evaluated using a ZH-ZKL dynamic plantar apex analyzer. Rats were placed on a raised platform with a wire mesh bottom, in a six-compartment structure with acrylic baffles. Rats were allowed at least 30 minutes to acclimatize before the experiment. During the test, pressure was applied to the rat's hind paw using a thin metal wire (until the rat exhibited a paw withdrawal response). The withdrawal threshold was automatically recorded (in grams). The process was repeated three times with a 30-second interval between each instance. The rats did not touch the wire mesh during the test.

[0124] Table 3. Sensory blocking effects of the compounds of the present invention in rats.

[0125]

[0126] The results are shown in Table 3. Compared with lidocaine, compounds 1, 3, 4, and 5 had a longer duration of anesthetic effect at a concentration of 70 mM. Compared with QX-314, compounds 1, 4, and 5 had a longer duration of anesthetic effect and a shorter onset time at a concentration of 70 mM.

[0127] Experiment on the effect of local anesthesia in a rat sensorimotor model:

[0128] Healthy, qualified rats were used. Each rat received 0.2 mL of the drug or control injection, injected near the sciatic nerve. Motor function was evaluated using the Extensor Postural Thrust (EPT) test: the rat was lifted vertically and its injected hind limb was placed on an electronic balance. The hind limb muscle strength at this point was represented by the value displayed on the balance. In cases of complete limb paralysis, the reading was the limb's own weight, approximately 20 g. A measurement exceeding half the difference between baseline and limb weight was considered a recovery of motor function; a value less than or equal to this was considered a loss of motor function.

[0129] Table 4. Motor blocking effect of the compounds of the present invention in rats

[0130]

[0131] The results are shown in Table 4. Compared with lidocaine, compounds 1, 3, 4, and 5 had a longer duration of anesthetic effect at a concentration of 70 mM. QX-314 is a quaternary ammonium salt of lidocaine and has a longer local anesthetic effect than lidocaine. However, single concentrations of QX-314 are difficult to cross the cell membrane to exert a local anesthetic effect; only high doses can exert a local anesthetic effect. Compared with QX-314, compounds 1, 4, and 5 had a longer duration of anesthetic effect and a shorter onset time at a concentration of 70 mM. In rat models, at a concentration of 70 mM, compound 1 showed a longer sensory blockade than motor blockade for approximately 92 hours (mean); at a concentration of 70 mM, compound 5 showed a longer sensory blockade than motor blockade for approximately 7 hours (mean). Traditional local anesthetics do not have specific selectivity in blocking nerves. During use, they broadly block multiple nerve fibers, affecting various nerve functions such as sensation, pain, movement, and the sympathetic nervous system. This pharmacological characteristic greatly limits the widespread clinical application of local anesthetics. Since sensory blockade is longer than motor blockade, the compound of the present invention has nerve blockade selectivity, making it an ideal local anesthetic in clinical practice. It minimizes the damage to the patient's motor function caused by local anesthetics and provides a longer duration of sensory blockade against pain, thereby achieving the requirement that sensory blockade is longer than motor blockade.

[0132] The long-acting local anesthetic compound of this invention employs a multimodal analgesia strategy, preferentially using nonsteroidal anti-inflammatory drugs (NSAIDs). By adding a local anesthetic adjuvant, a synergistic combination of the two is achieved, optimizing the drug structure and thus prolonging the effect of local anesthesia. It combines long-acting local anesthetic effects with selective local anesthetic effects, and can be used to prepare drugs with fewer side effects, greater safety, and both long-term and selective local anesthetic effects. In clinical applications, it can effectively relieve patients' intraoperative pain, creating favorable conditions for surgery, and has excellent application prospects.

Claims

1. A long-acting local anesthetic compound, characterized in that, The compound is selected from any of the compounds shown in 1 to 12: 。 2. A method for preparing the long-acting local anesthetic compound according to claim 1, characterized in that, The preparation method includes the following steps: reacting lidocaine or ropivacaine with bromoethanol to generate a quaternary ammonium salt intermediate, and then condensing it with a nonsteroidal anti-inflammatory drug to obtain the final product.

3. The use of the long-acting local anesthetic compound of claim 1 in the preparation of a medicament for local anesthetic.

4. A pharmaceutical composition, characterized in that, It comprises the long-acting local anesthetic compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The use of the pharmaceutical composition of claim 4 in the preparation of a medicament for local anesthetic.

6. The application according to claim 3 or 5, characterized in that, The local anesthetic is a long-acting local anesthetic and / or a selective local anesthetic, with an anesthetic duration exceeding 24 hours.

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