Long-acting local anesthesia compound as well as preparation method, application and pharmaceutical composition thereof

Abstract

The invention discloses a long-acting local anesthesia compound as well as a preparation method, application and a pharmaceutical composition thereof. The long-acting local anesthetic compound is obtained by reacting a local anesthetic with bromoethanol to generate a quaternary ammonium salt intermediate and condensing the quaternary ammonium salt intermediate with a non-steroidal anti-inflammatory drug, and the preparation method is simple and suitable for large-scale production; the prepared long-acting local anesthesia compound is long in lasting time, has anesthesia time exceeding 24 hours, has nerve block selectivity, reduces administration times, increases patient compliance, greatly reduces anesthesia risks, and has great application prospects.

Description

Technical Field

[0001] The invention relates to a long-acting local anesthetic compound, and also relates to a preparation method, application and pharmaceutical composition of the long-acting local anesthetic compound. Background Art

[0002] Local anesthetics (local anesthetics) are a type of drug that can reversibly block the occurrence and transmission of sensory nerve impulses at the site of medication, referred to as "local anesthetics". While maintaining consciousness, it can reversibly cause the disappearance of local tissue pain. Generally, the effect of local anesthetics is limited to the site of administration and disappears rapidly as the drug diffuses from the site of administration. Local anesthetics bind to voltage-gated sodium channels in cells on the nerve membrane to block the influx of sodium ions, thereby blocking the conduction of nerve impulses and ultimately achieving an anesthetic effect. The emergence and development of anesthetic drugs have an extremely important impact on modern medicine. Anesthesia can effectively relieve the pain of patients during surgery and create good conditions for surgery.

[0003] Because traditional local anesthetics are easy to diffuse and free, resulting in a short duration of action, analgesic pumps have to be used to maintain nerve blockade, and catheters are placed in the spinal canal, nerve roots, subcutaneous and other parts, which greatly increases medical costs and the incidence of infection. In addition, 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 who receive spinal anesthesia or nerve block anesthesia usually experience limb paralysis and circulatory fluctuations for several hours after surgery, thereby increasing anesthesia risks and medical expenses. The prior art has improved traditional local anesthetics. For example, after the tertiary amine N atom of lidocaine is ethyl-substituted, a quaternary ammonium salt compound called QX-314 (Figure a) is obtained, with the structural formula: N-diethylaminoacetyl-2,6-dimethylaniline (Strichartz GR.J GenPhysiol.1973Jul;62(1):37-57). QX-314 can enter nerve cells smoothly with the help of capsaicin (transient receptor potential channel vanilloid subtype 1 agonist, i.e. TRPV1Agonist), through the activation of TRPV 1 channel, thus producing long-term nerve blockade; however, the strong irritation of capsaicin makes it difficult to have application prospects. A single small dose of lidocaine quaternary ammonium salt cannot penetrate the cell membrane to exert a local anesthetic effect, and only a large dose can exert its efficacy.

[0004]

[0005] To prolong the duration of analgesia, one method is to use long-acting bupivacaine liposomes, which are expensive and difficult to obtain. Another method 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 their lipid solubility. Usually, increasing the alkyl substituent group increases lipophilicity and has stronger anesthetic efficacy. For example, tetracaine has an additional butyl group on the aromatic ring compared to procaine, which significantly increases its lipid solubility, while its duration and toxicity also increase significantly. The amino group of etidocaine has 3 more carbon atoms than lidocaine, but its lipid solubility increases 50 times, and its anesthetic effect and duration also increase accordingly, to about 4 hours. However, these simple chemical structure modifications still cannot achieve the ideal long-acting local anesthetic effect.

[0007] In order to achieve a better analgesic effect, a multimodal analgesic treatment method has been developed clinically, which mixes local anesthetics with nonsteroidal anti-inflammatory drugs for analgesia after small and medium-sized surgeries as a supplement when local analgesia is insufficient; for example, combined with opioids or tramadol or multimodal analgesia for postoperative analgesia in patients undergoing major surgery. However, the mixture of local anesthetics and nonsteroidal drugs may form precipitation, which may cause phlebitis, thrombosis or adverse reactions at the injection site after local injection, leading to serious consequences; for example, the co-use of lidocaine and lornoxicam can shorten the onset time, improve postoperative analgesia, and prolong the analgesic time, but the mixture of local anesthetics and nonsteroidal anti-inflammatory drugs may precipitate; diclofenac solution is incompatible with a mixture of bupivacaine, levobupivacaine or ropivacaine, and precipitation will occur even in the presence of sodium bicarbonate. Therefore, anesthetic drugs that can specifically inhibit pain without affecting motor nerves and autonomic nerves, and have long duration, good selectivity, and few side effects are urgently needed to be developed. Summary of the invention

[0008] Purpose of the invention: The purpose of the present invention is to provide a long-acting local anesthetic compound with a long anesthetic effect time and nerve block selectivity, and also provide a preparation method, application and pharmaceutical composition of the above-mentioned long-acting local anesthetic compound.

[0009] Technical solution: The present invention discloses a long-acting local anesthetic compound, as shown in Formula I:

[0010]

[0011] Among them, A is NSAIDs are nonsteroidal anti-inflammatory drugs. - It is an anion.

[0012] Wherein, the compound is

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

[0014] Among them, the X -It is a halide ion, sulfate, sulfite, bicarbonate, sulfonate, methanesulfonate or organic acid radical.

[0015] Wherein, the halogen ion is a fluoride ion, a chloride ion, a bromide ion or an iodide ion.

[0016] Wherein, the compound is a lidocaine quaternary ammonium salt derivative.

[0017] Wherein, the compound is selected from any one of the following compounds 1 to 12:

[0018]

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

[0020]

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

[0022] The above-mentioned long-acting local anesthetic compound can also be used in the preparation of local anesthetic drugs.

[0023] The present invention also discloses a pharmaceutical composition, comprising a long-acting local anesthetic compound shown in Formula I or a pharmaceutically acceptable salt or an isomer, solvate, or metabolite thereof, and a pharmaceutically acceptable carrier.

[0024] The above-mentioned pharmaceutical composition can also be used in the preparation of local anesthetic drugs.

[0025] Wherein, the local anesthetic drug contains 10-70 mM of the long-acting local anesthetic compound in a single dose, and more preferably 70 mM.

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

[0027] Principle of the invention: The long-acting local anesthetic compound of the present invention has a long-term local anesthetic effect after a single administration, and the nerve block time is longer than the motor nerve block time. It has both long-acting local anesthetic effect and selective local anesthetic effect, and overcomes the precipitation caused by physical mixing of non-steroidal anti-inflammatory drugs as local anesthetic adjuvants in clinical practice.

[0028] The long-acting local anesthetic compound of the present invention can fully exert the local anesthesia and pain relief effects of local analgesics and local anesthetics through the optimization of drug structure, thereby achieving a synergistic effect. Local analgesics work by reducing the transduction (non-steroidal anti-inflammatory drugs) or transmission (local anesthetics) of noxious signals; local anesthetics block the voltage-gated Na on the nerve cell membrane. + Channels, blocking nerve impulse conduction, thereby producing local anesthetic effects, reversibly causing the disappearance of local tissue pain. Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase activity, thereby reducing prostaglandins, exerting analgesic and anti-inflammatory effects, and have good analgesic effects on acute and chronic pain. Local NSAIDs make the drug action site more concentrated, and local preparations can reduce systemic absorption and adverse reactions after administration. Therefore, the quaternary ammonium salt derivatives of local anesthetics are synthesized with non-steroidal anti-inflammatory drugs and the structure is optimized, making the long-acting local anesthetic compound of the present invention very promising in clinical application.

[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, and the anesthesia time exceeds 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 long-acting local anesthetic compound of the present invention has a nerve block time that is longer than the motor nerve block time, has nerve block selectivity, reduces the number of dosing times, increases patient compliance, greatly reduces the risk of anesthesia, and has great application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0031] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of compound 1;

[0032] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound 2;

[0033] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of compound 3;

[0034] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of compound 4;

[0035] Figure 6 is the H NMR spectrum of compound 5;

[0036] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of compound 6;

[0037] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of compound 7;

[0038] Fig. 9is the hydrogen nuclear magnetic resonance spectrum of compound 8;

[0039] Fig.10 is the H NMR spectrum of compound 9;

[0040] Fig.11 is the carbon NMR spectrum of compound 1;

[0041] Fig.12 is the carbon NMR spectrum of compound 2;

[0042] Fig.13 is the carbon NMR spectrum of compound 3;

[0043] Fig.14 is the carbon NMR spectrum of compound 4;

[0044] Fig.15 is the carbon NMR spectrum of compound 5;

[0045] Fig.16 is the carbon NMR spectrum of compound 6;

[0046] Fig.17 is the carbon NMR spectrum of compound 7;

[0047] Fig.18 is the carbon NMR spectrum of compound 8;

[0048] Fig.19 is the carbon NMR spectrum of compound 9;

[0049] Fig. 20 is the hydrogen nuclear magnetic resonance spectrum of compound 10;

[0050] Fig.21 is the hydrogen nuclear magnetic resonance spectrum of compound 11;

[0051] Fig. 22 is the hydrogen nuclear magnetic resonance spectrum of compound 12;

[0052] Fig.23 Schematic diagram of the local anesthesia experimental results of compound 1, wherein A is the duration of motor block in mice, B is the duration of sensory block in mice, C is the duration of motor block in rats, and D is the duration of sensory block in rats;

[0053] Fig.24 Schematic diagram of the local anesthesia experimental results of compound 4, wherein A is the duration of motor block in mice, B is the duration of sensory block in mice, C is the duration of motor block in rats, and D is the duration of sensory block in rats;

[0054] Fig.25Schematic diagram of the local anesthesia experimental results of compound 5, wherein A is the duration of motor block in mice, B is the duration of sensory block in mice, C is the duration of motor block in rats, and D is the duration of sensory block in rats. DETAILED DESCRIPTION

[0055] The technical scheme of the present invention is further described below in conjunction with the examples. The test materials used in the examples can all be purchased through conventional channels.

[0056] Example 1

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

[0058]

[0059] 2.35 g of API a and 2.5 g of bromoethanol were added to a 100 mL round-bottom flask, stirred at 100 ° C, and left for about 15 hours to become brown and viscous. After adding EA and stirring, a large amount of solids precipitated. After stirring for 1 hour, filter, wash with EA while filtering, and dry to obtain 2.37 g of light pink powder intermediate 1a, which was used for the next step of Example 1-9. Yield: 65.83%. 1 HNMR (500MHz, Methanol-d 4 )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,6 H),3.37(s,1H),2.27(s,6H),1.44(t,6H).(+)-ESI-MS:m / z279.2070(calcd.279.2067for C 16 H 27 N 2 O 2 + [M–Br] + ).

[0060]

[0061] In a 100mL round-bottom flask, add 0.36g (1mmol, 1.0eq) of intermediate 1a, 0.21g (1mmol, 1.0eq) of 1b, 13mg (0.1mmol, 0.1eq) of DMAP, 15mL of dichloromethane, stir, add 0.23g (1.2mmol, 1.2eq) of EDCI and react at room temperature for 7h. Treat with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. The extract is dried over anhydrous sodium sulfate and spin-dried to obtain 0.56g of a transparent oil. The product is eluted with (DCM: MeOH = 15: 1) and spin-dried to obtain 0.47g of a milky white product 1, which is the long-acting local anesthetic compound 1 of the present 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 N 2 O 3 + [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 100mL round-bottom flask, 0.36g (1mmol, 1.0eq) of intermediate 1a, 0.3g (1mmol, 1.0eq) of 2b, 13mg (0.1mmol, 0.1eq) of DMAP, 15mL of dichloromethane were added, and after stirring, 0.23g (1.2mmol, 1.2eq) of EDCI was added and reacted at room temperature for 5h. It was treated with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. The extract was dried over anhydrous sodium sulfate and dried to obtain 0.43g of a light yellow-brown transparent oil. The impurities were removed by elution with (DCM:MeOH=40:1), and the product was eluted with (DCM:MeOH=15:1) to obtain 0.2g of a white solid product 2, which is the long-acting local anesthetic compound 2 of the present 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 Cl 2 N 3 O 3 + [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 100mL round-bottom flask, 0.36g (1mmol, 1.0eq) of 1a, 0.24g (1mmol, 1.0eq) of 3b, 10mg (0.1mmol, 0.1eq) of DMAP, 20mL of dichloromethane were added, and after stirring, 0.23g (1.2mmol, 1.2eq) of EDCI was added and reacted at room temperature for 1h. It was treated with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. The extract was dried over anhydrous sodium sulfate and spin-dried. The impurities were removed by elution with (DCM:MeOH=40:1), and the product was eluted with (DCM:MeOH=15:1) to obtain 0.3g of product 3, which is the long-acting local anesthetic compound 3 of the present invention. Yield: 51.11%. 1H 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 FN 2 O 3 + [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. Then, saturated NaHCO 3, washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.81 g of a light brown transparent oil. Purified by elution with a chromatographic column (DCM:MeOH=30:1), 0.4 g of a transparent oily product 4 was obtained, which is the long-acting local anesthetic compound 4 of the present invention. Yield: 46.51%. 1 H 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 N 2 O 4 + [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 mg (0.18 mmol, 1.2 eq) of EDCI was added and the mixture was reacted at room temperature for 2 h. Then, saturated NaHCO 3 , washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.66 g of a light brown transparent oil. Purified by elution with a chromatographic column (DCM:MeOH=25:1), 0.31 g of a transparent oily product 5 was obtained, which is the long-acting local anesthetic compound 5 of the present 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 N 2 O 4 + [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 mg (0.18 mmol, 1.2 eq) of EDCI was added and the mixture was reacted at room temperature for 1 h. Then, saturated NaHCO 3 , washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.68 g of a light yellow solid. Eluted through a chromatographic column (DCM:MeOH=30:1) to obtain 0.3 g of a light yellow solid product 6, which is the long-acting local anesthetic compound 6 of the present 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 C1N 3 O 5 + [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, 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 were added. After stirring, 0.23 mg (0.18 mmol, 1.2 eq) of EDCI was added and the mixture was reacted at room temperature for 1 h. Then, saturated NaHCO 3 , washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.28 g of a light yellow solid. Elute through a chromatographic column (DCM: MeOH = 30: 1). Then elute the product with (DCM: MeOH = 15: 1) to obtain 0.09 g of a transparent oily product 7, which is the long-acting local anesthetic compound 7 of the present 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 N 2 O 5 + [M–Br] + ).

[0086] Example 8

[0087] (Z)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-(2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetoxy)ethyl)-2-oxoethan-1-aminium (Compound 8) Preparation:

[0088]

[0089] 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 mg (0.18 mmol, 1.2 eq) of EDCI was added and the mixture was reacted at room temperature for 1 h. Then, saturated NaHCO 3 , washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.73 g of a yellow solid. Eluted by a chromatographic column (DCM:MeOH=30:1) to obtain 0.54 g of a yellow solid product 8, which is the long-acting local anesthetic compound 8 of the present 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 (126 MHz, DMSO-d 6 )δ169.91,162.35,162.07,147.25,147.17,146.92,140.65,139.14,138.87,135. 43,134.06,131.79,131.77,130.60,130.39,129.80,129.78,128.33,127.51,124 .45,123.76,123.69,111.19,111.01,106.75,106.56,58.60,57.44,57.05,56.02 ,43.63,31.07,18.68,10.78,8.13.(+)-ESI-MS:m / z617.2841(calcd.617.2844for C 36 H 42 FN 2 O 4 S + [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 (0.18 mmol, 1.2 eq) of EDCI was added and the mixture was reacted at room temperature for 1 h. Then, saturated NaHCO 3 , washed with 1 mol / L HCl, then washed with water and saturated brine, dried over anhydrous sodium sulfate and then spin-dried to obtain 0.69 g of a white solid. Eluted by a chromatographic column (DCM:MeOH=20:1) to obtain 0.65 g of a yellowish-white solid product 9, which is the long-acting local anesthetic compound 9 of the present 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, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.28 (s, 1H) dichloromethane peak, 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). 13 C NMR (126 MHz, DMSO-d 6)δ171.45,167.70,162.34,143.38,137.62,135.45,134.00,131.38,131.30,129.65,128.38,128.34,127.54,1 26.52,123.27,121.21,116.53,61.51,58.79,58.74,57.23,57.09,56.02,36.96,18.63,8.15.(+)-ESI-MS:m / z 614.2171(calcd.614.2183forC 32 H 38 Cl 2 N 3 O 5 + [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] Add 0.42g of the raw material drug c (1.5mmol, 1.0eq) and 0.46g of bromoethanol (3.75mmol, 2.5eq) to a 100mL conical flask, heat to reflux at 120 degrees, and track the reaction with thin layer chromatography. After seven hours, the ropivacaine reaction is complete, and after spin drying (removing excess bromoethanol), 0.6g of black viscous substance is obtained. The product is eluted through a chromatographic column, first eluted with (PE:EA=1:5), then eluted with (DCM:MeOH=1:1), and spin dried to obtain 0.3g of 1c, a brown solid intermediate. Used in the next step of Example 10-12. Yield: 49.17%.

[0098]

[0099] In a 100mL round-bottom flask, 0.4g of intermediate 1c (1mmol, 1.0eq), 0.165g (0.8mmol, 0.8eq) of 1b, 13mg (0.01mmol, 0.1eq) of DMAP, 15mL of dichloromethane were added, and 0.23mg (1.2mmol, 1.2eq) of EDCI was added after stirring. After reacting at room temperature for 4 hours, the plate was tapped, and the raw materials were basically reacted. It was treated with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. The extract was dried over anhydrous sodium sulfate and dried by rotation to obtain a transparent oily substance 0.38g of brown viscous product. The product was eluted by column chromatography, first with (PE:EA=1:1) and then with (DCM:MeOH=5:1) solvents, and 0.38g of yellow-brown viscous product was dried by rotation to obtain the long-acting local anesthetic compound 10 of the present 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 N 2 O 3 + [M–Br] + ).

[0100] Embodiment 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 100mL round-bottom flask, 0.4g of intermediate 1c (1mmol, 1.0eq) and 0.21g (1mmol, 0.9eq) of 4b, 13mg (0.1mmol, 0.1eq) of DMAP, 15mL of dichloromethane were added, and 0.23g (1.2mmol, 1.2eq) of EDCI was added after stirring. After reacting at room temperature for 7 hours, the plate was tapped and the reaction was complete. It was treated with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. It was dried with a small amount of anhydrous sodium sulfate and dried to obtain 0.4g of a brown viscous substance. The product was eluted through a column and dried to obtain 0.32g of a brown solid, which was the long-acting local anesthetic compound 11 of the present 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 N 2 O 4 + [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 100mL round-bottom flask, 0.4g of intermediate 1c (1mmol, 1.0eq), 0.23g (0.9mmol, 0.9eq) of 5b, 13mg (0.1mmol, 0.1eq) of DMAP, 15mL of dichloromethane were added, and after stirring, 0.23g (1.2mmol, 1.2eq) of EDCI was added, and the mixture was reacted at room temperature for 5 hours. It was treated with saturated sodium bicarbonate, 1mol / L hydrochloric acid, water, and saturated saline in sequence. It was dried with a small amount of anhydrous sodium sulfate and dried to obtain 0.45g of a brown viscous substance. The product was eluted through a column and dried to obtain 0.38g of a brown oily substance. This is the long-acting local anesthetic compound 12 of the present 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 N 2 O 4 + [M–Br] + ).

[0108] The local anesthetic effect experiment was conducted on the long-acting local anesthetic compound of the present invention:

[0109] Dosing concentration: lidocaine group concentration 2% (70mM), the drugs to be tested are quaternary ammonium compound QX-314 and the long-acting local anesthetic compound of the present invention, the concentrations are 10mM, 30mM, 70mM (corresponding to 0.5%, 1%, 2% concentrations of lidocaine, respectively), the data are expressed as means±SEM; specifically including the following experiments.

[0110] Experiment on the effect of local anesthesia on the mouse sensory block model:

[0111] Healthy qualified ICR mice were taken, n=6. The mice were placed in a restraint tube and the tip of their tail 2 cm was immersed in a 50°C water bath. The tail-flick latency was measured and animals with a latency of less than 3 s were selected. The injection needle was injected twice with 20 μL at the tail. The needle was inserted obliquely inward until the tip of the needle touched the coccygeal vertebrae and then withdrawn 1 mm before injection. The tail-flick latency was measured at 1, 10, 20, 30, 45, 60, 90 and 120 minutes after injection and every hour after injection until the end time was determined. At each sampling, the hot water bath time was a maximum of 4 s, and a tail-flick latency greater than 4 s was defined as sensory blockade. Because mice tend to struggle in the restraint tube, the beginning of sensory blockade was two consecutive readings with a tail-flick latency greater than 4 s, and similarly, the end of sensory blockade was two consecutive readings with a tail-flick latency less than 4 s.

[0112] Table 1. Sensory blocking effect of the compounds of the present invention on mice

[0113]

[0114]

[0115] The results are shown in Table 1. Compared with lidocaine, at a concentration of 70 mM, the anesthetic effects of compounds 1, 3, 4, and 5 of the present invention last longer. Compared with QX-314, at a concentration of 70 mM, the anesthetic effects of compounds 1 and 4 last longer and have a shorter onset time.

[0116] Experiment on the effect of local anesthesia on the mouse motor block model:

[0117] Healthy and qualified ICR mice were taken, n=8. The mice were placed in the middle of a 20×25 cm inverted net. Before administration, all mice were able to climb up the inverted net on all fours. The mice were placed in a restraint tube for injection, and the injection needle was used to inject in the popliteal region of the left hind limb. After the injection, the mice were removed from the restraint tube and placed on the inverted net. The time after the injection when the hind limbs lost the ability to hang on the inverted net was measured, and the test was performed at 1, 5, 10, 20, 30, 45 and 60 minutes after the injection and every hour after the injection. The animals were tested on the inverted net for at least 60 minutes. After this, only the mice whose injected hind limbs could not hang on the inverted net were monitored.

[0118] Table 2. Effect of the compounds of the present invention on the movement blockade of mice

[0119]

[0120]

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

[0122] Experiment on the effect of local anesthesia on the rat sensory block model:

[0123] Healthy and qualified rats were taken, and the injection volume for each rat was 0.2ml, which was injected near the sciatic nerve of the rat. Allodynia was determined by MWTs and evaluated using the ZH-ZKL dynamic plantar analyzer. The rats were placed on an elevated platform with a wire mesh at the bottom, and 6 compartments were made with acrylic plate baffles. The rats had to adapt for at least 30 minutes before the experiment. During the test, a metal wire was used to apply pressure to the rat's hind feet (until the mouse showed a paw retraction reaction), and the paw retraction threshold was automatically recorded (in g). The process was repeated three times with a 30s interval in between. The wire mesh was not touched during the test.

[0124] Table 3. Sensory blocking effect of the compounds of the present invention on rats

[0125]

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

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

[0128] Healthy and qualified rats were taken, and the injection volume for each rat was 0.2mL, which was injected near the sciatic nerve of the rat. The motor function of the rat was evaluated by the hind limb pedaling test (Extensor Postural Thrust, EPT): the rat was lifted vertically and the hind limb of the injected side was stepped on the electronic platform surface. At this time, the hind limb muscle strength of the rat was represented by the value displayed by the limb pedaling balance. When the limb is completely paralyzed, the reading is the weight of the limb itself, about 20g. The measured value exceeding half of the difference between the baseline and the limb weight is considered to have recovered the motor function, and less than or equal to this value is considered to have disappeared the motor function.

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

[0130]

[0131] The results are shown in Table 4. Compared with lidocaine, the anesthetic effect of compounds 1, 3, 4, and 5 lasts longer at a concentration of 70 mM. QX-314 is a quaternary ammonium salt of lidocaine, which has a longer local anesthetic effect than lidocaine, but a single concentration of QX-314 is difficult to exert a local anesthetic effect through the cell membrane, and a large dose can exert a local anesthetic effect. Compared with QX-314, at a concentration of 70 mM, the anesthetic effect of compounds 1, 4, and 5 lasts longer and has a shorter onset time. In the rat model, at a concentration of 70 mM, the sensory block of compound 1 is longer than the motor block for about 92 h (mean); at a concentration of 70 mM, the sensory block of compound 5 is longer than the motor block for about 7 h (mean). Traditional local anesthetics do not have specific selectivity for nerve blockade. During use, they widely block a variety of nerve fibers, affecting various nerve functions such as sensation, pain, movement, and sympathetic nerves. This pharmacological characteristic greatly limits the widespread application of local anesthetics in clinical practice. Since sensory blockade is longer than motor blockade, the compounds of the present invention have nerve block selectivity and are ideal local anesthetics in clinical practice. They can minimize the damage to patients' motor function caused by local anesthetics and provide a longer sensory blockade of pain, thereby meeting the requirement that sensory blockade is longer than motor blockade.

[0132] The long-acting local anesthetic compound of the present invention adopts a multimodal analgesic strategy, preferably non-steroidal anti-inflammatory drugs, and achieves a synergistic combination of the two by adding local anesthetic adjuvants, optimizing the drug structure to prolong the effect of local anesthesia, and has both long-acting local anesthetic effects and selective local anesthetic effects. It can be used to prepare drugs with fewer side effects, greater safety, and long-term local anesthesia and selective local anesthetic effects. In clinical applications, it can effectively relieve patients' pain during surgery, create good conditions for surgery, and has excellent application prospects.

Claims

1. A long-acting local anesthetic compound, It is characterized in that The compound is shown in Formula I: Among them, A is NSAIDs are nonsteroidal anti-inflammatory drugs. - It is an anion.

2. The compound according to claim 1, It is characterized in that The non-steroidal anti-inflammatory drug is a COX inhibitor, which is aspirin, ibuprofen, naproxen, flurbiprofen, diclofenac, ketoprofen, indomethacin or sulindac.

3. The compound according to claim 1, It is characterized in that The X - It is a halide ion, sulfate, sulfite, bicarbonate, sulfonate, methanesulfonate or organic acid radical.

4. The compound according to claim 1, It is characterized in that The compound is selected from any one of the compounds shown in 1 to 12:

5. A method for preparing the long-acting local anesthetic compound according to claim 1, It is characterized in that The preparation method comprises 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 to obtain the quaternary ammonium salt intermediate.

6. The method according to claim 5, It is characterized in that The local anesthetic is procaine, lidocaine, ropivacaine, etidocaine or bupivacaine.

7. Use of the long-acting local anesthetic compound according to claim 1 in the preparation of a local anesthetic drug.

8. A pharmaceutical composition, It is characterized in that It comprises a long-acting local anesthetic compound represented by formula I in claim 1 or a pharmaceutically acceptable salt or an isomer, solvate, or metabolite thereof, and a pharmaceutically acceptable carrier.

9. Use of the pharmaceutical composition according to claim 8 in the preparation of local anesthetic drugs.

10. The use according to claim 7 or 9, It is characterized in that The local anesthetic drug is a long-acting local anesthetic and / or a selective local anesthetic, and the anesthesia time exceeds 24 hours.

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