Polyethylene glycolated ropivacaine derivatives and uses thereof

Abstract

The present application provides a kind of polyglycolated ropivacaine derivative, with the structure of PEG-D p The PEG polyglycolated ropivacaine derivative described is significantly longer in analgesic duration compared to ropivacaine hydrochloride, and the analgesic effect of the double-end polyglycolated ropivacaine derivative is better than that of the four-arm or eight-arm polyglycolated ropivacaine derivative.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a polyethylene glycol-modified ropivacaine derivative and its application in analgesia or pain treatment. Background Technology

[0002] Ropivacaine is a long-acting amide-type local anesthetic with an onset time of approximately 10 minutes and a duration of action of 4-5 hours. It blocks sensory nerve fibers more effectively than motor nerve fibers, producing a dissociative blockade of sensory and motor nerves at low concentrations. This means ropivacaine primarily blocks sensory nerves to produce effective analgesia, with minimal or no effect on motor nerves, allowing patients to resume limb movement immediately post-surgery. Ropivacaine is less toxic than bupivacaine, with lower potential toxicity to the central nervous system and cardiovascular system, and is well-tolerated, making it a relatively safe local anesthetic.

[0003] Patents CN110960685A, CN106310289A, and CN107789628A disclose conjugates of polyethylene glycol (PEG) and local anesthetics. However, these patents all focus on studies of lidocaine or bupivacaine conjugates with PEG, comparing the analgesic intensity and duration of analgesia between four-armed and eight-armed PEG conjugates. No reports have been made on ropivacaine PEG conjugates and their effects. Summary of the Invention

[0004] This invention provides a polyethylene glycol-modified ropivacaine derivative having PEG-D p The structure;

[0005] Where D is:

[0006] PEG is a polyethylene glycol residue that contains at least (n is the number of repeating groups), and the molecular weight of the polyethylene glycol residues is 200 Da-100 KDa;

[0007] p is selected from an integer from 1 to 10, preferably 2, 3, 4, 6 or 8, and more preferably 2;

[0008] X - Selected from: F - Cl - ,Br - I - Methanesulfonate, ethylsulfonate, benzenesulfonate, citrate, lactate, succinate, fumarate, glutamate, citrate, salicylate, and maleate; preferably, X - Selected from: F - Cl - ,Br -I - Methanesulfonate, ethylsulfonate, and benzenesulfonate; most preferably, X - Selected from: F - Cl - ,Br - I - ;

[0009] R1 is selected from H or C. 1-6 Alkyl, preferably H, methyl, ethyl or propyl;

[0010] R2 is -O(C=O)(CH2) i CH3, i is selected from an integer from 0 to 6, preferably 1, 2 or 3, and preferably acetoxy, propionyloxy or butyryloxy; most preferably, R2 is acetoxy;

[0011] R3 is independently selected from H, -O (C=O) (CH2). i CH3 and C 1-6 Alkyl group, i is selected from integers from 0 to 6, preferably 1, 2 or 3, preferably H, methyl, ethyl, propyl, acetoxy, propionyloxy or butyryloxy; most preferably, R3 is H;

[0012] m is selected from an integer from 1 to 6, preferably 1, 2 or 3, and more preferably 1.

[0013] The PEG described in this invention can be a straight-chain, dual-terminal, Y-type, or multi-branched polyethylene glycol residue, including dual-terminal PEG, 4-arm PEG, 6-arm PEG, or 8-arm PEG, etc. The molecular weight of the PEG is between 200 Da and 100 KDa, for example, 1 KDa-10 KDa (specifically 1 KDa, 2 KDa, 3 KDa, 4 KDa, 5 KDa, 6 KDa, 7 KDa, 8 KDa, 9 KDa, or 10 KDa), 10 KDa-50 KDa (specifically 10 KDa, 15 KDa, 20 KDa, 25 KDa, 30 KDa, 35 KDa, 40 KDa), etc. The molecular weight of PEG is 45 kDa or 50 kDa or 50 kDa-100 kDa (specifically, it can be 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80, 85 kDa, 90 kDa, 95 kDa or 100 kDa), etc.; preferably, the molecular weight of PEG is 10 kDa-50 kDa, most preferably 10 kDa-40 kDa, such as between 10 kDa-20 kDa, between 20 kDa-25 kDa, between 25 kDa-30 kDa, between 30 kDa-35 kDa or between 35 kDa-40 kDa.

[0014] Furthermore, the PEG is composed of two-terminated polyethylene glycol residues and has the following structure:

[0015]

[0016] l is an integer from 2 to 1000, for example, l is an integer from 2 to 500, an integer from 2 to 250, an integer from 2 to 125, or an integer from 2 to 50; the double-ended polyethylene glycol residues can also be polyethylene glycol residues with a single molecular weight, for example, l is an integer from 10 to 30, including 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0017] Furthermore, when the PEG is a multi-branched polyethylene glycol, the conjugate has the following structure:

[0018]

[0019]

[0020] Wherein, w, q, s, u, v, x, and y are independently selected from integers of 2-500, for example, integers of 2-250, integers of 2-125, and integers of 2-50; the multi-branched polyethylene glycol may also be polyethylene glycol residues with a single molecular weight, for example, w, q, s, u, v, x, and y are independently selected from integers of 10-30, including 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0021] In a specific embodiment of the present invention, the polyethylene glycol-modified ropivacaine derivative is selected from the following compounds:

[0022]

[0023]

[0024] Surprisingly, among the polyethylene glycol-modified ropivacaine derivatives described in this invention, the bi-terminated polyethylene glycol-modified ropivacaine derivatives exhibit better analgesic effects than the tetra- or octa-terminated polyethylene glycol-modified ropivacaine derivatives.

[0025] therefore, This is a preferred compound of the present invention. The molecular weight of the polyethylene glycol residues in the preferred compound can be 1kDa-10kDa, and more preferably 2kDa-5kDa.

[0026] The present invention also provides a method for preparing a polyethylene glycol-modified ropivacaine derivative, comprising: reacting an M1 compound with ropivacaine to form a ropivacaine quaternary ammonium salt derivative; and reacting the ropivacaine quaternary ammonium salt derivative with PEG whose terminal group is modified with an azide group.

[0027]

[0028] Furthermore, the reaction between the ropivacaine quaternary ammonium salt derivative and PEG with azido-terminated groups includes: placing the ropivacaine quaternary ammonium salt derivative, PEG with azido-terminated groups, and ascorbic acid in a solvent, and adding an aqueous solution of copper sulfate pentahydrate dropwise to carry out the reaction.

[0029] Furthermore, after reacting the ropivacaine quaternary ammonium salt derivative with PEG whose terminal group is modified with an azide group, an aqueous solution of ammonium chloride and ethyl acetate are added to the reaction solution, the mixture is separated, the aqueous phase is extracted with ethyl acetate and / or dichloromethane, the organic phases are combined and dried.

[0030] The present invention also provides a pharmaceutical composition comprising the aforementioned polyethylene glycolated ropivacaine derivative and a pharmaceutically acceptable carrier or excipient.

[0031] Depending on the desired route of administration, the pharmaceutical composition will comprise about 1 to 99% by weight of the above-described conjugate and 99 to 1% by weight of a suitable carrier or pharmaceutical excipient. Preferably, the composition comprises about 5 to 75% by weight of the above-described conjugate, with the remainder being a suitable carrier or pharmaceutical excipient. More preferably, the composition comprises about 10 to 50% by weight of the above-described conjugate, with the remainder being a suitable carrier or pharmaceutical excipient.

[0032] The present invention also provides a method for relieving or treating pain, the method comprising administering to a patient the polyethylene glycol-modified ropivacaine derivative or the pharmaceutical composition thereof.

[0033] The present invention also provides the use of the PEGylated ropivacaine derivative or the pharmaceutical composition thereof in the preparation of medicaments for analgesia or treatment of pain.

[0034] Furthermore, the pain described includes acute pain, chronic pain, neuropathic pain, psychogenic pain, heat-induced pain, physical pain, pain during or after surgery, general nociception, or hyperalgesia. For example, pain may be selected from neuropathic pain, inflammatory pain, nociceptive pain, rheumatic pain, headache, lower back pain, pelvic pain, myofascial pain, vascular pain, migraine, trauma-related pain, inflammatory pain, arthritis pain, diabetic pain, cancer-related pain, or visceral pain, etc.

[0035] The present invention also provides the use of the PEGylated ropivacaine derivative or the pharmaceutical composition thereof in the preparation of a non-anesthetic analgesic.

[0036] The PEG-modified ropivacaine derivatives of this invention have a significantly longer analgesic duration compared to ropivacaine hydrochloride. In particular, the analgesic effect of the bi-terminated PEG-modified ropivacaine derivatives is superior to that of the tetra- or octa-terminated PEG-modified ropivacaine derivatives. Attached Figure Description

[0037] Figure 1 Compound T4-9R 1 H NMR spectrum;

[0038] Figure 2 Compound 8A4R 1 H NMR spectrum;

[0039] Figure 3 Compound 4A4R-20K 1 H NMR spectrum;

[0040] Figure 4 The compound is 4A4R-10K 1 H NMR spectrum;

[0041] Figure 5 Compound 4A4R-5K 1 H NMR spectrum;

[0042] Figure 6 The compound is 2A4R-5K 1 H NMR spectrum;

[0043] Figure 7 The compound is 2A4R-2K 1 H NMR spectrum;

[0044] Figure 8 Compound 2A4R-PEG24 1 H NMR spectrum;

[0045] Figure 9 Compound 2A4R-PEG24 1 H NMR spectrum. Detailed Implementation

[0046] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0047] The polyethylene glycol used in the examples was provided by Beijing Jiankai Technology Co., Ltd., and the others were commercially available reagents.

[0048] Example 1: Synthesis of compound T4-9R

[0049]

[0050] STEP 1:

[0051] In a three-necked flask, 66.5 g of NaH (1.67 mol, 2.3 eq) and 500 ml of a mixed solvent (DMSO:THF = 1:1) were added. Under nitrogen protection, the mixture was cooled to approximately 0°C in an ice-salt bath. T4-1 (100 g, 0.724 mol, 1 eq) (dissolved in 300 ml of the mixed solvent) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 2 hours. The mixture was then cooled again to 0°C in an ice-water bath. Propylene bromide (103.5 g, 0.87 mol, 1.2 eq) was added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and stirred overnight. For post-treatment, the reaction solution was poured into ice water, and the pH was adjusted to 3-5 with 4N hydrochloric acid aqueous solution. The solution was extracted three times with ethyl acetate (600 ml × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a gray solid crude product. This crude product was recrystallized from dichloromethane and dried to give 70 g of compound 1, with a yield of 55%.

[0052] STEP 2:

[0053] Compound 1 (66 g, 0.375 mol, 1 eq) was dissolved in 900 mL of dichloromethane. Triethylamine (114 g, 1.125 mol, 3 eq) was rapidly added dropwise under ice bath conditions. After the addition was complete, acetyl chloride (47 g, 0.6 mol, 1.6 eq) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred overnight. After the reaction was complete, the mixture was poured into ice water, and the pH was adjusted to approximately 3-5 with 4N hydrochloric acid aqueous solution while stirring. The dichloro phase was separated, and the aqueous phase was extracted twice with dichloromethane (250 mL × 2). The dichloro phases were combined and washed twice with water (500 mL × 2). The mixture was dried over anhydrous sodium sulfate and concentrated to give 88 g of crude compound 2.

[0054] STEP 3:

[0055] Compound 2 (85.0 g, 0.39 mol, 1 eq) was dissolved in 1.2 L THF and cooled in an ice-water bath. Sodium borohydride (18 g, 0.468 mol, 1.2 eq) was added in batches, and the mixture was stirred at 0°C for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into ice water, and the pH was adjusted to 3–5 with 4N hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 65 g of compound 3. The crude product yield was 75.8%.

[0056] STEP 4:

[0057] Compound 3 (50.0 g, 0.227 mol, 1 eq) was dissolved in 600 mL of dichloromethane. The solution was cooled in an ice-salt bath under nitrogen protection, and phosphorus tribromide (0.36 mol, 1.6 eq) was added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 2-3 hours, and the reaction was monitored by TLC until completion. For post-processing, the reaction solution was added to the stirred ice-water bath, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The dichloro phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to obtain 43 g of compound 4, with a yield of 67%.

[0058] STEP 5:

[0059] Ropivacaine (38.7 g, 0.134 mol, 1.0 eq) and compound 4 (38 g, 0.134 mol, 1.0 eq) were added to a 1 L single-necked flask, followed by the addition of 400 mL of acetonitrile. The mixture was heated to 45°C and stirred overnight. The mixture was monitored by TLC. The acetonitrile was evaporated to dryness, recrystallized from ethyl acetate, and dried to give 68 g of a white solid, T4-9R, in 88.8% yield.

[0060] MS m / z(ESI): 477.3 [M];

[0061] 1 H NMR (300MHz, DMSO-d) 6 ): δ10.35(s,1H),7.42(s,1H),7.32-7.26(m,2H),7.23-7.14(m,3H),5.25-5.20(m,1H),5.05-5.01(m,1H),4.93(s,2H),4.76-4.72(m,1 H),3.70-3.68(m,1H),3.65(s,1H),3.33-3.24(m,2H),2.42-2.21(m,13H),2.08-1.91(m,3H),1.80-1.75(m,2H),0.91(t,3H,J=7.2Hz).

[0062] NMR spectrum as follows Figure 1 As shown.

[0063] Example 2: Synthesis of compound 8A4R

[0064]

[0065] 8AR-PEG20K-N3 (30 g, 1.5 mmol), compound T4-9 (10.3 g, 18 mmol), and ascorbic acid (6.3 g, 36 mmol) were added to dimethyl sulfoxide (300 mL), stirred until homogeneous, and then an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (100 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 28.6 g of an off-white solid 8A4R, yield 78%.

[0066] 1 H NMR (300MHz, DMSO-d) 6 ): δ11.06(s,8H),8.17(s,8H),7.60(s,8H),7.24-7.18(m,16H),7.18-7.13(m,24H),5.2 9-5.20(m,20H),5.02-4.75(m,16H),4.57-4.53(m,16H),3.85-3.83(m,16H),3.81-3.76 (m,16H),3.74-3.49(m,1800H),3.39-3.27(m,24H),2.51-2.31(m,16H),2.26-2.19(m,7 2H), 2.18-2.01 (m, 8H), 2.00-1.85 (m, 16H), 1.84-1.62 (m, 16H), 0.90 (t, 24H, J = 7.2Hz).

[0067] NMR spectrum as follows Figure 2 As shown.

[0068] Example 3: Synthesis of compound 4A4R-20K

[0069]

[0070] 4AR-PEG20K-N3 (30 g, 1.5 mmol), compound T4-9 (5.2 g, 9 mmol), and ascorbic acid (63.2 g, 18 mmol) were added to dimethyl sulfoxide (200 mL), stirred until homogeneous, and then an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (100 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 30.0 g of a white solid, 4A4R-20K, in 81% yield.

[0071] 1 H NMR (300MHz, DMSO-d) 6 ): δ10.70(s,4H),8.13(s,4H),7.60(s,4H),7.24-7.18(m,8H),7.18-7.13(m,12H),5.28-5 .24(m,10H),5.05-4.97(m,4H),4.85-4.76(m,4H),4.56-4.53(m,8H),3.84-3.82(m,8H),3 .81-3.74(m,8H),3.63-3.40(m,1800H),3.38-3.27(m,12H),2.52-2.50(m,8H),2.30-2.19 (m,36H),2.18-2.01(m,4H),1.98-1.85(m,8H),1.84-1.62(m,8H),0.90(t,12H,J=7.2Hz).

[0072] NMR spectrum as follows Figure 3 As shown.

[0073] Example 4: Synthesis of compound 4A4R-10K

[0074]

[0075] 4AR-PEG10K-N3 (15 g, 1.5 mmol), compound T4-9 (5.2 g, 9 mmol), and ascorbic acid (63.2 g, 18 mmol) were added to dimethyl sulfoxide (200 mL), stirred until homogeneous, and then an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (100 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 14.6 g of a white solid, 4A4R-10K, in 80% yield.

[0076] 1 H NMR (300MHz, DMSO-d) 6 ): δ10.60(s,4H),8.16(s,4H),7.60(s,4H),7.24-7.20(m,8H),7.18-7.14(m,12H),5.27- 5.25(m,10H),5.19-5.00(m,4H),4.86-4.78(m,4H),4.56-4.53(m,8H),3.84-3.82(m,8H), 3.81-3.73(m,8H),3.57-3.42(m,900H),3.35-3.27(m,50H),2.52-2.51(m,8H),2.26-2.22 (m,36H),2.18-2.01(m,4H),1.98-1.85(m,8H),1.84-1.62(m,8H),0.90(t,12H,J=7.2Hz).

[0077] NMR spectrum as follows Figure 4 As shown.

[0078] Example 5: Synthesis of compound 4A4R-5K

[0079]

[0080] 4AR-PEG5K-N3 (7.5 g, 1.5 mmol), compound T4-9 (5.2 g, 9 mmol), and ascorbic acid (63.2 g, 18 mmol) were added to dimethyl sulfoxide (100 mL), stirred until homogeneous, and then an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (100 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 7.0 g of an off-white solid 4A4R-5K (78% yield).

[0081] 1 H NMR (300MHz, DMSO-d) 6 ): δ10.60(s,4H),8.13(s,4H),7.60(s,4H),7.27-7.23(m,8H),7.18-7.14(m,12H),5 .27-5.25(m,10H),5.06-5.93(m,4H),4.75-4.68(m,4H),4.56-4.53(m,8H),3.84-3.8 2(m,8H),3.81-3.73(m,8H),3.57-3.42(m,450H),3.35-3.27(m,8H),2.52-2.51(m,8H ),2.26-2.22(m,36H),2.12-1.85(m,12H),1.80-1.62(m,8H),0.90(t,12H,J=6.9Hz).

[0082] NMR spectrum as follows Figure 5 As shown.

[0083] Example 6 Synthesis of compound 2A4R-5K

[0084]

[0085] 2AR-PEG5K-N3 (7.5 g, 1.5 mmol), compound T4-9 (2.6 g, 4.5 mmol), and ascorbic acid (31.6 g, 9 mmol) were added to dimethyl sulfoxide (100 mL), stirred until homogeneous, and an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (100 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 7.8 g of a white solid 2A4R-5K (83% yield).

[0086] 1 H NMR (300MHz, DMSO-d) 6 ): δ10.60(s,2H),8.13(s,2H),7.60(s,2H),7.27-7.23(m,4H),7.18-7.14(m,6H),5 .27-5.25(m,5H),5.06-5.93(m,2H),4.75-4.68(m,2H),4.56-4.53(m,4H),3.84-3.8 2(m,4H),3.81-3.73(m,4H),3.57-3.42(m,450H),3.35-3.27(m,4H),2.52-2.51(m,4 H),2.26-2.22(m,18H),2.12-1.85(m,6H),1.80-1.62(m,4H),0.90(t,6H,J=6.9Hz).

[0087] NMR spectrum as follows Figure 6 As shown.

[0088] Example 7 Synthesis of compound 2A4R-2K

[0089]

[0090] 2AR-PEG2K-N3 (3.0 g, 1.5 mmol), compound T4-9 (2.6 g, 4.5 mmol), and ascorbic acid (31.6 g, 9 mmol) were added to dimethyl sulfoxide (30 mL), stirred until homogeneous, and an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (30 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once more with ethyl acetate and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 2.8 g of a white solid 2A4R-2K (85% yield).

[0091] 1 H NMR (300MHz, DMSO-d) 6): δ10.60(s,2H),8.13(s,2H),7.60(s,2H),7.27-7.23(m,4H),7.18-7.14(m,6H),5 .27-5.25(m,5H),5.06-5.93(m,2H),4.75-4.68(m,2H),4.56-4.53(m,4H),3.84-3.8 2(m,4H),3.81-3.73(m,4H),3.57-3.42(m,180H),3.35-3.26(m,4H),2.52-2.51(m,4 H),2.26-2.22(m,18H),2.12-1.85(m,6H),1.80-1.62(m,4H),0.90(t,6H,J=7.2Hz).

[0092] NMR spectrum as follows Figure 7 As shown.

[0093] Example 8 Synthesis of compound 2A4R-PEG24

[0094]

[0095] 2AR-PEG24-N3 (3.0 g, 1.5 mmol), compound T4-9 (2.6 g, 4.5 mmol), and ascorbic acid (31.6 g, 9 mmol) were added to dimethyl sulfoxide (30 mL), stirred until homogeneous, and an aqueous solution of copper sulfate pentahydrate (3.9 g, 15.6 mmol) (30 mL) was added dropwise. The mixture was stirred overnight at room temperature. 1 M ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The mixture was separated, and the aqueous phase was washed once with ethyl acetate and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was recrystallized from isopropanol, filtered, and the filter cake was dried under vacuum to give 2A4R-2K 2.7 g, yield 84%. MS m / z (ESI): 2078.9 [M]; 1 H NMR (300MHz, DMSO-d) 6 ): δ11.15(s,2H),8.14(s,2H),7.60(s,2H),7.28-7.24(m,4H),7.20-7.09 (m,6H),5.28-5.24(m,5H),5.09-4.91(m,4H),4.58-4.50(m,4H),3.84-3.8 2(m,4H),3.57-3.42(m,96H),3.35-3.26(m,4H),2.52-2.51(m,4H),2.26- 2.22(m,20H),2.12-1.85(m,6H),1.80-1.62(m,4H),0.89(t,6H,J=6.9Hz).

[0096] NMR spectrum as follows Figure 8 As shown.

[0097] Example 9: Compound Efficacy Study Using the Fleiss method

[0098] 1. Materials

[0099] Forty male SD rats, weighing 260-280 grams; ropivacaine hydrochloride injection; bi-terminal, four-armed, and eight-armed ropivacaine (4A4R-5K, 2A4R-2K, 8A4R) injections.

[0100] Among them, the two-terminal ropivacaine injection solution was obtained by dissolving compound 2A4R-2K prepared in Example 7 in physiological saline; the four-arm ropivacaine injection solution was obtained by dissolving compound 4A4R-5K prepared in Example 5 in physiological saline; and the eight-arm ropivacaine injection solution was obtained by dissolving compound 8A4R prepared in Example 2 in physiological saline.

[0101] 2 methods

[0102] 2.1 Grouping and Modeling

[0103] SD rats with normal pain thresholds were randomly divided into 5 groups of 8 rats each, and a pain model was established using the Brennan method. The specific method was as follows: Rats were fasted for 6 hours and deprived of water for 1 hour before surgery. After the pain threshold was measured using the Fleisham method, the rats were placed in a sealed anesthesia box and induced with 1.5-2% isoflurane. After the rats lost consciousness, they were removed, and the right hind foot was disinfected with iodine. A 1cm incision was made from 0.5cm proximal to the toe on the sole of the foot. After incising the skin and fascia, the foot muscles were lifted with ophthalmic forceps and longitudinally cut (maintaining the origin, insertion, and attachment of the muscles). Hemostasis was achieved by applying pressure. Before suturing, each group of animals was injected into the incision with 0.5ml of physiological saline, 10mg / kg of ropivacaine hydrochloride, and 10mg / kg of polyethylene glycol ropivacaine, respectively. After administration, the incision was sutured with 2-0 fine silk sutures, using 2 stitches. Throughout the entire operation, the rats were maintained under anesthesia with the same concentration of isoflurane via a face mask.

[0104] 2.2 Von Frey Test and Result Statistics

[0105] After the animals regained consciousness and returned to normal condition (approximately 1 hour post-surgery), pain threshold determination was performed using the Fleishort method. Pain thresholds were then measured at 1, 2, 4, 8, 12, 16, and 24 hours post-surgery. During pain threshold measurement, the surgical paw of each rat model was stimulated with gradually increasing force using a filament, and the threshold value (g) at which the animal exhibited a paw withdrawal response was recorded. Measurements were taken 2-3 times, and the average value was recorded. Experimental results were analyzed using SPSS 17.0. One-way ANOVA was used for comparisons between groups. P < 0.05 was considered statistically significant. The experimental results are shown in Table 1 below.

[0106] Table 1. Results of the Flimmer test

[0107]

[0108]

[0109] 2.3 Discussion of Results

[0110] The results show that PEG ropivacaine has a significantly longer duration of action than ropivacaine hydrochloride, and has a significant analgesic effect 8-12 hours after surgery. The analgesic effect of the bi-terminal drug is better than that of the quadri- and octetal drugs.

[0111] Example 10: Compound Efficacy Study Using Hot Plate Method

[0112] 1. Materials

[0113] Twenty-four male SD rats, weighing 260-280 grams, were used. The following injections were administered: physiological saline; ropivacaine hydrochloride injection; 2A4R-2K injection; and 4A4R-5K injection.

[0114] The preparation methods for Ropivacaine Hydrochloride Injection, 2A4R-2K Injection, and 4A4R-5K Injection are the same as in Example 9.

[0115] 2 Methods

[0116] 2.1 Grouping and Dosing

[0117] Twenty-four qualified rats (animals without motor disorders) were randomly divided into four groups of six each. Group 1 served as the control group, receiving physiological saline. The other groups received 4 mg / kg of bupivacaine hydrochloride injection, 2A4R-2K injection, and 4A4R-5K injection, respectively. The drug was administered via direct sciatic nerve injection. The rats were positioned dorsally, and the drug was injected around the right sciatic nerve trunk, located between the right buttock and right thigh.

[0118] 2.2 Motor blockade (four-level scoring):

[0119] The motor function of rats in each group was evaluated using a four-level motor blockade scoring method. The scoring criteria were as follows: 1 point for normal movements such as dorsiflexion, extension, and eversion of the paws; 2 points for dorsiflexion of the paws, which can bend or adduct and then extend again, but with weakened extension ability; 3 points for dorsiflexion of the paws, but no extension ability after curling; and 4 points for complete loss of dorsiflexion, curling, and extension of the paws, with gait defects observed in the rats. The motor blockade scores were measured at 0.5h, 1h, 2h, 4h, 8h, 12h, 16h, and 24h after drug administration.

[0120] 3. Experimental Results and Discussion

[0121] 3.1 Experimental Results

[0122] The experimental results are shown in Table 2.

[0123] Table 2 Results of Hot Plate Method

[0124]

[0125] 2.3 Discussion of Results

[0126] Ropivacaine hydrochloride had an anesthesia score of 1 after 2 hours, while the 2A4R-2K anesthesia score remained greater than 2 after 4 hours. This indicates that anesthetic drugs containing polyethylene glycol (PEG) have a significantly longer duration of action compared to ropivacaine, with the bi-pronged approach showing better anesthetic effect than the quadruple-pronged approach.

[0127] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A polyethylene glycolated ropivacaine derivative having the following structure: The molecular weight of the polyethylene glycol residues is 1kDa-10kDa; X - Selected from: F - Cl - ,Br - I - Methanesulfonate, ethylsulfonate, benzenesulfonate, lactate, succinate, fumarate, glutamate, citrate, salicylate, and maleate.

2. The polyethylene glycolated ropivacaine derivative of claim 1, X - Selected from: F - Cl - ,Br - I - Methanesulfonate, ethylsulfonate, and benzenesulfonate.

3. The polyethylene glycolated ropivacaine derivative of claim 1, wherein the polyethylene glycol residues have a molecular weight of 2kDa-5kDa.

4. The polyethylene glycol-modified ropivacaine derivative of claim 1, wherein the polyethylene glycol-modified ropivacaine derivative is selected from: ， The molecular weight of the polyethylene glycol residues is 2 kDa. 。 5. The method for preparing the polyethylene glycolated ropivacaine derivative according to claim 1, comprising: The M1 compound was reacted with ropivacaine to form a ropivacaine quaternary ammonium salt derivative; the ropivacaine quaternary ammonium salt derivative was then reacted with PEG with azido-terminated groups. 。 6. A pharmaceutical composition comprising the polyethylene glycolated ropivacaine derivative of any one of claims 1-4 and a pharmaceutically acceptable carrier or excipient.

7. The use of the polyethylene glycolated ropivacaine derivative according to any one of claims 1-4 or the pharmaceutical composition according to claim 6 in the preparation of analgesic or pain-relieving medicaments.

8. The application of claim 7, wherein the pain is selected from acute pain, chronic pain, neuropathic pain, psychogenic pain, heat-induced pain, physical pain, pain during or after surgery, general nociception, or hyperalgesia.

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