Non-steroidal anti-inflammatory drugs coupled with palmitoylethanolamide and compositions thereof

Abstract

The application discloses a non-steroidal anti-inflammatory drug and a hexadecanamide ethanol coupled drug and a composition thereof, the coupled drug is a compound represented by formula (I); wherein the NSAIDs are selected from non-steroidal anti-inflammatory drugs containing carboxyl; the NASIDs are non-steroidal anti-inflammatory drugs containing carboxyl, including any one of ibuprofen, ketoprofen, naproxen, indomethacin or flurbiprofen; the composition is composed of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, a tautomer, an endo-racemate, an exo-racemate, an enantiomer or a diastereomer thereof and a pharmaceutically acceptable excipient. The application couples NSAIDs and PEA into a prodrug based on clinical needs, on the one hand, the carboxylic acid of NSAIDs can be reduced to directly contact with gastric mucosa, thereby inhibiting the damage to gastric mucosa; on the other hand, the NSAIDs and PEA can play a synergistic effect through the complementary analgesic mechanism, reduce the effective dose and reduce the dose-related side effects.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to nonsteroidal anti-inflammatory drugs coupled with hexadecylamine ethanol and their compositions. Background Technology

[0002] The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain signals the body to defend against pathogens or harmful stimuli when pathological damage occurs; however, when these signals are abnormal or slowed, they can also harm health. Pain can be categorized into nociceptive pain (originating from tissue damage), neuropathic pain (originating from nerve damage), and nociplastic pain (originating from nervous system sensitivity). Today, pain severely impacts patients' quality of life and imposes a significant economic burden.

[0003] There are many ways to treat pain, including medication, psychotherapy, comprehensive treatment, and invasive surgery, but medication-based therapy remains the primary treatment method. Clinically, using a single medication may not achieve the desired effect; therefore, a personalized, multimodal, and interdisciplinary approach is currently recommended in clinical practice.

[0004] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a type of non-opioid medication that works by inhibiting cyclooxygenase (COX) activity and the production of prostaglandins from arachidonic acid. They are primarily used to treat pain and inflammation, such as chronic pain, osteoarthritis, rheumatoid arthritis, postoperative pain, and dysmenorrhea. Ibuprofen, ketoprofen, and naproxen are among the most commonly prescribed medications. Based on their chemical structure, NSAIDs can be broadly classified into salicylates, aryl and isoaryl acetic acid derivatives, indole derivatives, anthranilates, and enolates. According to 2018 statistics, over 30 million people take NSAIDs daily. In Europe, NSAIDs account for more than 7.7% of all prescriptions. In the United States, over 70 million NSAID prescriptions are issued annually, and combined with over-the-counter use, the annual consumption of NSAIDs exceeds 30 billion doses. Long-term use of these NSAIDs can lead to severe gastrointestinal damage and renal insufficiency, thus limiting their use.

[0005] Hexadecanoic acid ethanol (PEA) is an endogenous fatty acid amide, an endogenous lipid that regulates pain and inflammation, and belongs to the class of nuclear transcription factor agonists. PEA exerts its anti-inflammatory and analgesic effects through multiple mechanisms. It can directly activate peroxisome proliferator-activated receptor (PPAR-α) and orphan receptor (GPCR55) to exert its effects; PEA itself has a very weak affinity for the CB2 receptor, exhibiting a follower effect, and exerts its anti-inflammatory and analgesic effects indirectly by activating cannabinoid receptors CB1, CB2, or transient receptor potential vanillic acid type 1 receptor (TRPV1).

[0006] (1). PEA is metabolized by fatty amide hydrolase (FAAH) or N-acylethanolamine hydrolase (NAAA) to palmitic acid and ethanolamine. It can directly inhibit the expression of FAAH, thereby increasing the levels of endogenous AEA and 2-AG. AEA and 2-AG can directly activate CB2 or CB1 receptors and TRPV1 channels.

[0007] (2). PEA may induce allosteric regulation of TRPV1 channels, thereby enhancing the activation and desensitization of TRPV1 channels by AEA and 2-AG.

[0008] (3). PEA may also act on PPAR-α and activate the TRPV1 channel.

[0009] Because long-term use of NSAIDs can easily lead to adverse reactions, the most significant of which are gastrointestinal side effects. While NSAIDs exert their analgesic effect, they also inhibit prostaglandin synthesis, reducing the protective effect of prostaglandins on the gastrointestinal tract, or causing H... + Ions diffuse backwards into the mucosa, causing gastric damage and local irritation of the gastrointestinal tract. PEA is an endogenous lipophilic molecule with a relatively short duration of action, which limits its clinical application.

[0010] Prodrug design is an important drug design tool. Prodrugs are inactive compounds that are converted into active metabolites with the desired activity during metabolism, and can improve the adverse physicochemical and pharmacokinetic properties of various drugs. It has been reported that in 2019, 10% of drugs on the global market could be classified as prodrugs, and the number of approved prodrugs among all drugs launched on the market is considerable. This invention combines drugs with different mechanisms of action through drug conjugation to prepare prodrugs, optimizing drug structures to achieve synergistic effects and increase efficacy. Summary of the Invention

[0011] The purpose of this invention is to address the deficiencies of the prior art by providing a nonsteroidal anti-inflammatory drug coupled with a hexadecylamine ethanol drug and a combination thereof, thereby solving the problems raised in the background art.

[0012] To achieve the above objectives, the present invention provides the following technical solution: a nonsteroidal anti-inflammatory drug coupled with a hexadecanoic acid ethanol, wherein the coupled drug is a compound represented by formula (I);

[0013]

[0014] NSAIDs are selected from nonsteroidal anti-inflammatory drugs containing carboxyl groups.

[0015] As a preferred embodiment of the present invention, the NASIDs are nonsteroidal anti-inflammatory drugs containing carboxyl groups, including any one of ibuprofen, ketoprofen, naproxen, indomethacin, or flurbiprofen.

[0016] As a preferred embodiment of the present invention, the compound is any one of the following;

[0017]

[0018] 2-Palmamide ethyl (S)-2-(6-methoxynaphthyl-2-yl)propionate; Naproxen-hexadecanoic acid ethanol;

[0019]

[0020] 2-Palmamide ethyl 2-(4-isobutylphenyl)propionate; Ibuprofen-hexadecanoic acid ethanol;

[0021]

[0022] 2-Palmamide ethyl 2-(3-benzoylphenyl)propionate; Ketoprofen-hexadecanoic acid ethanol;

[0023]

[0024] 2-Palmamide ethyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate; Flurbiprofen-hexadecanoic acid ethanol

[0025]

[0026] 2-Palmamide ethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl) acetate; Indomethacin-hexadecylamide ethanol.

[0027] A composition of a nonsteroidal anti-inflammatory drug with hexadecanoic acid, the composition comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof, its tautomer, meso compound, racemic compound, enantiomer or diastereomer thereof, and a pharmaceutically acceptable excipient.

[0028] Applications of nonsteroidal anti-inflammatory drugs coupled with hexadecylamine ethanol and their combinations thereof; applications of compounds and pharmaceutical compositions in the preparation of drugs for the prevention or treatment of pain.

[0029] As a preferred embodiment of the present invention, the pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain.

[0030] The compounds of general formula (I) of the present invention, or their solvates, eutectics, isotopic substitutions, or mixtures thereof, and pharmaceutically acceptable excipients are prepared in a form suitable for administration via any appropriate route, wherein the active compound is preferably administered in a unit dose manner or in a manner that allows the patient to self-administer a single dose; the unit dose of the compounds or compositions provided by the present invention may be expressed as tablets, capsules, injections, granules, tinctures, lozenges, suppositories, regenerated powders, or liquid formulations.

[0031] The dosage of the compound or composition used in its administration typically varies depending on the severity of pain, the patient's weight, and the relative efficacy of the compound. As a general guideline, a suitable unit dose may be 0.01–1000 mg.

[0032] In addition to the active compound, the pharmaceutical composition provided by this invention may contain one or more excipients, selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0033] Pharmaceutical compositions containing active ingredients may be suitable for oral, injectable, or transdermal administration via patch delivery systems, such as tablets, lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, injections, lyophilized powders, or syrups or tinctures. Oral or injectable compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from: sweeteners, flavoring agents, coloring agents, pH adjusters, and preservatives.

[0034] The present invention also provides a method for preventing or treating a disease, the method comprising administering a therapeutically effective amount of the compound or composition of the present invention to a subject in need.

[0035] The diseases mentioned are pain-related diseases, including acute pain, such as acute soft tissue and joint injury pain, postoperative pain, acute herpes zoster pain, gout, etc.; and chronic pain, such as soft tissue and joint strain or degenerative pain, intervertebral disc pain, neurogenic pain, etc.

[0036] The pain-related diseases mentioned also include intractable pain, such as trigeminal neuralgia, postherpetic neuralgia, and diabetic peripheral neuropathy.

[0037] The pain-related diseases also include cancer pain, such as late-stage tumor pain and metastatic tumor pain. The pain-related diseases also include specific types of pain, such as intractable angina and idiopathic chest and abdominal pain.

[0038] The compounds provided by this invention may also contain isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this invention, except that hydrogen is replaced by "deuterium" or "tritium" or by using... 18 F-fluorine labeling ( 18 F isotope) to replace fluorine or use 11 C-, 13 C- or 14 C-enriched carbon ( 11 C-, 13 C- or 14 C-carbon labeling; 11 C, 13 C or 14 Compounds in which carbon atoms are replaced by carbon isotopes are within the scope of this invention. Such compounds can be used as analytical tools or probes, for example, in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. Deuterated compounds generally retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thereby providing certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirements).

[0039] The compounds provided by this invention also include various deuterated forms of general formula (I) compounds. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of general formula (I) compounds by referring to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of general formula (I) compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0040] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0041] The beneficial effects of this invention are: by combining drugs with different mechanisms of action through drug conjugation to prepare prodrugs, the structure of the drugs is optimized to achieve synergistic effects between the drugs and increase the therapeutic effect.

[0042] Based on clinical needs, this invention conjugates NSAIDs and PEA into a prodrug. On the one hand, this reduces the direct contact between the carboxylic acid of NSAIDs and the gastric mucosa, thereby inhibiting its damage to the gastric mucosa. On the other hand, the complementary analgesic mechanisms of NSAIDs and PEA can exert a synergistic effect, reducing their effective dose and dose-related side effects. Attached Figure Description

[0043] Figure 1 Ibuprofen-hexadecanoic acid conjugate 1 H-NMR spectrum;

[0044] Figure 2 Ibuprofen-hexadecanoic acid conjugate 13 C-NMR spectrum;

[0045] Figure 3 Ketoprofen-hexadecanoic acid-ethanol conjugate 1 H-NMR spectrum;

[0046] Figure 4 Ketoprofen-hexadecanoic acid-ethanol conjugate 13 C-NMR spectrum;

[0047] Figure 5 Flurbiprofen-hexadecanoic acid ethanol conjugate 1 H-NMR spectrum;

[0048] Figure 6 Indomethacin-hexadecanoic acid-ethanol conjugate 1 H-NMR spectrum;

[0049] Figure 7 The time-effect graph shows the analgesic effect of naproxen-hexadecanoic acid-ethanol conjugate in a mouse carrageenan-induced inflammatory pain model.

[0050] Figure 8 This is a time-effect graph showing the analgesic effect of indomethacin-hexadecanoic acid-ethanol conjugate in a mouse carrageenan-induced inflammatory pain model. Detailed Implementation

[0051] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0052] The structures of the compounds in the examples were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in ppm. NMR measurements were performed using a Bruker AVANCE III HD 500 NMR spectrometer with deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0053] MS measurements were performed using an Agilent 1260HPLC-6520 Accurate-Mass Q-Tof mass spectrometer under the following conditions: electrospray ionization (ESI) source, positive ion mode.

[0054] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0055] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0056] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃;

[0057] The reaction process in the examples was monitored using thin-layer chromatography (TLC).

[0058] Example 1: Synthesis of naproxen-hexadecanoic acid ethanol (1);

[0059]

[0060] In a 50 mL round-bottom flask at room temperature, add 300 mg PEA (1.0 mmol, 1.0 eq.), 230 mg naproxen (1 mmol, 1.0 eq.), 12 mg DMAP (0.1 mmol, 1.0 eq.), and 5 mL tetrahydrofuran. While stirring magnetically, add 230 mg EDCI (1.2 mmol, 1.2 eq.). After reacting at room temperature for 2 hours, monitor the reaction by TLC (PE:EA = 1:1, R0). f =0.7), the raw materials have reacted completely. After removing the solvent using a vacuum rotary evaporator (50℃), 20mL of dichloromethane was added, followed by washing with 10mL of 1mol / L hydrochloric acid, 10mL of water, and 10mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Further purification was performed using a silica gel column (eluent:PE:EA = 3:1) to obtain 503mg of a white to off-white solid, with a yield of 98.43%. 1HNMR (500MHz, CDCl3) δ7.73 (m, 2H), 7.69 (d, J = 1.8Hz, 1H), 7.42 (m, 1H), 7.1 8(m,1H),7.13(d,J=2.5Hz,1H),5.26(s,1H),4.17(m,2H),3.93(s,3H),3.89 (q,J=7.1Hz,1H),3.43(q,J=5.5Hz,2H),1.84–1.79(m,2H),1.61(d,J=7.1H z, 3H), 1.40 (q, J = 7.5Hz, 2H), 1.27 (d, J = 7.9Hz, 24H), 0.90 (t, J = 6.9Hz, 3H). 13 C NMR (126MHz, CDCl3) δ174.60,173.15,157.84,135.64,133.74,129.22,128.91,127.29,125.99,125.93,119.30,105.56,63.48,55. 31,45.42,38.41,36.43,31.94,29.72,29.70,29.68,29.65,29.52,29.38,29.33,29.21,25.50,22.71,18.03,14.13.(+)-HR-ESI-MS m / z 512.3738(calcd.512.3734for C 32 H 50 NO4 + [M+H] + IR: 3325.83cm -1 This is the absorption peak of the stretching vibration of the NH bond in the amide functional group; 2957.98 cm⁻¹ -1 2848.94cm -1 It is the absorption peak of the stretching vibration of the CH bond in saturated CH2 and CH3; 1729.90 cm⁻¹ -1 This is the absorption peak of the stretching vibration of the C=O bond in the amide; 1646.69 cm⁻¹ -1 1605.03cm -1 It is the absorption peak of the C=C stretching vibration of the benzene ring.

[0061] Example 2: Synthesis of ibuprofen-hexadecanoic acid ethanol (2);

[0062]

[0063] Add 300 mg PEA (1.0 mmol, 1.0 eq.), 210 mg ibuprofen (1 mmol, 1.0 eq.), 12 mg DMAP (0.1 mmol, 1.0 eq.), and 5 mL tetrahydrofuran to a 50 mL round-bottom flask at room temperature. Then add 230 mg EDCI (1.2 mmol, 1.2 eq.) while magnetically stirring. After reacting at room temperature for 2 hours, monitor the reaction by TLC (PE:EA = 1:1, R0). f =0.8), the raw materials have reacted completely. After removing the solvent using a vacuum rotary evaporator (50℃), 20mL of dichloromethane was added, followed by washing with 10mL of 1mol / L hydrochloric acid, 10mL of water, and 10mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Further purification was performed using a silica gel column (eluting agent:PE:EA = 3:1) to obtain 492mg of a white to off-white solid, with a yield of 99.19%. 1 HNMR (500MHz, CDCl3) δ7.24–7.20(m,2H),7.15–7.11(m,2H),5.36(t,J=5.9Hz,1H),4.26–4.07(m,2H),3.73(q,J=7.1Hz,1H),3.45(q,J= 5.4Hz,2H),2.47(d,J=7.2Hz,2H),2.05–2.00(m,2H),1.87(m,1H),1.59–1.53(m,2H),1.52(d,J=7.2Hz,3H),1.28(s,24H),0.91(m,9H). 13 C NMR (126MHz, CDCl3) δ174.68,173.14,140.77,137.77,129.45,127.09,63.41,45.08,45.03,38.49,36.60,31.93, 30.20,29.71,29.69,29.67,29.65,29.54,29.38,29.37,29.30,25.61,22.70,22.39,18.12,14.13.(+)-HR-ESI-MS m / z 488.4122(calcd.488.4098for C 31 H 54 NO3 + [M+H] + IR: 3329.39cm -1 This is the absorption peak of the stretching vibration of the NH bond in the amide functional group; 2920.54 cm⁻¹ -1 2850.41cm -1 Absorption peak of stretching vibration of CH bonds in saturated CH2 and CH3; 1730.43 cm⁻¹-1 It is the absorption peak of the stretching vibration of the C=O bond; 1650.03 cm⁻¹ -1 1548.94cm -1 It is the absorption peak of the C=C stretching vibration of the benzene ring.

[0064] Example 3: Synthesis of ketoprofen-hexadecanoic acid ethanol (3);

[0065]

[0066] Add 300 mg PEA (1.0 mmol, 1.0 eq.), 250 mg ketoprofen (1 mmol, 1.0 eq.), 12 mg DMAP (0.1 mmol, 1.0 eq.), and 5 mL tetrahydrofuran to a 50 mL round-bottom flask at room temperature. Then add 230 mg EDCI (1.2 mmol, 1.2 eq.) while magnetically stirring. After reacting at room temperature for 2 hours, monitor the reaction by TLC (PE:EA = 1:1, R0). f =0.6), the raw materials have reacted completely. After removing the solvent using a vacuum rotary evaporator (50℃), 20mL of dichloromethane was added, followed by washing with 10mL of 1mol / L hydrochloric acid, 10mL of water, and 10mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Further purification was performed using a silica gel column (eluting agent:PE:EA = 3:1) to obtain 397mg of a white to off-white solid, with a yield of 75.48%. 1 HNMR (500MHz, CDCl3) δ7.86–7.81(m,3H),7.69–7.62(m,2H),7.58–7.50(m,3H),7.47(t,J=7.7Hz,1H),5.90(s,1H),4.29–4.14(m,2H),3 .86(q,J=7.2Hz,1H),3.49(q,J=5.8Hz,2H),2.11(m,2H),1.70–1.60(m,2H),1.57(d,J=8.7Hz,3H),1.26(m,24H),0.90(t,J=6.9Hz,3H). 13C NMR (126MHz, CDCl3) δ196.63,173.90,173.56,141.00,138.02,137.19,132.77,131.45,130.13,129.13,129.05,128.51,128.40, 63.83,45.35,38.64,36.55,31.93,29.70,29.69,29.66,29.63,29.52,29.36,29.28,25.69,22.70,18.19,14.13.(+)-HR-ESI-MS m / z 536.3743(calcd.536.3734for C 34 H 50 NO4 + [M+H] + IR: 3306.15cm -1 This is the absorption peak of the stretching vibration of the NH bond in the amide functional group; 2916.51 cm⁻¹ -1 2848.80cm -1 It is the absorption peak of the stretching vibration of the CH bond in saturated CH2 and CH3; 1735.83 cm⁻¹ -1 This is the absorption peak of the stretching vibration of the C=O bond in the amide; 1680.93 cm⁻¹ -1 1552.12cm -1 It is the absorption peak of the C=C stretching vibration of the benzene ring.

[0067] Example 4: Synthesis of flurbiprofen-hexadecanoic acid ethanol (4);

[0068]

[0069] Add 245 mg (1.0 mmol, 1.0 eq.) of flurbiprofen to a 100 mL round-bottom flask, and dissolve it in 5 mL of dichloromethane by magnetic stirring at room temperature. Add 380 mg (3.0 mmol, 3.0 eq.) of oxaloyl chloride dropwise. After stirring until homogeneous, add a drop of DMF to the reaction solution using a capillary tube for catalysis. React at room temperature for 0.5 hours. After the reaction is complete, remove the solvent and unreacted oxaloyl chloride using a vacuum rotary evaporator (20 °C). Separately, prepare a 100 mL round-bottom flask, add 240 mg (0.8 mmol, 0.8 eq.) of PEA, 101 mg (1 mmol, 1.0 eq.) of triethylamine, and 5 mL of dichloromethane. Stir until homogeneous, add the evaporated residue, and react at room temperature for 4 hours, monitoring with TLC (DCM:MeOH = 10:1, R0). f=0.8) The reactant was stirred until no obvious change was observed. After the reaction was complete, 10 mL of saturated saline solution was added, and the mixture was stirred for 5 minutes. The organic phase was then separated using a separatory funnel. This operation was repeated 3 times. Finally, the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain a pale yellow solid. Further purification was performed using a silica gel column (eluent: pure dichloromethane) to give 180 mg of a white or off-white solid, with a yield of 34.26%. 1 H NMR (500MHz, CDCl3) δ7.56(d,J=7.6Hz,2H),7.44(m,4H),7.21–7.10(m,2H),5.52(t,J=5.8Hz,1H),4.21(s,2H),3.80(q,J=7.2Hz, 1H),3.51(q,J=5.5Hz,2H),2.09(t,J=7.7Hz,2H),1.56(t,J=6.6Hz,5H),1.37–1.20(m,24H),0.91(t,J=6.8Hz,3H).(+)-HR-ESI-MS m / z 526.3662(calcd.526.3691for C 33 H 49 FNO3 + [M+H] + ).

[0070] Example 5: Synthesis of indomethacin-hexadecanoic acid ethanol (5);

[0071]

[0072] Add 358 mg (1.0 mmol, 1.0 eq.) of indomethacin to a 100 mL round-bottom flask, and add 5 mL of dichloromethane. Stir magnetically at room temperature until homogeneous. Add 380 mg (3.0 mmol, 3.0 eq.) of oxaloyl chloride dropwise. After stirring until homogeneous, add a drop of DMF to the reaction solution using a capillary tube for catalysis. React at room temperature for 0.5 hours. After the reaction is complete, remove the solvent and unreacted oxaloyl chloride using a vacuum rotary evaporator (20 °C). Prepare another 100 mL round-bottom flask, add 240 mg (0.8 mmol, 0.8 eq.) of PEA, 101 mg (1 mmol, 1.0 eq.) of triethylamine, and 5 mL of dichloromethane. Stir until homogeneous, add the evaporated residue, and react at room temperature for 4 hours, monitoring with TLC (PE:EA = 1:1, R0). f =0.5) The starting material was stirred until no obvious change was observed. After the reaction was complete, 10 mL of saturated saline solution was added, and the mixture was stirred for 5 minutes. The organic phase was then separated using a separatory funnel. This operation was repeated 3 times. Finally, the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain a yellow solid. Further purification was performed using a silica gel column (eluting agent:PE:EA = 10:1) to obtain 180 mg of a white or off-white solid, with a yield of 28.19%.1 H NMR(500MHz, CDCl3)δ7.71–7.66(m,2H),7.53–7.47(m,2H),7.00(d,J=2.5Hz ,1H),6.91(d,J=9.0Hz,1H),6.71(m,1H),4.23–4.17(m,2H),3.87–3.82(m,3 H),3.71(s,2H),3.50(q,J=5.5Hz,2H),2.41(d,J=5.9Hz,3H),2.00(m,2H),1 .57–1.47(m,2H),1.36–1.20(m,24H),0.90(t,J=6.8Hz,3H).(+)-HR-ESI-MS m / z 639.3585(calcd.639.3559for C 37 H 52 ClN2O5 + [M+H] + ).

[0073] Example 6: Screening for the anti-inflammatory and analgesic effects of a nonsteroidal anti-inflammatory drug coupled with hexadecanoic acid ethanol;

[0074] Healthy female ICR mice, weighing (22±4g), were used. They were kept in an environment with a temperature of (22±2)℃, a relative humidity of (50±5)%, and a light / dark cycle of 12h / 12h (lights on / off at 8:00 AM / 8:00 PM). They had free access to food and water. They were fasted before the experiment.

[0075] A carrageenan (CAR)-induced inflammation model was established. Mice were fasted but given water the night before the experiment. Before the experiment, mice were moved to the experimental environment and allowed to acclimatize to the equipment for 30 minutes. Peripheral inflammation was induced by subcutaneous injection (i.pl.) of 20 μL of 1% carrageenan solution (dissolved in physiological saline) into the right hind paw. 2.5-3 hours later, the carrageenan-treated mice showed increased sensitivity to mechanical stimulation, manifested as a decreased withdrawal threshold. The mechanical pain threshold of the right hind paw was measured at 30, 60, 90, and 120 minutes after administration of 0.1 mL / 100 g via gavage.

[0076] Hyperalgesia was determined by withdrawal thresholds (MWTs) and assessed using the ZH-ZKL dynamic plantar apex analyzer. Mice were placed on an elevated platform with a wire mesh bottom, in 6-8 compartments made of acrylic panels. Mice were allowed at least 30 minutes to acclimatize before the experiment. During the test, pressure was applied to the mouse's hind paw using a thin metal wire (0.4 mm in diameter) until the mouse exhibited a withdrawal response. The withdrawal threshold was automatically recorded (in grams). The process was repeated three times with a 30-second interval between each test. The mice did not touch the wire mesh during the test.

[0077] Analgesic suppression rate (MPE%) = (Post-drug mechanical threshold - 0-min mechanical threshold) / (Pre-model baseline value - 0-min mechanical threshold) × 100%

[0078] Table 1: Carrageenan-induced inflammatory pain model induced by nonsteroidal anti-inflammatory drug-hexadecanoic acid-ethanol conjugation (50 mg / kg)

[0079]

[0080] Comparative analysis showed that naproxen-hexadecanoic acid ethanol (50 mg / kg) and indomethacin-hexadecanoic acid ethanol (50 mg / kg) had relatively strong analgesic effects, and further in-depth studies on their analgesic activity should be conducted.

[0081] Example 7: Evaluation of the anti-inflammatory and analgesic effects of naproxen-hexadecanoic acid ethanol conjugate;

[0082] The conjugate of naproxen and hexadecanoic acid has a dose-dependent analgesic effect on inflammatory pain. The maximum analgesic inhibition rates at three doses of 25, 50, and 100 mg / kg were 22.2%, 49.7%, and 58.4%, respectively. The calculated effect-limiting effect (EDS) was... 50 = 55.65 mg / kg (see) Figure 7 The presence of this compound indicates that it has a certain analgesic effect.

[0083] Example 8: Evaluation of the anti-inflammatory and analgesic effects of indomethacin-hexadecanoic acid ethanol conjugate;

[0084] The indomethacin-hexadecanoic acid conjugate exhibits dose-dependent analgesic effects on inflammatory pain. The maximum analgesic inhibition rates at four doses (12.5, 25, 50, and 100 mg / kg) were 20.8%, 36.2%, 62.1%, and 74.4%, respectively. The calculated efficacy... 50 = 37.86 mg / kg (see) Figure 8 The presence of this compound indicates that it has a strong analgesic effect.

[0085] The above embodiments merely illustrate several implementation methods of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A nonsteroidal anti-inflammatory drug coupled with hexadecanoic acid ethanol, characterized in that: The conjugate is a compound represented by formula (I); ； NSAIDs are nonsteroidal anti-inflammatory drugs containing carboxyl groups, selected from ibuprofen, ketoprofen, naproxen, indomethacin, or flurbiprofen.

2. The nonsteroidal anti-inflammatory drug and hexadecanoic acid-ethanol conjugate according to claim 1, characterized in that: The compound is any one of the following; ； 2-Palmamide ethyl (S)-2-(6-methoxynaphthyl-2-yl)propionate; Naproxen-hexadecanoic acid ethanol; ； 2-Palmamide ethyl 2-(4-isobutylphenyl)propionate; Ibuprofen-hexadecanoic acid ethanol; ； 2-Palmamide ethyl 2-(3-benzoylphenyl)propionate; Ketoprofen-hexadecanoic acid ethanol; ； 2-Palmamide ethyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate; Flurbiprofen-hexadecanoic acid ethanol ； 2-Palmamide ethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl) acetate; Indomethacin-hexadecylamide ethanol.

3. A composition comprising the nonsteroidal anti-inflammatory drug of claim 1 and a hexadecanoic acid-ethanol conjugate, characterized in that: The composition consists of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, its tautomer, meso compound, racemic compound, enantiomer or diastereomer thereof, and a pharmaceutically acceptable excipient.

4. Use of the compound of claim 1 or the composition of claim 3 in the preparation of a medicament for the prevention or treatment of pain.

5. The application according to claim 4, characterized in that: The pain is categorized as acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, and visceral pain.

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