CN116942840A - Non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and composition thereof - Google Patents

Non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and composition thereof Download PDF

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CN116942840A
CN116942840A CN202310728825.4A CN202310728825A CN116942840A CN 116942840 A CN116942840 A CN 116942840A CN 202310728825 A CN202310728825 A CN 202310728825A CN 116942840 A CN116942840 A CN 116942840A
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pain
hexadecamide
steroidal anti
ethanol
drug
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庄涛
钱坤
殷明月
陈寅
王真
夏思怡
李宗正
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Jiangsu Ocean University
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Jiangsu Ocean University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention discloses a coupling medicament of a non-steroidal anti-inflammatory drug and hexadecamide ethanol and a composition thereof, wherein the coupling medicament is a compound represented by a formula (I); wherein the NSAIDs are selected from the group consisting of carboxyl group containing non-steroidal anti-inflammatory drugs; the NASIDs are non-steroidal anti-inflammatory drugs containing carboxyl, and comprise any one of ibuprofen, ketoprofen, naproxen, indomethacin and flurbiprofen; the composition consists of a compound shown in a formula (I), pharmaceutically acceptable salts, tautomers, meso forms, racemates, enantiomers or diastereomers thereof and pharmaceutically acceptable auxiliary materials. According to the invention, based on clinical requirements, NSAIDs and PEA are coupled into prodrugs, on one hand, the direct contact between carboxylic acid of NSAIDs and gastric mucosa can be reduced, so that the damage to the gastric mucosa is inhibited; on the other hand, the synergistic effect can be achieved by complementation of the analgesic mechanism between NSAIDs and PEA, the effective dose is reduced, and the side effects related to the dose are reduced.

Description

Non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and composition thereof
Technical Field
The invention relates to the field of medicines, in particular to a non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and a composition thereof.
Background
The international association of pain research (IASP) defines pain as being associated with actual or potential tissue damage, or a similar unpleasant sensory and emotional experience. The body produces pathological lesions, and this pain signal alerts people to pathogens or some damaging stimulus, but also impairs human health when this signal is abnormal or slow. Pain can be divided into nociceptive pain (from tissue injury), neuropathic pain (from nerve injury), and plastic pain (from nervous system sensitivity). Today, pain has severely affected the quality of life of the patient and creates a great economic burden.
There are many ways in which pain can be treated, including drug therapy, psychotherapy, combination therapy, and invasive surgery, but drug-based therapy remains the primary treatment for pain. Clinically, the ideal curative effect may not be achieved by using a single therapeutic drug, and a personalized multi-mode and interdisciplinary therapeutic method is clinically recommended at present.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a different non-opioid, prostaglandins that inhibit Cyclooxygenase (COX) activity and arachidonic acid production, and are most commonly prescribed drugs for the treatment of pain and inflammatory patients, such as chronic pain, osteoarthritis, rheumatoid arthritis, postoperative pain, dysmenorrhea, and the like, such as ibuprofen, ketoprofen, and naproxen. NSAIDs can be broadly classified into salicylic acid, aryl and isoaryl acetic acid derivatives, indole derivatives, anthranilates and enolic acids according to their chemical structures. More than 3000 tens of thousands of NSAIDs were taken daily and in europe, NSAIDs account for more than 7.7% of all prescriptions. In the united states, NSAIDs are prescribed in excess of 7000 ten thousand parts per year, plus over-the-counter administration, with annual consumption of over 300 billion doses of NSAIDs. Prolonged use of these non-steroidal anti-inflammatory drugs can lead to serious gastrointestinal damage and renal insufficiency, limiting the use of these drugs.
Palmitoylethanolamide (PEA), an endogenous fatty acid amide, is an endogenous lipid that regulates pain and inflammation, belonging to the class of nuclear transcription factor agonists. PEA exerts anti-inflammatory analgesic effects through a variety of mechanisms, which can act by directly activating peroxisome proliferator-activated receptors (PPAR- α) and orphan receptors (GPCR 55); PEA itself has a very weak affinity for the CB2 receptor, it has a concomitant effect, exerting an anti-inflammatory analgesic effect by indirect activation of the cannabinoid receptors CB1, CB2 or the transient receptor potential vanilloid type 1 receptor (TRPV 1):
(1) The metabolism of PEA is hydrolyzed to palmitic acid and ethanolamine by fatty amide hydrolase (FAAH) or N-acyl ethanolamine hydrolytic acid amidase (NAAA). It can directly inhibit FAAH expression, thereby increasing endogenous AEA and 2-AG levels, which can directly activate CB2 or CB1 receptors and TRPV1 channels.
(2) PEA may cause allosteric modulation of TRPV1 channels, thereby enhancing activation and desensitization of TRPV1 channels by AEA and 2-AG.
(3) PEA may also act on PPAR-alpha to activate TRPV1 channels.
Adverse reactions are likely to occur due to long-term use of NSAIDs, the most important of which is gastrointestinal side effects. NSAIDs inhibit prostaglandin synthesis while exerting analgesic effect, reduce prostaglandin protection of gastrointestinal tract, or inhibit H due to NSAIDs + Ions are reversibly dispersed to the mucosa, resulting in gastric lesions that locally irritate the gastrointestinal tract. Whereas PEA is an endogenous lipophilicSex molecules, which have a relatively short duration of action, limit their clinical application.
Prodrug design is an important drug design tool. Prodrugs are inactive compounds that are converted during metabolism to the active metabolite with the desired activity, and can improve the physicochemical and pharmacokinetic properties of various drugs. It was reported that 10% of the drugs on the global market in 2019 can be classified as prodrugs, and that the number of approved prodrugs is considerable among all drugs on the market. The invention combines medicines with different action mechanisms in a medicine coupling mode to prepare the prodrug, optimizes the medicine structure, achieves the synergistic effect between the medicines and increases the curative effect.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and providing a non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and a composition thereof, so as to solve the problems of the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions: the non-steroidal anti-inflammatory drug is coupled with hexadecamide ethanol, and the coupled drug is a compound represented by a formula (I);
wherein the NSAIDs are selected from non-steroidal anti-inflammatory drugs containing a carboxyl group.
As a preferable technical scheme of the invention, the NASIDs are non-steroidal anti-inflammatory drugs containing carboxyl, and the NASIDs comprise any one of ibuprofen, ketoprofen, naproxen, indomethacin and flurbiprofen.
As a preferable technical scheme of the invention, the compound is any one of the following compounds;
2-palmitoylethyl (S) -2- (6-methoxynaphthalen-2-yl) propionate; naproxen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (4-isobutylphenyl) propionate; ibuprofen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (3-benzoylphenyl) propionate; ketoprofen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (2-fluoro- [1,1' -biphenyl ] -4-yl) propionate; flurbiprofen-hexadecamide ethanol
2-palmitoylethyl 2- (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indol-3-yl) acetate; indomethacin-hexadecamide ethanol.
The composition of the non-steroidal anti-inflammatory drug and the palmitoylethanolamide consists of a compound represented by a formula (I), pharmaceutically acceptable salts thereof, tautomers thereof, meso forms, racemates, enantiomers or diastereomers thereof and pharmaceutically acceptable auxiliary materials.
The application of a non-steroidal anti-inflammatory drug and a hexadecamide ethanol coupling drug and a composition thereof in preparing a drug for preventing or treating pain.
As a preferred embodiment of the invention, the pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancerous pain, hyperalgesia and visceral pain.
The compound of formula (I) of the present invention, or a solvate thereof, or a co-crystal thereof, or an isotopically substituted form thereof, or a mixture thereof, and pharmaceutically acceptable excipients are formulated into a form suitable for administration by any suitable route, the active compound preferably being administered in unit doses, or in such a way that the patient can self-administer the single dose; the unit dose of the compound or the composition provided by the invention can be expressed in a tablet, a capsule, an injection, a granule, a tincture, a lozenge, a suppository, a regenerated medicinal powder or a liquid preparation.
The dosage of the compound or composition used in the method of use will generally vary with the severity of the pain, the weight of the patient and the relative efficacy of the compound. As a general guideline, suitable unit doses may be from 0.01 to 1000mg.
The pharmaceutical composition provided by the invention can contain one or more auxiliary materials besides active compounds, wherein the auxiliary materials are selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the composition may contain from 0.1 to 99 weight percent of the active compound.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, injection or transdermal administration in a patch delivery system, for example tablets, dragees, lozenges, aqueous or oily 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 the group consisting of sweetening agents, flavoring agents, coloring agents, pH adjusting agents and preserving agents.
The invention also provides a method of preventing or treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
The diseases are pain related diseases, including acute pain, such as soft tissue and joint acute injury pain, postoperative pain, acute herpes zoster pain, gout and the like; chronic pain, such as soft tissue and joint strain or degeneration pain, intervertebral disc-derived pain, nerve-derived pain, etc.;
the pain-related diseases also include intractable pain, such as trigeminal neuralgia, post-herpetic neuralgia, diabetic peripheral neuralgia, etc.;
the pain-related diseases also include cancer pain, such as late stage tumor pain, tumor metastasis pain, and the like. The pain-related diseases include specific pain, such as intractable angina, idiopathic chest and abdominal pain, and the like.
The compounds provided herein may also include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, having the structure of the invention, except for replacing hydrogen with "deuterium" or "tritium" or for using 18 F-fluorine labeling [ ] 18 F isotope) instead of fluorine or with 11 C-， 13 C-or 14 C-enriched carbon 11 C-， 13 C-or 14 C-carbon labeling; 11 C， 13 c or 14 C isotopes) are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases or as tracers for pharmacodynamic pharmacokinetic or receptor studies. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements).
The compounds provided herein also include various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of general formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated forms of the compounds of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The beneficial effects of the invention are as follows: the invention combines medicines with different action mechanisms in a medicine coupling mode to prepare the prodrug, optimizes the medicine structure, achieves the synergistic effect between the medicines and increases the curative effect.
According to the invention, based on clinical requirements, NSAIDs and PEA are coupled into prodrugs, on one hand, the direct contact between carboxylic acid of NSAIDs and gastric mucosa can be reduced, so that the damage to the gastric mucosa is inhibited; on the other hand, the synergistic effect can be achieved by complementation of the analgesic mechanism between NSAIDs and PEA, the effective dose is reduced, and the side effects related to the dose are reduced.
Drawings
FIG. 1 shows ibuprofen-hexadecamide ethanol coupled drug 1 H-NMR spectrum;
FIG. 2 shows ibuprofen-hexadecamide ethanol coupled drug 13 C-NMR spectrum;
FIG. 3 is a diagram of a ketoprofen-hexadecamide ethanol coupled drug 1 H-NMR spectrum;
FIG. 4 is a diagram of a ketoprofen-hexadecamide ethanol coupled drug 13 C-NMR spectrum;
FIG. 5 shows flurbiprofen-hexadecamide ethanol coupled drug 1 H-NMR spectrum;
FIG. 6 is a diagram of an indomethacin-hexadecamide ethanol coupled drug 1 H-NMR spectrum;
FIG. 7 is a graph showing the time course of analgesic effect of naproxen-hexadecamide ethanol coupled drug in a model of inflammatory pain in carrageenan in mice;
fig. 8 is a graph showing the time course of analgesic effect of indomethacin-hexadecamide ethanol coupled drug in a model of inflammatory pain in carrageenan in mice.
Detailed Description
The preferred embodiments of the present invention will be described in detail below with reference to the attached drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making clear and defining the scope of the present invention.
The structure of the compounds of the examples was determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in ppm. NMR was performed using a BrukerAVANCE III HD 500 magnetonuclear apparatus with deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
MS was determined using an Agilent 1260HPLC-6520 Accudate-Mass Q-Tof Mass spectrometer, test conditions: electrospray ion source (ESI), positive ion mode.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier;
the embodiment has no special description, the reaction temperature is room temperature and is 20-30 ℃;
the reaction progress in the examples was monitored by Thin Layer Chromatography (TLC).
Example 1: synthesizing naproxen-hexadecamide ethanol (1);
PEA 300mg (1.0 mmol,1.0 eq.) was added to a 50mL eggplant-shaped bottle at room temperature, naproxen 230mg (1 mmol,1.0 eq.), DMAP 12mg (0.1 mmol,1.0 eq.), tetrahydrofuran 5mL, EDCI 230mg (1.2 mmol,1.2 eq.) was added under magnetic stirring, and after 2 hours of reaction at room temperature, TLC monitoring (PE: EA=1:1, R f =0.7), the starting material was reacted. After removal of the solvent by vacuum rotary evaporator (50 ℃) 20mL of dichloromethane was added, washed once with 10mL of 1mol/L hydrochloric acid, once with 10mL of water and once with 10mL of saturated saline solution, the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying, and further purified by silica gel chromatography (eluent PE: ea=3:1) to give 503mg of white to off-white solid with a yield of 98.43%. 1 H NMR(500MHz,CDCl 3 )δ7.73(m,2H),7.69(d,J＝1.8Hz,1H),7.42(m,1H),7.18(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＝7.1Hz,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,CDCl 3 )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 NO 4 + [M+H] + )。IR:3325.83cm -1 Is the telescopic vibration absorption peak of the N-H bond of the amide functional group; 2957.98cm -1 、2848.94cm -1 Is saturated CH 2 And CH (CH) 3 A telescopic vibration absorption peak of the C-H bond; 1729.90cm -1 Is the telescopic vibration absorption peak of the amide c=o bond; 1646.69cm -1 、1605.03cm -1 Is the benzene ring c=c stretching vibration absorption peak.
Example 2: synthesizing ibuprofen-hexadecamide ethanol (2);
PEA 300mg (1.0 mmol,1.0 eq.) was added to a 50mL eggplant-shaped bottle at room temperature, ibuprofen 210mg (1 mmol,1.0 eq.), DMAP 12mg (0.1 mmol,1.0 eq.), tetrahydrofuran 5mL, EDCI 230mg (1.2 mmol,1.2 eq.) was added under magnetic stirring, and after 2 hours of reaction at room temperature, TLC monitoring (PE: EA=1:1, R) was performed f =0.8), the starting material has reacted. After removal of the solvent by vacuum rotary evaporator (50 ℃) 20mL of dichloromethane was added, washed once with 10mL of 1mol/L hydrochloric acid, once with 10mL of water and once with 10mL of saturated saline solution, the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying, and further purified by silica gel chromatography (eluent PE: ea=3:1) to yield 492mg of white to off-white solid with a yield of 99.19%. 1 H NMR(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,CDCl 3 )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 NO 3 + [M+H] + )。IR:3329.39cm -1 Is the telescopic vibration absorption peak of the N-H bond of the amide functional group; 2920.54cm -1 、2850.41cm -1 Saturated CH 2 And CH (CH) 3 A telescopic vibration absorption peak of the C-H bond; 1730.43cm -1 Is the telescopic vibration absorption peak of c=o bond; 1650.03cm -1 、1548.94cm -1 Is the benzene ring c=c stretching vibration absorption peak.
Example 3: synthesizing ketoprofen-hexadecamide ethanol (3);
PEA 300mg (1.0 mmol,1.0 eq.) in a 50mL eggplant-shaped bottle at room temperature, ketoprofen 250mg (1 mmol,1.0 eq.), DMAP 12mg (0.1 mmol,1.0 eq.), tetrahydrofuran 5mL, EDCI 230mg (1.2 mmol,1.2 eq.) under magnetic stirring, and TLC monitoring after 2 hours of reaction at room temperature (PE: EA=1:1, R f =0.6), the starting material has reacted. After removal of the solvent by vacuum rotary evaporator (50 ℃) 20mL of dichloromethane was added, washed once with 10mL of 1mol/L hydrochloric acid, once with 10mL of water and once with 10mL of saturated saline solution, the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying, and further purified by silica gel chromatography (eluent PE: ea=3:1) to yield 397mg of white to off-white solid with a yield of 75.48%. 1 H NMR(500MHz,CDCl 3 )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). 13 C NMR(126MHz,CDCl 3 )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 NO 4 + [M+H] + )。IR:3306.15cm -1 Is the telescopic vibration absorption peak of the N-H bond of the amide functional group; 2916.51cm -1 、2848.80cm -1 Is saturated CH 2 And CH (CH) 3 A telescopic vibration absorption peak of the C-H bond; 1735.83cm -1 Is the telescopic vibration absorption peak of the amide c=o bond; 1680.93cm -1 、1552.12cm -1 Is the benzene ring c=c stretching vibration absorption peak.
Example 4: synthesizing flurbiprofen-hexadecamide ethanol (4);
245mg (1.0 mmol,1.0 eq.) of flurbiprofen are placed in a 100mL eggplant-shaped bottle and dissolved by magnetic stirring at room temperature with 5mL of dichloromethane. 380mg (3.0 mmol,3.0 eq.) of oxalyl chloride is added dropwise, after stirring uniformly, a drop of DMF is dipped in a capillary tube and added into the reaction solution for catalysis, and the reaction is carried out for 0.5 hours at room temperature. After the reaction was completed, the solvent and the unreacted oxalyl chloride were removed by vacuum rotary evaporator (20 ℃). A100 mL eggplant-shaped bottle was additionally prepared, 240mg (0.8 mmol,0.8 eq.) of PEA, 101mg (1 mmol,1.0 eq.) of triethylamine and 5mL of dichloromethane were added and stirred well, the just-dried residue was added and reacted at room temperature for 4 hours, during which time it was monitored by TLC (DCM: meOH=10:1, R f =0.8) raw material to no significant change. After the reaction, 10mL of a saturated saline solution was added, and after stirring for 5 minutes, the organic phase was separated from the separating funnel, the operation was repeated 3 times, and finally, the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying to obtain a pale yellow solid. Further purification using a silica gel column (pure dichloromethane as eluent) afforded 180mg of a white or off-white solid in 34.26% yield. 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 FNO 3 + [M+H] + )。
Example 5: synthesizing indomethacin-hexadecamide ethanol (5);
358mg (1.0 mmol,1.0 eq.) of indomethacin are placed in a 100mL eggplant-shaped bottle and 5mL of dichloromethane are added and stirred magnetically at room temperature. 380mg (3.0 mmol,3.0 eq.) of oxalyl chloride is added dropwise, after stirring uniformly, a drop of DMF is dipped in a capillary tube and added into the reaction solution for catalysis, and the reaction is carried out for 0.5 hours at room temperature. After the reaction was completed, the solvent and the unreacted oxalyl chloride were removed by vacuum rotary evaporator (20 ℃). A100 mL eggplant-shaped bottle was prepared, 240mg (0.8 mmol,0.8 eq.) of PEA, 101mg (1 mmol,1.0 eq.) of triethylamine and 5mL of methylene chloride were added and stirred well, the residue immediately after spin-drying was added and reacted at room temperature for 4 hours, during which time it was monitored by TLC (PE: EA=1:1, R f =0.5) raw material to no significant change. After the reaction, 10mL of a saturated saline solution was added, and after stirring for 5 minutes, the organic phase was separated from the separating funnel, the operation was repeated 3 times, and finally, the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying to obtain a yellow solid. Further purification using a silica gel column (eluent PE: ea=10:1) afforded 180mg of white or off-white solid in 28.19% yield. 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,3H),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 ClN 2 O 5 + [M+H] + )。
Example 6: screening the non-steroidal anti-inflammatory drug-hexadecamide ethanol coupled anti-inflammatory analgesic effect;
the animals used were healthy female ICR mice, body weight (22.+ -.4 g). The animal can live in the environment with the temperature of 22+/-2 ℃, the relative humidity of 50+/-5% and the light and shade period of 12h/12h (on/off time of 8:00AM/20:00 PM), and can eat and drink water freely. Fasted prior to the experiment.
Carrageenan (CAR) induced inflammation model mice fasted but were not water-interrupted overnight prior to the experiment, and the mice were moved to the experimental environment and acclimatized for 30min before the start of the experiment. Mice injected subcutaneously (i.pl.) into the right hind foot sole with 20 μl of 1% carrageenan solution (in physiological saline) induced peripheral inflammation, and 2.5-3 hours later carrageenan-treated mice had an increased sensitivity to mechanical stimuli, which exhibited a decrease in the paw withdrawal threshold. The mechanical pain threshold of the right hind foot plantar of the mice was measured at 30min,60min,90min,120min after administration of 0.1mL/100g of the intragastric administration.
Hyperalgesia was determined by means of footshrink thresholds (MWTs) and assessed using a ZH-ZKL dynamic plantar analyzer. The mice were placed on an overhead bench with a wire mesh at the bottom, 6-8 compartments were made with acrylic plates and the mice had to be acclimatized for at least 30min before the experiment, pressure was applied to the hind paw of the mice with one wire (diameter 0.4 mm) during the test (until the mice developed a paw withdrawal response), the paw withdrawal threshold was recorded automatically (units are in g), the process was repeated three times, an interval of 30s in between. The test procedure does not touch the wire mesh.
Analgesic inhibition rate (MPE%) = (mechanical threshold after dosing-0 min mechanical threshold)/(baseline before modeling-0 min mechanical threshold) ×100%
Table 1: model of non-steroidal anti-inflammatory drug-hexadecamide ethanol conjugated (50 mg/kg) carrageenan-induced inflammatory pain
By contrast analysis, the analgesic effects of naproxen-hexadecamide ethanol (50 mg/kg) and indomethacin-hexadecamide ethanol (50 mg/kg) are relatively strong, and further, a deeper analgesic activity study is developed on the naproxen-hexadecamide ethanol and the indomethacin-hexadecamide ethanol.
Example 7: evaluating anti-inflammatory and analgesic effects of naproxen-hexadecamide ethanol coupled medicine;
the coupled medicine of naproxen-hexadecamide ethanol has dose-dependent analgesic effect on inflammatory pain, and the maximum analgesic inhibition rate at three doses of 25, 50 and 100mg/kg is 22.2%, 49.7% and 58.4%, respectively, and ED is calculated 50 = 55.65mg/kg (see fig. 7), indicating that the compound has a certain analgesic effect.
Example 8: evaluating anti-inflammatory and analgesic effects of indomethacin-hexadecamide ethanol coupled medicine;
the indomethacin-hexadecamide ethanol coupled medicine has dose-dependent analgesic effect on inflammatory pain, and the maximum analgesic inhibition rate at four doses of 12.5, 25, 50 and 100mg/kg is respectively 20.8%, 36.2%, 62.1% and 74.4%, and ED is calculated 50 =37.86 mg/kg (see fig. 8), indicating that the compound has a strong analgesic effect.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.

Claims (6)

1. The non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug is characterized in that: the coupling medicine is a compound represented by a formula (I);
wherein the NSAIDs are selected from non-steroidal anti-inflammatory drugs containing a carboxyl group.
2. The non-steroidal anti-inflammatory drug coupled with palmitoylethanolamide as claimed in claim 1, wherein: the NASIDs are non-steroidal anti-inflammatory drugs containing carboxyl, and comprise any one of ibuprofen, ketoprofen, naproxen, indomethacin and flurbiprofen.
3. The non-steroidal anti-inflammatory drug coupled with palmitoylethanolamide according to claim 1 or 2, characterized in that: the compound is any one of the following;
2-palmitoylethyl (S) -2- (6-methoxynaphthalen-2-yl) propionate; naproxen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (4-isobutylphenyl) propionate; ibuprofen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (3-benzoylphenyl) propionate; ketoprofen-hexadecamide ethanol;
2-palmitoylamide ethyl 2- (2-fluoro- [1,1' -biphenyl ] -4-yl) propionate; flurbiprofen-hexadecamide ethanol;
2-palmitoylethyl 2- (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indol-3-yl) acetate; indomethacin-hexadecamide ethanol.
4. A composition of a non-steroidal anti-inflammatory drug and a palmitoylethanolamide conjugated drug according to claim 1, characterized in that: the composition consists of a compound shown in a formula (I), pharmaceutically acceptable salts, tautomers, meso forms, racemates, enantiomers or diastereomers thereof and pharmaceutically acceptable auxiliary materials.
5. The application of the non-steroidal anti-inflammatory drug and the hexadecamide ethanol coupling drug and the composition thereof is characterized in that: use of a compound according to claim 1 and a pharmaceutical composition according to claim 4 for the preparation of a medicament for the prophylaxis or treatment of pain.
6. The use of a non-steroidal anti-inflammatory drug coupled with palmitoylethanolamide as claimed in claim 5, and a composition thereof, wherein: the pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancerous pain, hyperalgesia and visceral pain.
CN202310728825.4A 2023-06-19 2023-06-19 Non-steroidal anti-inflammatory drug and hexadecamide ethanol coupling drug and composition thereof Pending CN116942840A (en)

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