Flurbiprofen derivatives and their use in medicine

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a kind of flurbiprofen derivatives and its application in medicine, and pharmaceutical composition comprising such compounds and its application in medicine. Specifically, the present application provides a compound as shown in formula (I), or stereoisomer, geometric isomer, tautomer, metabolite or salt of the compound shown in formula (I), and pharmaceutical composition comprising such compounds and their application in medicine, Q-P-Z (I).

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of flurbiprofen derivatives, their preparation methods, pharmaceutical compositions, stereoisomers, geometric isomers, tautomers, metabolites, salts, and their use in the preparation of drugs for the treatment and / or prevention of acute and chronic pain and neuropathic pain. Background Technology

[0002] Pain is a complex physiological and psychological activity, described as "an unpleasant sensory and emotional experience associated with tissue damage or potential tissue damage," and is considered the fifth vital sign after heart rate, blood pressure, pulse, and respiration. Acute and chronic pain are among the most prevalent health problems today, complex diseases requiring treatment. It is reported that approximately one-fifth of the population in the United States and Europe suffers from this condition, while globally, chronic pain has a prevalence of 12% to 30%. If pain is not relieved, it can cause or worsen symptoms such as anxiety, depression, fatigue, insomnia, and loss of appetite. It can also lead to increased blood pressure, tachycardia, elevated blood sugar, and decreased immunity, severely impacting daily activities, self-care abilities, social interactions, and overall quality of life. Therefore, effectively addressing this condition is a thorny challenge facing countries worldwide.

[0003] Neuropathic pain is a common symptom in neurology. This type of pain refers to pain felt without external stimulation, also known as spontaneous pain. There are many types of spontaneous pain, which can be divided into peripheral neuropathic pain and central neuropathic pain according to the location of the lesion. Pain with an unknown cause is called primary neuropathic pain, while pain with a clear cause is called secondary (or symptomatic) neuropathic pain. The lesion can be located in the nerve root, nerve plexus, or nerve trunk. It is often named after the peripheral nerve involved in the lesion.

[0004] Drug therapy is the fundamental method for controlling pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a commonly used type of anti-inflammatory and analgesic medication in clinical practice. NSAIDs are a class of anti-inflammatory drugs that do not contain a steroidal structure. Since the first synthesis of aspirin, more than a hundred different types and thousands of brands have been marketed. These drugs have anti-inflammatory, antirheumatic, analgesic, antipyretic, and anticoagulant effects, and are widely used clinically to relieve symptoms of osteoarthritis, rheumatoid arthritis, various types of fever, and various types of pain.

[0005] Flurbiprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) in clinical practice. It is a potent phenylpropionate antipyretic, anti-inflammatory, and analgesic that inhibits cyclooxygenase, the enzyme that synthesizes prostaglandins, thereby exerting its analgesic, anti-inflammatory, and antipyretic effects. It boasts advantages such as high efficacy, low toxicity, good tolerability, and few side effects. Studies show that flurbiprofen is a non-selective COX inhibitor, inhibiting both COX-1 and COX-2, and can also inhibit excessive activation of microglia, reducing inflammatory responses in the nervous system. Flurbiprofen's anti-inflammatory and analgesic effects are 250 times and 50 times that of aspirin, respectively. It is rapidly absorbed orally and has lower toxicity, making it one of the most potent known propionate NSAIDs. However, flurbiprofen also has gastrointestinal adverse reactions such as indigestion, nausea, diarrhea, and abdominal pain.

[0006] This invention researches and develops a class of flurbiprofen derivatives with novel chemical structures. These derivatives can be rapidly converted into flurbiprofen in vivo and exhibit multi-target effects. The new compounds have the potential to overcome gastrointestinal adverse reactions such as indigestion, nausea, diarrhea, and abdominal pain associated with oral flurbiprofen. Furthermore, while exerting the anti-inflammatory and analgesic effects of flurbiprofen, these compounds can also be used to prevent / treat peripheral neuropathic pain, thus meeting urgent clinical needs and possessing promising market prospects. Summary of the Invention

[0007] The purpose of this invention is to provide a flurbiprofen derivative compound (I), its pharmaceutically acceptable salt, its tautomer or stereoisomer, which, compared with the existing drug flurbiprofen, has the potential to overcome the gastrointestinal adverse reactions of flurbiprofen, has multi-target action, and can be used in the preparation of medicaments for the treatment and / or prevention of acute and chronic pain and neuropathic pain.

[0008] On the one hand, the present invention provides the compounds represented by formula (I) or stereoisomers, geometric isomers, tautomers, metabolites, and pharmaceutically acceptable salts thereof:

[0009] QPZ(I);

[0010] in,

[0011] Q is Dashed lines indicate key connections;

[0012] P is

[0013] Among them, R 1 C 1-10 Alkyl, C 1-10 Alkyl groups may optionally be replaced by hydroxyl, amino, cyano, or C groups. 1-6 Alkyl substitution;

[0014] X1, X2 and X3 are each independently selected from O, S, NH and CH2;

[0015] m and n are each independently selected from 0, 1, and 2;

[0016] Z is selected from C 5-10 cycloalkyl,

[0017] Among them, C 5-10 The cycloalkyl group may optionally be surrounded by 1-3 amino, carboxyl, methylcarboxyl, methylamino, or C groups. 1-3 Alkyl substitution.

[0018] In some implementations, P is selected from the following structure: C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-O-(C=O)-, C 1-6 Alkoxy,

[0019] Preferably, P is selected from C. 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-O-(C=O)-;

[0020] Further preferred, P is selected from C 1-3 alkyl, C 1-3 Alkyl-O-(C=O)-;

[0021] Furthermore, preferably, P is selected from -CH2-,

[0022] In some implementation schemes, Z is selected from Preferably, Z is selected from

[0023] In some implementation schemes, Z is

[0024] in, It can be further oxidized by 1-3 amino groups, methylamino groups, triethylamine groups, carboxyl groups, methylcarboxyl groups, C 1-3 Alkyl groups are substituted;

[0025] Preferably, Z is selected from

[0026] In some embodiments, the flurbiprofen derivative is selected from any of the following structures:

[0027]

[0028]

[0029] On the other hand, the present invention provides a method for preparing a flurbiprofen derivative as described above, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a stereoisomer thereof;

[0030] On the other hand, the present invention provides a pharmaceutical composition comprising, as described above, a flurbiprofen derivative thereof, a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, and a carrier and / or excipients thereof.

[0031] In some embodiments, the composition further comprises a pharmaceutically acceptable surfactant and a carrier.

[0032] On the other hand, the present invention provides the use of the flurbiprofen derivatives, pharmaceutically acceptable salts thereof, tautomers thereof or stereoisomers thereof having multi-target effects, in the preparation of medicaments for the treatment and / or prevention of acute and chronic pain and neuropathic pain; the aforementioned acute and chronic pain and neuropathic pain include, but are not limited to, osteoarthritis, frozen shoulder, tendonitis and tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, myalgia, swelling caused by trauma, rheumatoid arthritis, ankylosing spondylitis, pain caused by sprains and strains, dysmenorrhea, postoperative pain, toothache, herpetic neuralgia and other diseases.

[0033] The compounds represented by formula (I) may exist in different stereoisomers, optical isomers, or tautomers. This invention includes all such isomers and tautomers, mixtures thereof in various proportions, and isotopic forms such as compounds containing deuterium.

[0034] The isotope-enriched compounds have the structures described by the general formulas given in this invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0035] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R,S)- configurations.

[0036] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. Other aspects will be described in more detail and in full below.

[0037] Definitions and general terms

[0038] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0039] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0040] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0041] Unless otherwise stated, the following definitions as used in this invention shall apply. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the *Handbook of Chemistry and Physics*, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0042] Unless otherwise stated or there is an obvious conflict in the context, the articles “a,” “an,” and “described” as used in this invention are intended to include “at least one” or “one or more.” Therefore, these articles as used in this invention refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or employed in the embodiments described.

[0043] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0044] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0045] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0046] A diastereomer is a stereoisomer that has two or more chiral neutral molecules that are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography, for example, by HPLC.

[0047] The stereochemical definitions and rules used in this invention generally follow the descriptions in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0048] Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the plane-polarized light rotation caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

[0049] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0050] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0051] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0052] Racemic derivatives of any resulting end product or intermediate can be separated into optical enantiomers using known methods familiar to those skilled in the art, such as by separating the obtained diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared via asymmetric synthesis.

[0053] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. Specifically, examples of "one or more" refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The substituents described therein can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, heterocyclic alkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkylacyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, heterocyclic acyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amide, sulfonyl, aminosulfonyl, etc.

[0054] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0055] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, this invention includes every independent secondary combination of the various members of these group types and scopes. For example, the terms "C1-C6 alkyl" or "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0056] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms; wherein the alkyl group is optionally substituted by one or more substituents described in this invention. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 8 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 6 carbon atoms; in still another embodiment, the alkyl group contains 1 to 4 carbon atoms; and in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

[0057] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and so on. Pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), etc.

[0058] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-10 carbon atoms; in another embodiment, the alkoxy group contains 1-8 carbon atoms; in one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0059] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, -CH2F, -CHF2, -CH2Cl, -CH2Br, -CF3, -CH2CF3, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CHF2, -CH2CH2CF3, -CH2CH2CH2F, -CH2CH2CH2Cl, -CH2CH2CH2Br, -CHFCH2CH3, -CHClCH2CH3, etc.

[0060] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3-10 carbon atoms; in another embodiment, it comprises 3-8 carbon atoms; and in yet another embodiment, it comprises 3-6 carbon atoms. The cycloalkyl group may optionally be substituted by one or more substituents described in this invention. Examples of such substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

[0061] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0062] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0063] The pharmaceutical compositions disclosed in this invention comprise therapeutically effective amounts of one or more flurbiprofen derivatives or pharmaceutically acceptable salts thereof, and may further contain one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of drug or agent that elicits a biological or pharmaceutical response in a tissue, system, or animal targeted by an investigator or physician; the "composition" refers to a product obtained by mixing one or more substances or components; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance, which carries or transports a chemical substance. Ideally, the pharmaceutical compositions provided by this invention contain flurbiprofen derivatives or pharmaceutically acceptable salts as active ingredients comprising 5% to 99.5% of the total weight, with the remainder comprising less than 95% of the total weight.

[0064] Detailed description of the compounds of the present invention

[0065] General Synthesis Process

[0066] The following describes the preparation of the compounds of the present invention. Unless otherwise specified, the compounds of the present invention can be prepared by the methods described herein. The raw materials, reagents, etc., used to prepare the compounds of the present invention are commercially available or can be prepared by conventional methods in the art. In this specification, if there are any differences between chemical names and chemical structures, the structure is preferred.

[0067] The testing conditions for the proton NMR spectrum of this invention are: room temperature, a Bruker 400MHz or 600MHz NMR spectrometer, with CD13, d 6 -DMSO, CD3OD or d 6 - Acetone is used as the solvent (reported in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0068] The following abbreviations are used throughout this invention:

[0069] g; mg; mol; mmol; h; min; L; mL; M mol / L; PE petroleum ether; EA ethyl acetate; DMF N,N-dimethylformamide; THF tetrahydrofuran.

[0070] The following synthesis schemes and examples are used to further illustrate the content of the present invention. Specific Implementation

[0071] Example A Intermediate 1: Synthesis of (S)-3-(((tert-Butoxycarbonyl)amino)methyl)-5-methylhexanoic acid

[0072]

[0073] Pregabalin (15.9 g, 0.1 mol) was dissolved in THF (120 mL). The reaction mixture was placed in an ice bath. Then, an aqueous solution of NaOH (16.0 g, 0.4 mol) (120 mL) was added to the reaction mixture. Next, Boc₂O (26.2 g, 0.12 mol) was slowly added dropwise. After the addition was complete, the reaction mixture was moved to room temperature and stirred overnight. The reaction was monitored by TLC. After the starting material disappeared, the organic solvent was evaporated, and an equal volume of water was added. The aqueous phase was extracted with ethyl acetate (60 mL × 2), and the pH was adjusted to 1 with 6N HCl. The aqueous phase was then extracted with V... DCM / V MeOH Extracted at a ratio of 20:1 (80 mL × 3), the organic phases were combined and dried by rotary evaporation to give intermediate 1, a white solid (20.2 g, yield: 78.0%). ESI-MS (m / z): 260.2 [M+H]+ .

[0074] Example B Intermediate 2: Synthesis of (S)-3-(((tert-Butoxycarbonyl)amino)methyl)-5-methylhexanoate benzyl ester

[0075]

[0076] Intermediate 1 (4.0 g, 15.4 mmol) was dissolved in DMF (25 mL), and K2CO3 (4.0 g, 23.1 mmol) and BnBr (3.3 g, 19.2 mmol) were added to the solution. The reaction mixture was then stirred at room temperature for 6 hours. After most of the starting material was consumed by TLC, the reaction mixture was poured into 150 mL of ice water and extracted three times with EA. The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA =25:1 to 10:1 to obtain intermediate 2, which is a pale yellow liquid (4.4g, yield: 81.6%).

[0077] ESI-MS (m / z): 350.2 [M+H] + .

[0078] 1 HNMR(400MHz, CDCl3), δ7.35(m,5H),5.11(s,2H),4.67(s,1H)3.22-2.95(m, 2H),2.33-2.09(m,3H),1.64(m,1H),1.42(s,9H),1.14(m,2H),0.85(m,6H).

[0079] Example C Intermediate 3: Synthesis of (S)-3-(aminomethyl)-5-methylhexanoate benzyl ester hydrochloride

[0080]

[0081] Intermediate 2 (4.4 g, 12.6 mmol) was dissolved in EA (25 mL). Dioxane hydrochloride (4 M, 25 mL) was then slowly added to the reaction solution. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After the starting material disappeared, the reaction solution was directly evaporated to dryness to obtain intermediate 3, which was a milky white solid (3.5 g, yield: 97.2%). ESI-MS (m / z): 250.1 [M+H] + Example D Intermediate 4: Synthesis of (S)-3-((((chloromethoxy)carbonyl)amino)methyl)-5-methylhexanoate benzyl ester

[0082]

[0083] Intermediate 3 (3.5 g, 12.2 mmol) was dissolved in THF (70 mL). The reaction mixture was placed in an ice bath. DIEA (3.9 g, 30.5 mmol) was slowly added to the reaction mixture, followed by methyl chloroformate (1.8 g, 14.0 mmol) added dropwise. The reaction mixture was stirred in an ice bath for half an hour, then moved to room temperature and stirred for another 2 hours. The reaction was monitored by TLC. After the starting material disappeared, the solid was filtered off, and the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA =20:1 to 8:1 to obtain intermediate 4, which is a pale yellow liquid (3.3g, yield: 78.8%).

[0084] ESI-MS (m / z): 342.2 [M+H] + .

[0085] 1 HNMR(400MHz, CDCl3), δ7.34(m,5H),5.74(s,2H),5.25(br,1H),5.14(m,2H),3.3 1(m,1H),3.14(m,1H),2.39-2.18(m,3H),1.66(m,1H),1.16(m,2H),0.90(m,6H).

[0086] Example E: Intermediate 8: Synthesis of methyl chloro2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0087]

[0088] Flurbiprofen (1.0 g, 4.1 mmol) was dissolved in DCM (10 mL). Then, an aqueous solution of TBAHSO4 (2.8 g, 8.2 mmol) (10 mL) was slowly added to the reaction mixture. The reaction mixture was then placed in an ice bath. Next, chloromethylsulfonyl chloride (1.0 g, 6.2 mmol) was slowly added dropwise to the reaction mixture. The reaction was then stirred overnight at room temperature. The reaction was monitored by TLC. After the starting material disappeared, the mixture was separated. The aqueous phase was extracted again with DCM (10 mL × 2), and the combined organic phases were evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA The ratio of intermediate 8 to intermediate 8 was increased from 30:1 to 15:1. Intermediate 8 was a colorless oil (1.1 g, yield: 88.6%). ESI-MS (m / z): 304.2 [M+H] + .

[0089] Example 1 Synthesis of compound (1): (3S)-3-(((((((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)oxy)methoxy)carbonyl)amino)methyl)-5-methylhexanoic acid

[0090]

[0091] Step 1: Synthesis of Intermediate 5: (3S)-3-((((((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)oxy)methoxy)carbonyl)amino)methyl)-5-methylhexanoate benzyl ester

[0092]

[0093] Intermediate 4 (3.3 g, 9.7 mmol) and flurbiprofen (2.4 g, 9.8 mmol) were dissolved in acetone (30 mL). NaI (1.7 g, 11.6 mmol) and KHCO3 (1.9 g, 19.4 mmol) were then added to the solution, and the reaction mixture was stirred overnight at 55 °C. TLC monitoring showed that most of the starting material was consumed. After filtering off the solid, the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA The ratio of intermediate 5 to intermediate 6 was increased from 12:1 to 5:1 to obtain intermediate 5, which was a colorless oil (4.8 g, yield: 90.5%). ESI-MS (m / z): 549.2 [M+H] + .

[0094] Step 2: Synthesis of compound (1)

[0095]

[0096] Intermediate 5 (4.8 g, 8.7 mmol) was dissolved in MeOH (40 mL) and THF (60 mL). Pd(OH)₂ / C (10% Pd, 50% water content, 1.0 g) was added to the solution. After replacing the H₂ with the reaction solution, the reaction was stirred at room temperature for 4 hours under H₂ atmosphere. TLC monitoring showed that most of the starting material was consumed. After filtering off Pd(OH)₂ / C, the solvent was removed by evaporation to obtain the crude product. The crude product was purified by short column chromatography with EA elution to obtain the target compound (1), which was a pale yellow oil (3.3 g, yield: 82.2%).

[0097] ESI-MS (m / z): 460.2 [M+H] + .

[0098] 1HNMR (400MHz, CDCl3), δ 7.53-7.34 (m, 6H), 7.12 (m, 2H), 5.74 (m, 2H), 5.32 (m, 1H), 3.80 (m, 1H), 3.32-3.08 (m, 2H), 2.35-2.05 (m, 3H), 1.64-1.52 (m, 4H), 1.15 (m, 2H), 0.88 (m, 6H). Example 2 Compound (2): Synthesis of ((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)oxy)methyl(3S)-3-((((((isobutyryloxy)methoxy)carbonyl)amino)methyl)-5-methylhexanoate

[0099]

[0100] Step 1: Synthesis of Intermediate 6: (S)-3-(((((isobutyryloxy)methoxy)carbonyl)amino)methyl)-5-methylhexanoate benzyl ester

[0101]

[0102] Intermediate 4 (0.50 g, 1.46 mmol) and isobutyric acid (0.14 g, 1.61 mmol) were dissolved in acetone (4 mL). NaI (0.26 g, 1.75 mmol) and KHCO3 (0.29 g, 2.92 mmol) were then added to the solution, and the reaction mixture was stirred overnight at 55 °C. TLC monitoring showed that most of the starting material was consumed. After filtering off the solid, the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA The ratio of 12:1 to 5:1 yielded intermediate 6, a pale yellow oil (0.35 g, yield: 60.8%). ESI-MS (m / z): 394.2 [M+H] + .

[0103] Step 2: Synthesis of Intermediate 7: (S)-3-(((((isobutyryloxy)methoxy)carbonyl)amino)methyl)-5-methylhexanoic acid

[0104]

[0105] Intermediate 6 (0.35 g, 0.89 mmol) was dissolved in MeOH (5 mL) and THF (5 mL). Pd(OH)₂ / C (70 mg) was then added to the solution. After replacing the H₂ concentration with the reaction mixture, the reaction was stirred at room temperature for 3 hours under an H₂ atmosphere. TLC monitoring showed that most of the starting material was consumed. After filtering off Pd(OH)₂ / C, the solvent was evaporated to obtain intermediate 7, a pale yellow oil (0.26 g, yield: 96.4%). ESI-MS (m / z): 304.1 [M+H] + .

[0106] Step 3: Synthesis of compound (2)

[0107]

[0108] Intermediate 8 (0.30 g, 1.02 mmol) and intermediate 7 (0.32 g, 1.07 mmol) were dissolved in acetone (5 mL). NaI (0.17 g, 1.12 mmol) and KHCO3 (0.20 g, 2.04 mmol) were then added to the solution, and the reaction mixture was stirred overnight at 55 °C. TLC monitoring showed that most of the starting material was consumed. After filtering off the solid, the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA = 12:1 to 5:1 to obtain compound (2), which is a colorless oil (0.29 g, yield: 50.6%).

[0109] ESI-MS (m / z): 560.2 [M+H] + .

[0110] 1 HNMR(400MHz, CDCl3), δ7.56-7.37(m,6H),7.15(m,2H),5.80-5.73(m,4H),5.03(m,1H),3.82(m,1H),3.2 8(m,1H),3.07(m,1H),2.61(m,1H),2.35-2.11(m,3H),1.65-1.57(m,4H),1.20-1.09(m,8H),0.88(m,6H).

[0111] Example 3: Synthesis of Compound (3): 3-((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)oxy)-2-hydroxypropyl(3S)-3-(aminomethyl)-5-methylhexanoate

[0112]

[0113]

[0114] Step 1: Synthesis of Intermediate 9: Ethylene oxide-2-ylmethyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0115]

[0116] Flurbiprofen (4.0 g, 16.4 mmol), HATU (7.5 g, 19.7 mmol), and DIEA (4.2 g, 32.8 mmol) were dissolved in THF (40 mL). The reaction mixture was stirred at room temperature for 30 minutes, then glycidyl ether (1.1 g, 24.6 mol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC. Afterward, the organic solvent was evaporated to dryness, and the mixture was reconstituted with EA. The solution was then washed with 1N HCl (30 mL) and 1N Na2CO3 (30 mL), and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography with a polarity of V. 正己烷 / V EA =25:1 to 10:1 to obtain intermediate 9, which is a pale yellow liquid (2.3g, yield: 46.8%).

[0117] ESI-MS (m / z): 301.1 [M+H] + .

[0118] 1 HNMR(400MHz, CDCl3), δ7.57-7.37(m,6H),7.18(m,2H),4.48(m,1H),4.01-3.81(m,2H),3.22(m,1H),2.84(m,1H),2.62(m,1H),1.58(m,3H).

[0119] Step 2: Synthesis of Intermediate 10: 3-((2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)oxy)-2-hydroxypropyl(3S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoate

[0120]

[0121] Intermediate 9 (2.3 g, 7.7 mmol) and intermediate 1 (2.1 g, 8.1 mmol) were dissolved in MeCN (20 mL), and TBAB (0.2 g, 0.7 mmol) was added to the solution. The reaction mixture was then refluxed for 36 hours. TLC monitoring showed that most of the starting material had been consumed. The organic solvent was then evaporated to dryness, reconstituted with EA, washed with 1N Na₂CO₃ (30 mL) saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / VEA The ratio of intermediate 10 to 4:1 was adjusted to obtain intermediate 10, which was a colorless oil (3.1 g, yield: 72.3%). ESI-MS (m / z): 582.2 [M+Na] + .

[0122] Step 3: Synthesis of compound (3)

[0123]

[0124] Intermediate 10 (0.50 g, 0.89 mmol) was dissolved in DCM (6 mL). The reaction was placed in an ice bath. Then, dioxane hydrochloride (4 M, 2.5 mL) was slowly added to the reaction solution. The reaction solution was stirred at 0 °C and monitored by TLC. After the starting material disappeared, the solution was immediately evaporated at low temperature to obtain compound (3). Compound (3) was a milky white gel (0.43 g, yield: 96.9%).

[0125] ESI-MS (m / z): 460.1 [M+H] + .

[0126] 1 HNMR(400MHz, CDCl3), δ8.06(br,3H),7.53-7.34(m,6H),7.13(m,2H),5.14(br,1H),4.31-3. 65(m,6H),3.08-2.97(m,2H),2.62-2.35(m,2H),1.61-1.52(m,4H),1.25(m,3H),0.90(m,6H).

[0127] Example 4: Synthesis of Compound (4): 1-(((((2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)oxy)ethyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0128]

[0129] Step 1: Synthesis of Intermediate 11: 1-Chloroethyl ((2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate

[0130]

[0131] (2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol (5.0 g, 32.5 mmol) was dissolved in DCM (60 mL). Pyridine (3.9 g, 49.0 mmol) was slowly added to the reaction mixture, which was then placed in an ice bath. 1-Chloroethylcarbonyl chloride (5.8 g, 40.6 mmol) was then slowly added dropwise to the reaction mixture. The reaction was then stirred overnight at room temperature. The reaction was monitored by TLC. After the starting material disappeared, the mixture was separated. The aqueous phase was extracted again with DCM (60 mL × 2). The organic phases were combined and washed once each with 1N HCl (40 mL) and 40 mL saturated brine. The mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography with a polarity V eluent. 正己烷 / V EA = 30:1 to 15:1 to obtain intermediate 11, which is a colorless oil (6.4 g, yield: 75.7%).

[0132] 1 HNMR (400MHz, CDCl3), δ5.69(q,J=7.2Hz,1H),3.79(m,1H),1.92(q,J=7.2Hz,3H),1.78-1.32(m,7H),1.02-0.97(m,9H).

[0133] Step 2: Synthesis of compound (4)

[0134]

[0135] Intermediate 11 (0.5 g, 1.9 mmol) and flurbiprofen (0.51 g, 2.1 mmol) were dissolved in acetonitrile (8 mL). NaI (0.33 g, 2.2 mmol) and K₂CO₃ (0.52 g, 3.8 mmol) were then added to the solution, and the reaction mixture was stirred overnight at 55 °C. TLC monitoring showed that most of the starting material was consumed. After filtering off the solid, the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA = 20:1 to 8:1 to obtain compound (4), which is a colorless oil (0.41 g, yield: 45.6%).

[0136] ESI-MS (m / z): 468.2 [M+H] + .

[0137] 1HNMR(400MHz, CDCl3), δ7.54-7.35(m,6H),7.13(m,2H),5.68(q,J=7.2Hz,1H),3.86(q,J =8.0Hz,1H),3.77(m,1H),1.93(q,J=7.2Hz,3H),1.77-1.31(m,10H),1.02-0.97(m,9H).

[0138] Example 5: Synthesis of Compound (5): (2-(diethylamino)ethoxy)methyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate

[0139]

[0140] Intermediate 8 (0.50 g, 1.71 mmol) and diethylaminoethanol (0.24 g, 2.06 mmol) were dissolved in MeCN (10 mL). KI (0.34 g, 2.06 mmol) and Et3N (0.35 g, 3.42 mmol) were then added to the solution, and the reaction mixture was stirred overnight at room temperature. TLC monitoring showed that most of the starting material had been consumed. The solid was then filtered off, and the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. DCM / V MeOH = 50:1 to 20:1 to obtain compound (5), which is a colorless oil (0.31 g, yield: 50.6%).

[0141] ESI-MS (m / z): 374.2 [M+H] + .

[0142] 1 HNMR (400MHz, CDCl3), δ7.55-7.35(m,6H),7.14(m,2H),5.72(m,2H),3.84(q,J=8. 0Hz,1H),3.60(m,2H),3.01(m,4H),2.51(m,2H),1.60(d,J=8Hz,3H),1.02(m,6H).

[0143] Example 6: Synthesis of compound (6): 1-(2-(diethylamino)ethoxy)ethyl 1-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid

[0144]

[0145] Step 1: Intermediate 12: Synthesis of 1-chloroethyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid

[0146]

[0147] Flurbiprofen (10.0 g, 41.0 mmol) was dissolved in DCM (100 mL). Then, an aqueous solution of TBAHSO4 (27.8 g, 82.0 mmol) (100 mL) was slowly added to the reaction mixture. The reaction mixture was then placed in an ice bath. Next, 1-chloroethylsulfonyl chloride (11.1 g, 62.0 mmol) was slowly added dropwise to the reaction mixture. The reaction was then stirred overnight at room temperature. The reaction was monitored by TLC. After the starting material disappeared, the mixture was separated. The aqueous phase was extracted again with DCM (60 mL), and the combined organic phases were evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. 正己烷 / V EA = 30:1 to 15:1 to obtain intermediate 12, which is a colorless oil (11.2 g, yield: 88.0%).

[0148] 1 HNMR (400MHz, CDCl3), δ7.57-7.37(m,6H),7.15(m,2H),5.69(q,J=7.2Hz,1H),3.84(q,J=8.0Hz,1H),1.91(d,J=7.2Hz,3H),1.59(d,J=8Hz,3H).

[0149] Step 2: Synthesis of compound (6)

[0150]

[0151] Intermediate 12 (0.50 g, 1.61 mmol) and diethylaminoethanol (0.24 g, 1.93 mmol) were dissolved in MeCN (10 mL). KI (0.29 g, 1.77 mmol) and Et3N (0.33 g, 3.22 mmol) were then added to the solution, and the reaction mixture was stirred overnight at room temperature. TLC monitoring showed that most of the starting material had been consumed. The solid was then filtered off, and the solvent was removed by evaporation to obtain the crude product. The crude product was purified by column chromatography using a polar V eluent. DCM / V MeOH =50:1 to 20:1 to obtain compound (6), which is a colorless oil (0.28 g, yield: 44.7%).

[0152] ESI-MS (m / z): 388.2 [M+H] + .

[0153] 1HNMR(400MHz, CDCl3), δ7.55-7.35(m,6H),7.14(m,2H),5.69(q,J=7.2Hz,1H),3.84(q,J=8.0Hz,1H ),3.59(m,2H),3.02(m,4H),2.51(m,2H),1.91(d,J=7.2Hz,3H),1.60(d,J=8.0Hz,3H),1.03(m,6H).

[0154] Pharmacokinetics and bioavailability of flurbiprofen derivatives in rats according to this invention

[0155] Experimental methods:

[0156] Thirty male SD rats (200-300g) were randomly divided into three groups (n=10): control group 1 (flurbiprofen), experimental groups (compound (1) and compound (3)). Control group 1 (5mg / kg), compound (1) (9.41mg / kg), and compound (3) (10.15mg / kg) were injected, respectively, with each group receiving an equimolar dose of flurbiprofen at a volume of 10mL / kg. Blood samples were collected before administration and at 15min, 30min, 1h, 2h, 4h, 8h, 12h, and 24h after administration. Plasma was collected by centrifugation, and the concentration of flurbiprofen in the plasma was measured. The experimental results are shown in Table 1.

[0157] Table 1: Pharmacokinetic parameters of flurbiprofen in plasma of rats after oral administration (Mean ± SD) in the experimental and control groups.

[0158]

[0159] Experimental conclusions: The experimental results show that, compared with the control group 1, the plasma AUC (h*ng / mL, 188432.7, 207141.6 and 117806.3, respectively) of compounds (1) and (3) increased the plasma AUC of flurbiprofen by 60% and 76%, respectively. The bioavailability of flurbiprofen in plasma was also improved in both compounds (1) and (3). Compounds (1) and (3) can exert better anti-inflammatory and analgesic effects through flurbiprofen. This study investigates the analgesic effect of flurbiprofen derivatives in a carrageenan-induced SD rat inflammatory pain model.

[0160] Experimental methods:

[0161] Male SD rats that passed quarantine were subjected to the Von Frey test (i.e., claw retraction pressure value). Based on the claw retraction pressure value and the animal's body weight, 10 animals were selected as the normal group, and the remaining animals were used to establish the model. The animals were anesthetized with isoflurane, and 100 μL of 1% carrageenan solution was injected subcutaneously into the palm of the left hind paw. After 0.5 h of modeling, the animals were screened and grouped. The Von Frey test was performed, and 40 animals with a significant decrease in claw retraction pressure value were selected and randomly divided into 4 groups: model group, control group 1 (flurbiprofen, 5 mg / kg), low-dose group of compound (1) (compound (1), 4.7 mg / kg), and high-dose group of compound (1) (compound (1), 9.4 mg / kg), with 10 animals in each group. The high-dose group of compound (1) and control group 1 were administered at equimolar mass.

[0162] Immediately after model establishment and grouping, each group was administered a single dose of compound (1). The normal group (group 1) and model group (group 2) received negative controls, control group 1 (group 3) received flurbiprofen, and the compound (1) groups (groups 4 and 5) received different doses of compound (1). All groups received a single tail vein administration. Von Frey tests were performed once after model establishment and at 0.5 h and 2 h after drug administration. The experimental results are shown in Table 2.

[0163] Table 2: Statistical data on paw retraction pressure values ​​in a carrageenan-induced inflammatory pain model in SD rats induced by a single intravenous injection of flurbiprofen derivatives (Mean±SD, n=10)

[0164] Group Before administration 0.5 h after administration 2 hours after administration normal group 29.6±8.5 31.6±5.8 32.9±5.8 Model group <![CDATA[11.7±2.4 ### ]]> <![CDATA[11.9±1.8 ### ]]> <![CDATA[11.5±2.9 ### ]]> Control group 1 <![CDATA[11.6±2.3 ### ]]> <![CDATA[16.4±3.8 * ]]> <![CDATA[21.6±4.8 *** ]]> Compound (1) low-dose group <![CDATA[11.6±3.0 ### ]]> <![CDATA[17.8±4.9 * ]]> <![CDATA[18.4±5.0 ** ]]> High-dose group of compound (1) <![CDATA[11.4±2.7 ### ]]> <![CDATA[23.1±5.6 *** ]]> <![CDATA[23.0±6.1 *** ]]>

[0165] Note: Compared with the normal group, " ### "" indicates P ≤ 0.001; compared with the model group, " * " ** " *** "" represents P≤0.05, P≤0.01, and P≤0.001, respectively.

[0166] Experimental conclusion: When compound (1) was administered in equimolar amounts to the high-dose group and the control group 1, the results showed that the high-dose group of compound (1) exhibited a certain superior analgesic effect compared to the control group 1 (flurbiprofen). This indicates that the flurbiprofen derivative of the present invention can exert better anti-inflammatory and analgesic effects.

[0167] Transdermal absorption study of flurbiprofen derivatives of this invention

[0168] Experimental methods:

[0169] The flurbiprofen derivative compounds of this invention are all prepared as 5% gel formulations. Approximately 0.1g of the compound gel is weighed and evenly applied to the treated rat skin (effective penetration area 3.14cm²). 2The skin was then placed on the stratum corneum of the skin, and the skin was fixed between the supply pool and the receiving pool, with the stratum corneum layer covered with the gel patch facing towards the supply pool. 7.5 mL of receiving solution was added to the receiving pool, and a magnetic stir bar was placed in the groove at the bottom of the receiving pool. The stirring speed was 200 rpm, and the temperature was 37 ± 0.2℃. Samples were taken at 1, 2, and 4 hours, with 2 mL of receiving solution aspirated each time. An equal volume of receiving solution at the same temperature was then added immediately. The experiment was terminated after 4 hours. The experimental results are shown in Table 3.

[0170] Table 3. Cumulative transdermal penetration of compounds.

[0171]

[0172]

[0173] Experimental conclusions: The experimental results show that when the receiving solution is 8 mL DMSO + 4 mL PEG400 + 28 mL physiological saline, the cumulative transdermal transdermal transfusion rate of compound (1) is higher than that of the control group (flurbiprofen). This indicates that the flurbiprofen derivative of the present invention can more easily penetrate the skin surface than flurbiprofen, thereby exerting a corresponding effect at the painful site.

[0174] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A flurbiprofen derivative and a pharmaceutically acceptable salt thereof, characterized in that, It has one of the following structures:

2. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the flurbiprofen derivative as claimed in claim 1, and its pharmaceutically acceptable salts and pharmaceutically acceptable carriers and / or excipients.

3. Use of the flurbiprofen derivative of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for the treatment and / or prevention of acute and chronic pain and neuropathic pain.

4. Use of the flurbiprofen derivative of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for the treatment or prevention of the following diseases: muscle pain, swelling due to trauma, pain caused by sprains and strains, dysmenorrhea, postoperative pain, toothache, and herpetic neuralgia.

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